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1
Radioactivity, Radionuclides, and
Radiopharmaceuticals
CHAPTER OUTLINE
Basic Isotope Notation
Nuclear Stability and Decay
Radionuclide Production
Radioactive Decay
Radionuclide Generator Systems
Radionuclides and Radiopharmaceuticals for Imaging
Single Photon
Positron Emitters
Biologic Agents and Nanoparticles
Adverse Reactions
BASIC ISOTOPE NOTATION
The atom may be thought of as a collection of protons,
neutrons, and electrons. The protons and neutrons are
found in the nucleus, and shells of electrons orbit the
nucleus with discrete energy levels. The number of neutrons
is usually designated by N. The number of protons is rep-
resented by Z (also called the atomic number). The atomic
mass number, or the total number of nuclear particles, is
represented by A and is simply the sum of N and Z. The
symbolism used to designate atoms of a certain element
having the chemical symbol X is given by ZA X N . For example,
the notation 131
53 I78 refers to a certain isotope of iodine. In
this instance, 131 refers to the total number of protons and
neutrons in the nucleus. By definition, all isotopes of a given
element have the same number of protons and differ only
in the number of neutrons. For example, all isotopes of
iodine have 53 protons.
Nuclear Stability and Decay
A given element may have many isotopes, and some of these
isotopes have unstable nuclear configurations of protons
and neutrons. These isotopes often seek greater stability by
decay or disintegration of the nucleus to a more stable form.
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Investigational Radiopharmaceuticals
Radiopharmacy Quality Control
Generator and Radionuclide Purity
Radiochemical Labeling
Unsealed Radionuclides Used for Therapy
Phosphorus-32, Yttrium-90, and Gold-198
Iodine-131
Strontium-89, Samarium-153, Rhenium-186, and
Radium-223
Of the known stable nuclides, most have even numbers of
neutrons and protons. Nuclides with odd numbers of neu-
trons and protons are usually unstable. Nuclear instability
may result from either neutron or proton excess. Nuclear
decay may involve a simple release of energy from the nucleus
or may actually cause a change in the number of protons or
neutrons within the nucleus. When decay involves a change
in the number of protons, there is a change of element. This
is termed a transmutation. Isotopes attempting to reach stabil-
ity by emitting radiation are radionuclides.
Several mechanisms of decay achieve stability. One of
these is alpha-particle emission. In this case, an alpha (α)
particle, consisting of two protons and two neutrons, is
released from the nucleus, with a resulting decrease in the
atomic mass number (A) by four and reduction of both Z
and N by two. The mass of the released alpha particles is so
great that they travel only a few centimeters in air and are
unable to penetrate even thin paper. These properties cause
alpha-particle emitters to be essentially useless for imaging
purposes.
Beta-particle emission is another process for achieving
stability and is found primarily in nuclides with a neutron
excess. In this case, a beta (β−) particle (electron) is emitted
from the nucleus accompanied by an antineutrino; as a
result, one of the neutrons may be thought of as being
2 C HA P T E R 1 Radioactivity, Radionuclides, and Radiopharmaceuticals

A A
Z
X Z
X

A A
Z+1
Y Z-1
Y
Beta particle emission Electron capture
(Z increases by 1, N decreases by 1) (Z decreases by 1, N increases by 1)

A A
Z
X Z
X

A A
Z-1
Y Z
X
Positron emission Isomeric transition
(Z decreases by 1, N increases by 1) (no change in N or Z)

• Fig. 1.1 Decay schemes of radionuclides from unstable states (top line of each diagram) to more stable
states (bottom line).

transformed into a proton, which remains in the nucleus.
Thus, beta-particle emission decreases the number of neu-
trons (N) by one and increases the number of protons (Z)
by one, so that A remains unchanged (Fig. 1.1). When Z is
increased, the arrow in the decay scheme shown in Fig. 1.1
points toward the right, and the downward direction indi-
cates a more stable state. The energy spectrum of beta-
particle emission ranges from a certain maximum down to
zero; the mean energy of the spectrum is about one-third
of the maximum. A 2-MeV beta particle has a range of
about 1 cm in soft tissue and is therefore not useful for
imaging purposes.
Electron capture occurs in a neutron-deficient nuclide
when one of the inner orbital electrons is captured by a
proton in the nucleus, forming a neutron and a neutrino.
This can occur when not enough energy is available for
positron emission, and electron capture is therefore an alter-
native to positron decay. Because a nuclear proton is essen-
tially changed to a neutron, N increases by one, and Z
decreases by one; therefore, A remains unchanged (see Fig.
1.1). Electron capture may be accompanied by gamma
emission and is always accompanied by characteristic radia-
tion, either of which may be used in imaging.
If, in any of these attempts at stabilization, the nucleus
still has excess energy, it may be emitted as nonparticulate
radiation, with Z and N remaining the same. Any process
in which energy is given off as gamma rays and in which
the numbers of protons and neutrons are not changed is
called isomeric transition (see Fig. 1.1). An alternative to
isomeric transition is internal conversion. In internal conver-
sion, the excess energy of the nucleus is transmitted to one
of the orbital electrons; this electron may be ejected from
the atom, which is followed by characteristic radiation when
the electron is replaced. This process usually competes with
gamma-ray emission and can occur only if the amount of
energy given to the orbital electron exceeds the binding
energy of that electron in its orbit.
The ratio of internal conversion electrons to gamma-ray
emissions for a particular radioisotope is designated by the
symbol α. (This should not be confused with the symbol
for an alpha particle.) For an isotope such as technetium-
99m (99mTc), α is low, indicating that most emissions occur
as gamma rays with little internal conversion. A low conver-
sion ratio is preferable for in vivo usage because it implies
a greater number of gamma emissions for imaging and a
reduced number of conversion electrons, which are absorbed
by the body and thus add to the patient’s radiation dose.
In many instances, a gamma-ray photon is emitted almost
instantaneously after particulate decay. If there is a measur-
able delay in the emission of the gamma-ray photon and
the resulting decay process is an isomeric transition, this
intermediate excited state of the isotope is referred to as

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 CHAPTER 1 Radioactivity, Radionuclides, and Radiopharmaceuticals 3

99m
142.7 keV Tc (6.03 h)

Gamma 1

140.5 keV

Gamma 2 Gamma 3

99
0 keV Tc (2.1 x 109 yr)
98.6% 1.4%

• Fig. 1.2 Decay scheme of technetium-99m.

metastable. The most well-known metastable isotope is 99mTc

(the m refers to metastable). This isotope decays by isomeric
transition to a more stable state, as indicated in Fig. 1.2. In
the decay scheme, the arrows point straight down, showing 511 keV photons
that there is no change in Z. Also, 99mTc may decay by one
of several routes of gamma-ray emission.
In cases in which there are too many protons in the
nucleus (a neutron-deficient nuclide), decay may proceed
in such a manner that a proton may be thought of as being
converted into a neutron. This results in positron (β+) emis- β
sion, which is always accompanied by a neutrino. This obvi-
180 degrees / 0.25 degrees
ously increases N by one and decreases Z by one, again β
leaving A unchanged (see Fig. 1.1). The downward arrow
in the decay scheme again indicates a more stable state, and
its leftward direction indicates that Z is decreased. Positron
emission cannot occur unless at least 1.02 MeV of energy
is available to the nucleus.
When a positron is emitted, it travels for a short distance
from its site of origin, gradually losing energy to the tissue
through which it moves. When most of its kinetic energy
has been lost, the positron reacts with a resident electron in
an annihilation reaction. This reaction generates two • Fig. 1.3 Positron Decay. After the positron (β+) is emitted from the
511-keV gamma photons, which are emitted in opposite radionuclide, it travels some distance before interacting with an elec-
directions at about (but not exactly) 180 degrees from each tron (β−) and undergoing annihilation, resulting in emission of two
511-keV photons at 180 degrees from each other.
other (Fig. 1.3).

RADIONUCLIDE PRODUCTION
bombarding particle are listed on the left side of the equa-
Most radioactive material that does not occur naturally can tion and the product and any accompanying particulate or
be produced by particulate bombardment or nuclear fission. gamma emissions are indicated on the right. For example,
Both methods alter the neutron-to-proton ratio in the
nucleus to produce an unstable isotope. Bombardment A
Z X + n (neutron ) → A +1
Z X + γ or more specifically
essentially consists of the irradiation of the nuclei of selected
42 Mo + γ
Mo + n (neutron ) → 99
98
target elements with neutrons in a nuclear reactor or with 42
charged particles (alpha particles, protons, or deuterons)
from a cyclotron. Bombardment reactions may be summa- These equations may be further abbreviated using paren-
rized by equations in which the target element and thetical notation. The molybdenum reaction presented

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4 C HA P T E R 1 Radioactivity, Radionuclides, and Radiopharmaceuticals
previously is thus represented as 98Mo (n, γ) 99Mo. The
target and product are noted on the outside of the paren-
theses, which contain the bombarding particle on the left
and any subsequent emissions on the right.
Once bombardment is completed, the daughter isotope
must be physically separated from any remaining and
unchanged target nuclei, as well as from any target contami-
nants. Thus, it is obvious that the completeness of this final
separation process and the initial elemental purity of the
target are vital factors in obtaining a product of high specific
activity. Because cyclotron isotope production almost always
involves a transmutation (change of Z) from one element
to another, this process aids greatly in the separation of the
radionuclides to obtain carrier-free isotopes (i.e., isotopes
that have none of the stable element accompanying them).
Radionuclides made by neutron bombardment, which does
not result in a change of elemental species (e.g., 98Mo [n, γ]
99
Mo), are not carrier free because the chemical properties
of the products are identical, and thus radionuclides are not
as easily separated.
Fission isotopes are simply the daughter products of
nuclear fission of uranium-235 (235U) or plutonium-239
(239Pu) in a reactor and represent a multitude of radioactive
materials, with atomic numbers in the range of roughly half
that of 235U. These include iodine-131 (131I), xenon-133
(133Xe), strontium-90 (90Sr), molybdenum-99 (99Mo), and
cesium-137 (137Cs), among others. Because many of these
isotopes are present together in the fission products, the
desired isotope must be carefully isolated to exclude as many
contaminants as possible. Although this is sometimes diffi-
cult, many carrier-free isotopes are produced in this manner.
Neutron bombardment and nuclear fission almost always
produce isotopes with neutron excess, which decay by beta
emission. Some isotopes, such as 99Mo, may be produced
by either method. Cyclotron-produced isotopes are usually
neutron deficient and decay by electron capture or positron
emission. Some common examples of cyclotron-produced
isotopes include iodine-123 (123I), fluorine-18 (18F),
gallium-67 (67Ga), indium-111 (111In), and thallium-201
(201Tl). In general, cyclotron-generated radionuclides are
more expensive than are those produced by neutron bom-
bardment or fission.
Positron-emitting radionuclides are most commonly
produced in cyclotrons by charged-particle bombardment
of a stable element with protons, deuterons, or helium
nuclei. The produced radionuclides have an excess of
protons and decay by the emission of positrons.
RADIOACTIVE DECAY
The amount of radioactivity present (the number of disin-
tegrations per second) is referred to as activity. In the past,
the unit of radioactivity has been the curie (Ci), which is
3.7 × 1010 disintegrations per second. Because the curie is
an inconvenient unit, it has been largely replaced by an
international unit called a becquerel (Bq), which is 1 disin-
tegration per second. Conversion tables are found in
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Appendixes B.1 and B.2. Specific activity refers to the activ-
ity per unit mass of material (mCi/g or Bq/g). For a carrier-
free isotope, the longer the half-life of the isotope, the lower
is its specific activity.
Radionuclides decay in an exponential fashion, and the
term half-life is often used casually to characterize decay.
Half-life usually refers to the physical half-life, which is the
amount of time necessary for a radionuclide to be reduced
to half of its existing activity. The physical half-life (Tp) is
equal to 0.693/λ, where λ is the decay constant. Thus, λ
and the physical half-life have characteristic values for each
radioactive nuclide. Decay tables for various radionuclides
are presented in Appendix C.
A formula that the nuclear medicine physician should be
familiar with is the following:
A = A 0e −0.693 Tp( t )
This formula can be used to find the activity (A) of a
particular radioisotope present at a given time (t) and having
started with activity (A0) at time 0. For instance, if you had
5 mCi (185 MBq) of 99mTc at 9:00 a.m. today, how much
would remain at 9:00 a.m. tomorrow? In this case, Tp of
99m
Tc is 6 hours, t is 24 hours, and e is a mathematical
constant. Thus,
−0.693
(t )
A = A0e Tp
−0.693
( 24 hours )
A = A0e 6 hours
−0.693
( 24 hours )
A = 5 mCi e 6 hours
A = 5 mCi e −0.1155 ( 24 hours )
A = 5 mCi e −2.772
1
A = 5 mCi e 2.772
1 
A = 5 mCi 
 15.99 
A = 0.31 mCi
Thus, after 24 hours, the amount of 99mTc remaining is
0.31 mCi (11 MBq).
In addition to the physical half-life or physical decay of
a radionuclide, two other half-life terms are commonly
used. Biologic half-life refers to the time it takes an organism
to eliminate half of an administered compound or chemical
on a strictly biologic basis. Thus, if a stable chemical com-
pound were given to a person, and half of it were eliminated
by the body (perhaps in the urine) within 3 hours, the
biologic half-life would be 3 hours. The effective half-life
incorporates both the physical and biologic half-lives.
Therefore, when speaking of the effective half-life of a par-
ticular radiopharmaceutical in humans, one needs to know
 CHAPTER 1
the physical half-life of the radioisotope used as a tag or
label, as well as the biologic half-life of the tagged com-
pound. If these are known, the following formula can be
used to calculate the effective half-life:
Te = (T p × Tb ) (T p + Tb )
where
Te = effective half-life
T p = physical half-life
Tb = biologic halff-life
If the biologic half-life is 3 hours and the physical half-
life is 6 hours, then the effective half-life is 2 hours. Note
that the effective half-life is always shorter than either the
physical or biologic half-life.
RADIONUCLIDE GENERATOR SYSTEMS
A number of radionuclides of interest in nuclear medicine
are short-lived isotopes that emit only gamma rays and
decay by isomeric transition. Because it is often impractical
for an imaging laboratory to be located near a reactor or a
cyclotron, generator systems that permit on-site availability
of these isotopes have achieved wide use. Some isotopes
available from generators include technetium-99m, indium-
113m (113mIn), krypton-81m (81mKr), rubidium-82 (82Rb),
strontium-87m (87mSr), and gallium-68 (68Ga).
Inside the most common generator (99Mo-99mTc), a
radionuclide “parent” with a relatively long half-life is firmly
affixed to an ion exchange column. A 99Mo-99mTc generator
consists of an alumina column on which 99Mo is bound.
The parent isotope (67-hour half-life) decays to its radioac-
tive daughter, 99mTc, which is a different element with a
shorter half-life (6 hours). Because the daughter is only
loosely bound on the column, it may be removed, or washed
off, with an elution liquid such as normal (0.9%) saline.
Wet and dry 99Mo-99mTc generator systems are available and
differ only slightly. A wet system (most common in com-
mercial radiopharmacies) has a saline reservoir and a vacuum
vial that draws saline across the column. With a dry system
(most common in imaging clinics), a specific amount of
saline in a vial is placed on the generator entry port and
drawn across by a vacuum vial (Fig. 1.4).
After the daughter is separated from the column, the
buildup process is begun again by the residual parent
isotope. Uncommonly, some of the parent isotope (99Mo)
or alumina is removed from the column during elution and
appears in the eluate containing the daughter isotope. This
is termed breakthrough.
To make efficient use of a generator, elution times should
be spaced appropriately to allow for reaccumulation of the
daughter isotope on the column. The short-lived daughter
reaches maximum activity when the rate of decay of the
daughter equals its rate of production. At this equilibrium
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Radioactivity, Radionuclides, and Radiopharmaceuticals 5
Saline vial Vacuum vial
Lead
Mo-99
alumina
column
Lead shield
• Fig. 1.4 Generator. Schematic of dry molybdenum-99/technetium-
99m generator system.
point, for instance, the amount of daughter is slightly
greater than the activity of the parent (Fig. 1.5). When the
parent isotope has a half-life somewhat greater than that of
the daughter, the equilibrium attained is said to be a tran-
sient equilibrium. In the case of a 99Mo-99mTc generator,
because 12% of 99Mo decays directly to 99Tc without pro-
ducing 99mTc, the activity of 99mTc in the generator only
reaches 97% of the 99Mo activity.
Most generators used in hospitals have 99Mo activity
levels of about 1 to 19 Ci (3.7 to 70.3 GBq). The amount
of 99mTc in the generator reaches about half the theoretical
maximum in one half-life (6 hours). It reaches about three-
fourths of the theoretical maximum in about two half-lives,
and so on (see Appendix C.1). This indicates that if one
elutes all of the 99mTc daughter from a 99Mo generator, 24
hours later (four half-lives), the amount of 99mTc present in
the generator will have returned to about 95% of the theo-
retical maximum.
Other, much less common photon-emitting radionu-
clide generator systems include rubidium-81 (81Rb) (4.5
hours)/81mKr (13 seconds), tin-13 (113Sn) (115 days)/113mIn
(1.7 hours), yttrium-87 (87Y) (3.3 days)/87mSr (2.8 hours),
and tellurium-132 (132Te) (3.2 days)/132I (2.3 hours).
Although generator systems are most often used to produce
photon-emitting radionuclides, certain generators can
produce positron emitters. These include strontium-82
(82Sr) (25 days)/82Rb (1.3 minutes). 82Rb is a potassium
analog and can be used for myocardial perfusion imaging
using positron emission tomography (PET). Gallium-68
(68 minutes) is another positron emitter that can be pro-
duced from a germanium-68 (68Ge) (271 days) generator.
6 C HA P T E R 1 Radioactivity, Radionuclides, and Radiopharmaceuticals

100
99mTc

separation 99mTc

transient
75 equilibrium

Activity %
50 99mTc

growth

99Mo decay
25

0
6 24 48 72
Hours
• Fig. 1.5 Radionuclide Buildup and Decay in a Generator. General schematic representation of
molybdenum-99 (99Mo) decay and technetium-99m (99mTc) buildup in a generator eluted at 0 hours
and again at 24 hours. See text regarding the reason that in reality the 99mTc activity never actually
exceeds 99Mo.

in Appendix E. Issues related to pediatric dose and preg-

RADIONUCLIDES AND RADIOPHARMA-
CEUTICALS FOR IMAGING
In evaluating the choice of a radionuclide to be used in the
nuclear medicine laboratory, the following characteristics
are desirable:
• Minimum of particulate emission
• Primary photon energy between 50 and 500 keV
• Physical half-life greater than the time required to prepare
material for injection
• Effective half-life longer than the examination time
• Suitable chemical form and reactivity
• Low toxicity
• Stability or near-stability of the product
The radionuclides most commonly used are shown in
Tables 1.1 and 1.2. A radionuclide that has desirable
imaging properties can usually be used to make a variety of
radiopharmaceuticals. This is done by coupling the radio-
nuclide with various stable compounds that are localized by
organs or disease states. Many radionuclides are radiophar-
maceuticals in their own right and can be administered
without alteration to obtain useful images. Commonly used
imaging radiopharmaceuticals are shown in Table 1.3. The
biologic behavior of most of these radionuclides can be
markedly altered by a combination with additional sub-
stances to form other radiopharmaceuticals.
Mechanisms of localization for some of these radio-
pharmaceuticals are listed in Table 1.4. The various
radiopharmaceuticals used in imaging procedures are addi-
tionally discussed in the appropriate chapters. Dosimetry
and protocols for the various radionuclides are presented
nancy and breastfeeding are in Appendixes D and G.
Although the localizing properties of radiopharmaceuti-
cals are generally sufficient to obtain adequate diagnostic
images, the localizing mechanisms may be altered by various
conditions in an individual patient, including the adminis-
tration of other medications.
Single Photon
Technetium-99m
Technetium-99m fulfills many of the criteria of an ideal
radionuclide and is used in more than 80% of nuclear
imaging procedures in the United States. It has no partic-
ulate emission, a 6-hour half-life, and a predominant
(98%) 140-keV photon. The decay mode is 88% isomeric
transition and only a small amount (12%) of internal
conversion.
Technetium-99m is obtained by separating it from the
parent 99Mo (67-hour half-life) in a generator system.
Molybdenum-99 for generators is generally produced by
neutron irradiation of 98Mo or by chemical separation of
235
U fission products. In the latter case, 99Mo is nearly
carrier free and has a high specific activity. In the alumina
generator system, the molybdenum activity is absorbed on
an alumina column. By passing physiologic saline over the
column, 99mTc is eluted or washed off as sodium pertechne-
tate (Na 99mTcO4–).
Technetium can exist in a variety of valence states,
ranging from −1 to +7. When eluted from an alumina
column generator, 99mTc is present primarily as heptavalent

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 CHAPTER 1 Radioactivity, Radionuclides, and Radiopharmaceuticals 7

TABLE
1.1 Characteristics of Commonly Used Radionuclides

Symbol Physical Half-Life Approximate Energy

Photon-Emitting Radionuclides for Gamma (keV)
Imaging
99m
Technetium-99m Tc 6h 140
99
Molybdenum-99 Mo 67 h 181, 740, 780
123
Iodine-123 I 13.2 h 159
131
Iodine-131 I 8.0 days 364
133
Xenon-133 Xe 5.3 days 81
67
Gallium-67 Ga 78.3 h 93, 184, 296, 388
111
Indium-111 In 67 h 173, 247
113m
Indium-113m In 1.7 h 392
201
Thallium-201 Tl 73.1 h 69, 81 (x-rays from mercury daughter)
81m
Krypton-81m Kr 13 s 191
Positron-Emitting Radionuclides Positron (MeV) (Image 511-keV
for Imaging Photons)
11
Carbon-11 C 20.3 min 0.960
13
Nitrogen-13 N 10 min 1.198
15
Oxygen-15 O 124 s 1.730
18
Fluorine-18 F 110 min 0.634
68
Gallium-68 Ga 68 min 1.9
82
Rubidium-82 Rb 1.27 min 3.150
Unsealed Radionuclides Used for Emissions
Therapy
89
Strontium-89 Sr 50.5 days 1.46 MeV max; 0.58 MeV mean beta;
910 keV gamma (0.01%)
90
Yttrium-90 Y 64 h 2.2 MeV max; 0.93 MeV mean beta
131
Iodine-131 I 8.0 days 0.19 MeV mean beta; 364 keV gamma
(82%)
153
Samarium-153 Sm 46 h 0.81 MeV max; 0.23 MeV mean beta;
103 keV gamma (28%)
186
Rhenium-186 Re 90 h 0.34 MeV mean beta; 186 keV gamma (9%)
223
Radium-223 Ra 11.4 days 5–7.5 MeV alpha (94%);
beta 1 MeV (< 4%);
gamma (< 2%)

Note: The approximate range (cm) of a beta particle in tissue is the energy (MeV) divided by 2.

(+7) pertechnetate (TcO4–). In the preparation of radio-
pharmaceuticals, 99mTc pertechnetate can be reduced from
+7 to a lower valence state, usually +4, to permit the label-
ing of various chelates. This is generally accomplished with
stannous (tin) ions.
As pertechnetate, the technetium ion is a singly charged
anion and is similar in size to the iodide ion. After intrave-
nous injection, 99mTc pertechnetate is loosely bound to
protein and rapidly leaves the plasma compartment. More
than half leaves the plasma within several minutes and is
distributed in the extracellular fluid. It rapidly concentrates
in the salivary glands, choroid plexus, thyroid gland, gastric
mucosa, and functioning breast tissue; during pregnancy, it
crosses the placenta.
Excretion is by the gastrointestinal and renal routes.
Although 99mTc pertechnetate is excreted by glomerular fil-
tration, it is partially reabsorbed by the renal tubules; as a
result, only 30% is eliminated in the urine during the first

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8 C HA P T E R 1 Radioactivity, Radionuclides, and Radiopharmaceuticals

TABLE
1.2 Characteristics of Common Positron Emission Tomography (PET) Radionuclides

Maximal and Maximum and

Nuclide (Decay Physical Average Positron Mean Range in
Product) Half-Life Decay Mode Energy (keV) Water (mm) Production Reaction
14
Carbon-11 20.3 min 99.8% positron 960, 385 4.1, 1.1 N(p,alpha)11C*
(Boron-11) 0.2% electron
capture
16
Nitrogen-13 10 min 100% positron 1198, 491 5.1, 1.4 O(p,alpha)13N; 13
C(p,n)13N
(Carbon-13)
15
Oxygen-15 124 s 99.9% positron 1730, 735 7.3, 1.5 N(p,n)15O; 14
N(d,n)15O
(Nitrogen-15)
18
Fluorine-18 110 min 97% positron 634, 250 2.4, 1.0 O(p,n)18F; 20Ne(d,alpha)18F;
16
(Oxygen-18) 3% electron capture O(3He,alpha)18F
68
Gallium-68 68 min 100% positron 1899 8.9, 2.9 Ge generator (T 12 271 days)
(Zinc-68)
82
Rubidium-82 75 s 96% positron 3150, 1385 14.1, 5.9 Sr generator (T 12 25.3 days)
(Krypton-82) 4% electron capture

*This symbolism means that a proton is accelerated into an atom of nitrogen-14, causing the ejection of an alpha particle from the nucleus to produce an atom
of carbon-11.

Ant Ant of tissue between the radionuclide and the detector removes
about half of the photons of interest, and 4 inches removes
about three-fourths.

Iodine-123 and -131

30 min 2h
• Fig. 1.6 Whole-Body Distribution of Technetium-99m Sodium
Pertechnetate. Activity is seen in the salivary glands, thyroid gland,
saliva, stomach, and bladder.
day. The ion is also secreted directly into the stomach and
colon, with a much smaller amount coming from the small
bowel. The colon is the critical organ and receives about 1
to 2 rad/10 mCi (0.04 mGy/MBq) of 99mTc pertechnetate
administered. The biodistribution of 99mTc pertechnetate is
shown in Fig. 1.6. The principal emission (140-keV photon)
of 99mTc has a half-value layer (HVL) of 0.028 cm in lead
and 4.5 cm in water. Because tissue is close to water in terms
of attenuation characteristics, it is clear that about 2 inches
Two isotopes of iodine (123I and 131I) are clinically useful for
imaging and may be administered as iodide. Iodine-123 has
a 13.2-hour half-life and decays by electron capture to
tellurium-123 (123Te). The photons emitted are 28-keV
(92%) and 159-keV (84%) gamma rays. Iodine-123 is
usually produced in a cyclotron by bombardment of
antimony-121 (121Sb) or tellurium-122 or -124 (122Te or
124
Te). Another method is to bombard iodine-127 (127I) to
produce 123Xe and let this decay to 123I. Contamination with
124
I may increase the radiation dose; because 124I is long
lived, its proportion in an 123I preparation increases
with time.
Iodine-131 is a much less satisfactory isotope from an
imaging viewpoint because of the high radiation dose to the
thyroid and its relatively high photon energy. However, it
is widely available, is relatively inexpensive, and has a rela-
tively long shelf life. Iodine-131 has a half-life of 8.06 days
and decays by beta-particle emission to a stable 131Xe. The
principal mean beta energy (90%) is 192 keV. Several
gamma rays are also emitted, and the predominant photon
is 364 keV (82% abundance) (HVL in water of 6.4 cm).
When iodine is orally administered as the iodide ion, it
is readily absorbed from the gastrointestinal tract and dis-
tributed in the extracellular fluid. It is concentrated in a
manner similar to that for 99mTc pertechnetate in the sali-
vary glands, thyroid, and gastric mucosa. As with pertech-
netate, there is renal filtration with significant tubular

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 CHAPTER 1 Radioactivity, Radionuclides, and Radiopharmaceuticals 9

TABLE
1.3 Imaging Radiopharmaceuticals

Radionuclide Radiopharmaceutical Uses

Carbon-11 Acetate Prostate
Nitrogen-13 Ammonia Cardiac perfusion
Oxygen-15 Gas Brain perfusion
Water Metabolic agent
Fluorine-18 FDG (fluorodeoxyglucose) Tumor, cardiac viability, brain metabolism, infection
Sodium Bone
Florbetapir Amyloid
Gallium-67 Citrate Infection, tumor
Gallium-68 DOTATATE Neuroendocrine tumor
Krypton-81m Gas Pulmonary ventilation
Rubidium-82 Chloride Myocardial perfusion
Technetium-99m Diphosphonate Bone
DISIDA (diisopropyl iminodiacetic acid) Biliary
DMSA (dimercaptosuccinic acid) Renal cortical
DTPA (diethylenetriamine pentaacetic acid) Renal dynamic, brain, lung ventilation
ECD (ethyl cysteinate dimmer) Brain perfusion
Glucoheptonate Brain, renal dynamic
HMPAO (hexamethylpropyleneamine oxine) Brain perfusion
HMPAO labeled white cells Infection
Labeled red cells Gastrointestinal (GI) blood loss, cardiac function,
hepatic hemangioma
MAA (macroaggregated albumin) Lung perfusion, LeVeen shunt patency, intraarterial
liver
MAG3 (mercaptoacetyltriglycine) Renal
Mebrofenin Biliary
Pertechnetate Thyroid, salivary glands, Meckel diverticulum,
testicular
Sestamibi Myocardial perfusion, parathyroid, breast
Sulfur colloid Liver/spleen, red bone marrow, esophageal transit,
gastric emptying
Sulfur colloid (filtered) Lymphoscintigraphy
Tetrofosmin Myocardial perfusion
Indium-111 DTPA Cerebrospinal fluid (CSF) flow, gastric liquid
emptying
Oxine labeled white cells Infection
Pentetreotide Somatostatin receptor tumors
Iodine-123 Sodium Thyroid
MIBI (metaiodobenzylguanidine) Pheochromocytoma, adrenal medullary, neural
crest tumors
Iodine-131 Sodium Thyroid cancer
Xenon-133 Gas Lung ventilation
Thallium-201 Chloride Myocardial perfusion

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10 C HA P T E R 1 Radioactivity, Radionuclides, and Radiopharmaceuticals

TABLE
1.4 Mechanisms of Localization and Examples

Capillary blockade Macroaggregated albumin in lung

Diffusion Filtration of DTPA by kidney
Sequestration Leukocytes for abscess scanning
Labeled platelets (damaged endothelium)
Heat-damaged red blood cells for splenic scanning
Phagocytosis Colloid scanning for liver and spleen, bone marrow, and lymph nodes
Receptor binding Neuroreceptor imaging
Active transport Iodocholesterol in adrenal scanning
Iodine or pertechnetate (accumulation by choroid plexus, Meckel diverticulum, salivary gland,
stomach, and thyroid)
Technetium-99m IDA analogs in liver/biliary tract
Orthoiodohippurate in renal tubules
Thallous ions in myocardium
Metabolism Fluorodeoxyglucose imaging of brain, tumor, and myocardium
Compartmental containment Labeled red blood cells for gated blood pool studies
Compartmental leakage Labeled red blood cells for detection of gastrointestinal bleeding
Physicochemical adsorption Phosphate bone-scanning agents
Antibody–antigen reactions Tumor imaging, monoclonal antibodies

DTPA, Diethylenetriaminepentaacetic acid; IDA, iminodiacetic acid.

reabsorption. Urinary excretion is the predominant route
(35% to 75% in 24 hours), although there is some fecal
excretion as well. Iodine-131 trapped and organified by the
normal thyroid has an effective half-life of about 7 days.
Iodine is a useful radionuclide because it is chemically reac-
tive and is used to produce a variety of radiopharmaceuti-
cals, which are discussed in later clinical chapters.
Xenon-133
Xenon is a relatively insoluble inert gas and is most com-
monly used for pulmonary ventilation studies. Xenon is
commercially available in unit-dose vials or in 1 Ci (37 GBq)
glass ampules. Xenon is highly soluble in oil and fat, and
there is some adsorption of xenon onto plastic syringes.
Xenon-133 has a physical half-life of 5.3 days. The prin-
cipal gamma photon has an energy of 81 keV and emits a
374-keV beta particle. With normal pulmonary function,
its biologic half-life is about 30 seconds. Some disadvan-
tages of 133Xe include its relatively low photon energy, beta-
particle emission, and some solubility in both blood
and fat.
Gallium-67
Gallium-67 has a physical half-life of 78.3 hours and decays
by electron capture, emitting gamma radiation. It can be
produced by a variety of reactions in a cyclotron. The prin-
cipal gamma photons from 67Ga are 93 keV (40%), 184 keV
(24%), 296 keV (22%), and 388 keV (7%). An easy way
to remember these energies is to round off the figures (i.e.,
90, 190, 290, and 390 keV).
When injected intravenously, most 67Ga is immediately
bound to plasma proteins, primarily transferrin. During
the first 12 to 24 hours, excretion from the body is pri-
marily through the kidneys, with 20% to 25% of the
administered dose being excreted by 24 hours. After that
time, the intestinal mucosa becomes the major route of
elimination. Typically on images, activity is seen in the
liver and to a lesser extent the spleen. In addition to activ-
ity within the axial skeleton, liver, spleen, and bowel, con-
centration is also seen in the salivary and lacrimal glands,
as well as in the breasts and external genitalia. If imaging
is performed in the first 24 hours, kidney and bladder
activity may also be noted.
Indium-111
Indium is a metal that can be used as an iron analog; it is
similar to gallium. Isotopes of interest are 111In and 113mIn.
Indium-111 has a physical half-life of 67 hours and is pro-
duced by a cyclotron. The principal photons are 173 keV
(89%) and 247 keV (94%). Indium-113m can be conve-
niently produced by using a 113Sn generator system. It has

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 CHAPTER 1
a physical half-life of 1.7 hours and a photon of about
392 keV. Indium-111 can be prepared as a chelate with
diethylenetriaminepentaacetic acid (DTPA). Because of its
long half-life, the 111In chelate can be used for intracranial
cisternography. Indium-111 is also used to label platelets,
white cells, monoclonal antibodies, and peptides. Indium-
111 oxine labeled white cells are commonly used to scan
for infections. On these images, activity is seen mostly in
the spleen and to a lesser extent in the liver and bone
marrow (see Chapter 12).
Thallium-201
When a thallium metal target is bombarded with protons
in a cyclotron, lead 201 (201Pb) is produced, which can be
separated from the thallium target and allowed to decay to
201
Tl. Thallium-201 has a physical half-life of 73.1 hours
and decays by electron capture to mercury-201 (201Hg).
Mercury-201 emits characteristic x-rays with energies from
68 to 80 keV (94.5%) and much smaller amounts of
gamma rays with higher energies. The relatively low energy
of the major emissions can cause significant attenuation by
tissue between the radionuclide and the gamma camera.
The HVL in water is about 4 cm. For these reasons, attenu-
ation correction methodologies have been developed (see
Chapter 2). Because 201Tl is produced by a cyclotron, it is
expensive. Thallium-201 is normally administered as a chlo-
ride and rapidly clears from the blood with a half-life
between 30 seconds and 3 minutes. Because it is roughly
a potassium analog, it is rapidly distributed throughout
the body, particularly in skeletal and cardiac muscle.
Thallium-202 (95% photon at 439 keV) contamination
should be less than 0.5% and, if present in greater quanti-
ties, can significantly degrade images.
Cell membrane
Glucose
Glucose
18
F-FDG transporter
(GLUT)
• Fig. 1.7 18
F-FDG Metabolism. Although 18F-FDG is transported into the cell in the same manner as
glucose, it cannot be dephosphorylated and remains in the cell. FDG, Fluorodeoxyglucose.
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Radioactivity, Radionuclides, and Radiopharmaceuticals 11
Positron Emitters
Fluorine-18
The most commonly used positron-emitting radiopharma-
ceutical in clinical imaging is the glucose analog fluorine-18
fluorodeoxyglucose (18F-FDG). Many tumor cells use large
amounts of glucose as an energy source and possess increased
expression of glucose transporters (especially GLUT1) and
increased hexokinase activity (especially HK2). Glucose
transporters transfer glucose and fluorodeoxyglucose into
the cells, where they are phosphorylated by hexokinases (Fig.
1.7). The rate-limiting step in this process is at the hexoki-
nase level and not at glucose transport. Although phosphor-
ylated glucose can be further metabolized, phosphorylated
FDG cannot be rapidly metabolized and 18F-FDG is essen-
tially trapped within the cell in proportion to the rate of
glucose metabolism. This allows sufficient time to image
its distribution in normal and abnormal bodily tissues. A
notable exception to the trapping of phosphorylated FDG
is the liver, in which an abundance of phosphatases causes
enhanced dephosphorylation of FDG-6-phosphate, which
accelerates its washout from that organ.
Although 18F-FDG reaches a plateau of accumulation in
tumors at about 45 minutes after injection, the tumor-to-
background ratio is best at 2 to 3 hours. Highest activity
levels at 2 hours are seen in the brain, heart (if not fasting),
and urinary system.
The effective dose to the patient for most 18F-FDG PET
scans is about 0.1 rem (1 mSv) or about 0.093 rem/mCi
(0.025 mSv/MBq). Pregnancy and breastfeeding are
common concerns when administering radionuclides to
women. Fetal dose estimates after administration of
13.5 mCi (500 MBq) of 18F-FDG to the mother are about
Intracellular
Glucose
Phosphorylation
Glucose 6-p
Glucose
18
F-FDG
Phosphorylation
18
F-FDG 6-p
Blocked
12 C HA P T E R 1 Radioactivity, Radionuclides, and Radiopharmaceuticals
1400 mrem (14 mSv) in early pregnancy and about 400
mrem (4 mSv) at term. Although 18F-FDG can accumulate
in breast tissue, it is not secreted to any significant degree
in the milk. It is usually recommended that the mother not
cuddle or breastfeed the infant for about 8 hours after
injection.
Fluorine-18 as a florbetapir is now used as a brain
amyloid imaging agent (see Chapter 3). Fluorine-18 is also
used in a sodium form as a skeletal imaging agent. Excretion
is predominantly via the kidneys. Images are similar to those
obtained with technetium phosphate compounds. This is
discussed in further detail in Chapter 8.
Other Positron Emitters
The positron emitters carbon-11, nitrogen-13, and
oxygen-15 are not used commonly in clinical practice pri-
marily because of their short half-lives (2–20 minutes) and
thus the need for a cyclotron simultaneously operating
on-site. Carbon-11 acetate and palmitate are metabolic
agents, carbon monoxide can be used for blood volume
determinations, and there are a few carbon-11 labeled
receptor binding agents. Nitrogen-13 ammonia is a perfu-
sion agent and nitrogen glutamate is a metabolic agent.
Oxygen-15 carbon dioxide and water are perfusion agents,
and oxygen as a gas is a metabolic agent.
Rubidium-82 chloride is obtained from a generator and
used for myocardial perfusion studies; however, widespread
clinical use has been limited by cost issues and the very short
half-life (1.27 minutes) requiring almost continuous pro-
duction during the procedure. Generator produced
gallium-68 is used as a label for radiopharmaceuticals used
in imaging neuroendocrine tumors.
Biologic Agents and Nanoparticles
During the past several years, much interest has been gener-
ated in the development of labeled antibodies for the immu-
nodetection and immunotherapy of a variety of diseases,
particularly those of an oncologic nature. However, it was
not until the development of methods of producing and
labeling monoclonal antibodies that the clinical potential of
such agents could be seriously explored. Growing interest
in antibody therapies developed to antigens on subgroups
of tumors and even tumors from individual patients has
given rise to prospects for realizing the potential for devel-
opment of patient-specific oncologic therapies.
Monoclonal antibodies are so named because when
developed against a given antigen, they are absolutely iden-
tical to one another. The technique for producing mono-
clonal antibodies first involves the immunization of an
animal, generally a mouse, with a specific antigen. This
antigen can be virtually anything capable of inducing the B
lymphocytes to begin producing antibodies against the
injected substance. Once this is done, the B lymphocytes
are harvested from the mouse and placed in a tube contain-
ing mouse myeloma cells. Fusion of these myeloma cells
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with the B lymphocytes then takes place, forming what is
known as hybridoma. This hybridoma has the ability to
continue producing antigen-specific antibodies based on
the B-lymphocyte parent and, at the same time, to perpetu-
ate itself based on the characteristic of continual mitosis
conferred on it by the myeloma cells.
Once produced, monoclonal antibodies, or fragments
thereof, may be labeled with radionuclides and used to map
the distribution of specific antigens in vivo. Although the
concept initially appears simple, substantial problems exist
that limit the clinical application of monoclonal antibodies
for tumor imaging. Not the least of these problems is the
selection of an appropriate specific antigen, the successful
labeling of the antibody, significant cross-reactivity with
other antigens, and poor target-to-nontarget ratios in vivo.
Immune responses to the foreign antibody protein in
humans have provided a further barrier to successful wide-
spread use. When the antibodies are produced in a murine
system, human antimouse antibody (HAMA) develops in
up to 40% of patients receiving a single dose of the whole
antibody. As solutions to these drawbacks are devised,
monoclonal antibodies are gradually becoming part of the
radiopharmaceutical armamentarium of diagnostic and
therapeutic nuclear medicine. Radiolabels currently include
radioiodines, 111In, 99mTc, and 90Y.
Nanoparticles have received recent interest, particularly
for potential cardiovascular imaging and therapeutic appli-
cations, but their clinical use remains very limited. Nanopar-
ticles have diameters that range from a few to several
hundred nanometers. A nanometer is one billionth (10-9)
of a meter. In contrast, a small molecule is <1 nm and a
microparticle is usually >1 µm. Small nanoparticles have
relatively fast blood clearance by renal filtration and large
nanoparticles are cleared by the phagocytic system of liver
and spleen. Most intermediate nanoparticles do not pene-
trate normal endothelium but will cross damaged endothe-
lium and remain longer than small molecules. It is hoped
that the cores and surfaces of nanoparticles can be modified
to contain multiple imaging and functional agents.
Adverse Reactions
As drugs, radiopharmaceuticals are extremely safe: mild
reactions are uncommon, and severe reactions are very rare.
There are less than 200 serious reactions reported in the
worldwide literature even though tens of millions of doses
are administered annually. An adverse reaction may be
defined as an unanticipated patient response to the nonra-
dioactive component of a radiopharmaceutical; this reaction
is not caused by the radiation itself. Overdoses of radioactiv-
ity represent reportable events (see Chapter 13) and are not
adverse reactions. The only adverse effect of a radiopharma-
ceutical that is required to be reported is one associated with
an investigational drug.
The incidence of reactions to radiopharmaceuticals in the
United States is about 2.1–2.3 per 100,000 administrations.
Most reported adverse reactions are allergic in nature,
 CHAPTER 1 Radioactivity, Radionuclides, and Radiopharmaceuticals 13

although some vasovagal reactions have occurred. The clini-
cal manifestations of most reactions are rash, itching, dizzi-
ness, nausea, chills, flushing, hives, and vomiting. These
reactions may occur within 5 minutes or up to 48 hours
after injection. Rash or itching, dizziness, and/or headache
have most commonly been reported with 111In WBC, 99mTc
MAG3, 99mTc sestamibi, 99mTc bone agents, and 18F-FDG.
Severe reactions involving anaphylactic shock or cardiac
arrest are reported in less than 3% of adverse reactions and
have been associated with radiolabeled MDP, sulfur colloid,
MAG3, MIBG, and FDG. Neurologic events (pain, hypes-
thesia, and paresthesia) have occasionally been associated
with 99mTc-estamibi and 99mTc-tetrofosmin. Adverse effects
with albumin particulates have been reported, owing to
pulmonary capillary vascular blockage in patients with
already diminished pulmonary vascular capacity.
Reactions related to pyrogens or additives have become
exceedingly rare because of the extensive quality control
used in the manufacture and preparation of radiopharma-
ceuticals. Pyrogen reactions may be suspected if more than
one patient receiving a dose from a single vial of a radio-
pharmaceutical has experienced an adverse effect.
Common nonradioactive pharmaceuticals used in
nuclear medicine are dipyridamole and glucagon. Adverse
reactions (usually headache) have been reported to occur in
up to 45% of patients. Severe reactions to these occur in
about 6 per 100,000 administrations and include pro-
longed chest pain, syncope (dipyridamole), and anaphy-
laxis (glucagon). Furosemide used in renal imaging may
trigger severe reactions in patients with sulfa allergies, and
another loop diuretic, ethacrynic acid, has been suggested
as an alternative in those patients. Anaphylactic reactions
have also been reported in up to 1% of patients receiving
isosulfan blue dye during sentinel lymph node procedures.
complete drug labeling, including the most desirable dose
and the safety and effectiveness of the drug.
Most reimbursement organizations and third-party
payers will not pay for a drug unless it is fully approved
by the FDA, and a number of approved drugs may not
be reimbursed unless they are used for the approved
indications.
RADIOPHARMACY QUALITY CONTROL
Most nuclear medicine departments now get “unit doses”
for individual patient use from commercial radiopharma-
cies. Such doses are prepared in an off-site commercial
radiopharmacy, with each measured dose fulfilling the
ordering specifications of the laboratory in which it will be
used. Doses are supplied in syringes appropriately labeled
with the radiopharmaceutical, patient name, activity at
a specific time, and expiration date/time, if appropriate.
Prior to patient administration, the activity must be cal-
culated through a decay correction of the stated activity
on the syringe label, or it may be directly measured in a
dose calibrator, if desired. There also should be photopeak
analysis at the time of imaging. Additional quality control
should be requested from the radiopharmacy if the images
demonstrate an unexpected biodistribution of activity
(Fig. 1.8).
Because most departments no longer use 99Mo/99mTc
generators to elute technetium or compound radiopharma-
ceuticals from kits, the burden of most radiopharmaceutical
quality assurance issues has been shifted to others. However,
it is still important to understand the quality control

Investigational Radiopharmaceuticals
Any new radiopharmaceutical must be treated as an inves-
tigational new drug (IND) and must go through the process
outlined in the Guidelines for the Clinical Evaluation of
Radiopharmaceutical Drugs of the US Food and Drug
Administration (FDA). Either manufacturers or health
practitioners can file an IND application. Initially, the
application must include complete composition of the
drug, source, manufacturing data, and preclinical investiga-
tions, including animal studies.
Clinical investigation of INDs occurs in three phases.
Phase one is early testing in humans to determine toxicity,
pharmacokinetics, and effectiveness. These studies usually
involve a small number of people and are conducted under
carefully controlled circumstances. Phase two trials are con-
trolled trials to test both for effectiveness in treatment of a
specific disease and for evaluation of risk. Phase three, clini-
cal investigation, involves extensive clinical trials, provided
• Fig. 1.8 Arterial Injection. An inadvertent arterial injection during
that information obtained in phases one and two demon- administration of 18F-FDG caused intense activity distal to the injection
strates reasonable assurance of safety and effectiveness. site. This is known as the “glove phenomenon.” (Case courtesy Harry
Phase three studies acquire necessary information for Agress, MD.)

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14 C HA P T E R 1 Radioactivity, Radionuclides, and Radiopharmaceuticals

processes and principles in case there is an adverse reaction
or the radiopharmaceutical does not localize in the patient’s
tissues as expected.
For those who continue to prepare radiopharmaceuti-
cals in the nuclear medicine department, there are new,
complex, and potentially very expensive requirements
(US Pharmacopeia [USP] Chapter 797) concerning the
compounding of sterile preparations. This USP chapter
provides strict requirements for inspection standards,
licensing, and accreditation. Preparation of kits is consid-
ered low-risk level but still requires International Organiza-
tion for Standardization (ISO) class 5 laminar airflow hood
in an ISO class 8 clean room with an ante area. These areas
must also be routinely monitored for cleanliness, and there
must be a specific quality assurance program, written proof
of staff training, equipment maintenance, and calibration.
Regardless of whether radiopharmaceuticals are commer-
cially obtained or prepared in-house, there are strict US
Nuclear Regulatory Commission (USNRC) requirements
for receipt, management, and disposal. These are outlined
in Chapter 13.
Generator and Radionuclide Purity
The first step in quality control is to ensure that the radio-
nuclide is pure (Table 1.5). Radionuclide purity is the per-
centage of activity present that is due to the radionuclide
of interest. Because 99mTc normally is obtained by eluting
or “milking” a molybdenum generator, there must be
assurance that only 99mTc is eluted. Most 99Mo-99mTc gen-
erators are fission produced, and radionuclide impurities
such as 99Mo, iodine-131 (131I), and ruthenium-103 (103Ru)
may be present. The amount of 99Mo contamination, or
breakthrough, during elution is normally determined by
placing the eluate from the generator in a lead shield and
measuring the penetration of any 99Mo (740- and 780-keV)
photons. The presence of other radionuclides may be deter-
mined by multichannel analysis or by counting of the
eluate at different times to allow for decay. The latter
method indicates whether the half-life of the contaminant
is or is not consistent with that of 99Mo.
The USNRC and USP regulations allow no more than
0.15 µCi (0.005 MBq) of 99Mo per 1 mCi (37 MBq) of
99m
Tc at the time of administration. Because 99mTc decays
much faster than 99Mo, the relative amount of any molyb-
denum contaminant rises with time. Thus, if the 99Mo in
an eluate from a generator was barely acceptable at 8:00
a.m., it will likely become unacceptable later the same day.
The elution column inside the generator is made of
alumina (Al2O3). If, during elution, sufficient alumina
breaks through, the eluate may become cloudy. The presence
of aluminum ion (Al3+) should be ascertained at the time of
eluting 99mTc from the generator. Small amounts of alumi-
num ion may be detected with an indicator paper similar to
the pH paper used in chemistry. If aluminum ion is present,
a red color develops. The maximum permissible amount of
aluminum ion is 10 µg/mL of 99mTc eluate with a fission
generator. If too much aluminum is present, technetium–
aluminum particles form, which are manifested clinically by
hepatic uptake. Excessive aluminum ion may also cause
aggregation of sulfur colloid preparations, resulting in lung
uptake. The purpose of ethylenediaminetetra-acetic acid
(EDTA) in sulfur colloid kits is to bind excess Al3+ and thus
to prevent such problems. Agglutination of red blood cells

TABLE
1.5 Radiopharmaceutical Quality Control

Tests Problem Limits Comment

Radionuclide purity 99
Mo breakthrough 0.15 µCi Mo/mCi Tc
99 99m
Test every generator elution for 99Mo. Note:
99
Mo/99mTc 99 99m
(0.15 kBq Mo/MBq Tc) Because of the longer half-life of 99Mo, a
generator dose that was just compliant at the time of
preparation may not be compliant at the time
of administration.
82
Sr/82Rb generator 82
Sr breakthrough 0.02 µCi 82Sr/mCi 82Rb Test every generator elution. Limits are at time
(0.02 kBq 82Sr/MBq 82Rb) of patient administration.
85
Sr contamination 0.2 µCi 85Sr/mCi 82Rb
(0.2 kBq 85Sr/MBq 82Rb)
Radiochemical 99m
Tc not in +7 valence 95% or more must be in Most radiopharmaceuticals must be at least
purity state. Free 99mTc +7 90% pure (i.e., 90% of the radioisotope
pertechnetate, bound in the desired chemical form). The +4,
hydrolyzed, or +5, and +6 valence states are impurities.
reduced moieties Detect with (instant) thin-layer
chromatography (TLC).
Chemical purity Alumina breakthrough <10 µg/mL Detected visually by paper colorimetric test.
99
Mo/99mTc Done for every generator elution.
generator

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may also occur when inordinate amounts of aluminum ion
are contained in 99mTc pertechnetate solutions.
Product standards and quality control requirements for
PET radiopharmaceuticals are provided by both the USP
and guidance from the FDA (which, in some instances, is
more restrictive). For 18F-FDG injection, the FDA indi-
cates that (1) the solution must be colorless and free from
particulate matter when observed visually (appearance), (2)
the half-life must be measured to be between 105 and
115 minutes (radionuclide identity), (3) no more than
4% of free 18F− must be present in an injection (radio-
chemical impurity), (4) no less than 90% of the radio-
activity must locate at a specific spot on chromatography
(radiochemical purity), and (5) additional tests for chemi-
cal purity must ensure that various reagents, unwanted
products, or residual organic solvents are not present
in excess.
Radiochemical Labeling
Once radionuclide purity is ensured, a prepackaged kit con-
taining an unlabeled pharmaceutical may be used to produce
a radiochemical compound. Radiochemical purity is defined
as the percent of the total radioactivity present in the desired
chemical form in a radiopharmaceutical preparation. Assess-
ment of chemical purity of 99mTc radiopharmaceuticals is
performed by determining the degree of successful tagging
of the agent contained in the kit and the amount of residual
(unbound 99mTc) in the preparation. The degree of purity
may reflect the proficiency of those who prepare the kits or
simply any lot-to-lot or manufacturer-to-manufacturer vari-
ability in the kits.
Instant thin-layer chromatography is usually performed
to assess RCP, using silica gel impregnated in glass fiber
sheets or strips. By using various solvents, impurities can be
identified by their different migrations in the particular
solvent used.
A drop of the radiochemical compound to be analyzed
is placed on the strip, and the solvent is applied. As the
solvent approaches the end of the sheet, an assessment is
made of the radioactivity present at the point of origin and
at the advancing solvent front. Although this may be per-
formed by various scanning methods, the simplest way is to
cut the fiber strip into segments and count them individu-
ally in a well counter. If this is done, the technician must
be extremely careful to put only a very small amount of
activity at the spot of origin because well counters are effi-
cient and it is easy to exceed their count rate capability.
The most common 99mTc radiopharmaceuticals are pre-
pared by adding 99mTc freshly eluted from a generator to a
cold kit, as prescribed by the kit manufacturer. The eluate
of the generator should be 99mTcO4– (+7) (i.e., pertechne-
tate). Because pertechnetate in this valence state is relatively
stable, it cannot tag a cold kit preparation and must be
reduced to a lower valence state (+3, +4, +5). This is done
by using a reducing agent such as stannous chloride, which
is generally present in the reaction vial.
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Radioactivity, Radionuclides, and Radiopharmaceuticals 15
Most radiochemical impurities obtained in a kit prepara-
tion are the result of interaction of either oxygen or water
with the contents of the kit or vial. If air reaches the vial
contents, stannous chloride may be oxidized to stannic
chloride even before introduction of 99mTc into the vial. If
this happens, the production of reactive technetium is no
longer possible, and free pertechnetate becomes an impu-
rity. If moisture reaches the vial contents, stannous chloride
becomes hydrolyzed, and the formation of stannous hydrox-
ide, a colloid, results.
Reactive reduced technetium may also become hydro-
lyzed, forming technetium dioxide. This hydrolyzed,
reduced form of technetium is insoluble and is another
impurity that must be tested. Technetium that has been
tagged to a compound can reoxidize and revert to
pertechnetate.
To minimize oxidation problems, most cold kits are
purged with nitrogen, and additional antioxidants, such as
ascorbic acid, may also have been added. It is still extremely
important not to inject air into the reaction vial when pre-
paring a radiopharmaceutical. An often overlooked source
of problems is the sterile saline used in preparation of the
kits. This saline should be free of preservatives because bac-
teriostatic agents often interfere with the tagging process.
To check for the presence of free pertechnetate, the
radiopharmaceutical is placed on the chromatographic
strip, and acetone is used as the solvent. Most tagged radio-
pharmaceuticals remain at the origin, whereas the free
pertechnetate advances with the solvent front (Fig. 1.9). To
assess the presence of hydrolyzed technetium or technetium
dioxide, saline is used as the solvent. In this case, techne-
tium dioxide remains at the origin, whereas those radio-
pharmaceuticals that are soluble in saline, such as DTPA
and pertechnetate, advance with the solvent front. For some
compounds that are insoluble in saline, such as macroag-
gregated albumin (MAA), it is not possible to assess the
presence of technetium dioxide by using instant thin-layer
chromatography.
USP regulations define the lower limits of acceptability
for radiochemical purity as 95% for pertechnetate, 92% for
99m
Tc sulfur colloid, and 90% for all other 99mTc radiophar-
maceuticals. Once the chromatographic procedures are
established, they take little time to perform and ideally
should be done before patient injection.
One reason for performing thin-layer chromatography
before patient injection is that simple errors can cause the
radiolabeling to be completely ineffective. For example, in
the production of sulfur colloid, one kit normally calls
for injection of syringe A first and then for injection of
syringe B into the reaction vial. If these two injections are
reversed, no sulfur colloid is produced, and there is a large
amount of free 99mTc pertechnetate. Thus, a liver scan is
not possible with the agent. Free 99mTc pertechnetate is
seen as unexpected activity in both the thyroid and stomach
(Fig. 1.10).
The 99mTc radiopharmaceuticals that are produced with
stannous chloride reduction or stannous chelates include
16 C HA P T E R 1 Radioactivity, Radionuclides, and Radiopharmaceuticals

99mTcSC

Acetone
solvent front

Activity
99mTcO
4

Origin Distance

99mTcDTPA

Saline
solvent front
Activity

99mTcO
2

Origin Distance
• Fig. 1.9 Chromatography. (Top) Acetone chromatography is used to check for the presence of free
pertechnetate, which migrates with the acetone solvent front. (Bottom) To check for technetium dioxide
(99mTcO2), saline is used; those radiopharmaceuticals that are soluble in saline advance with the solvent.

Ant MAA, phosphate compounds, and glucoheptonate. The

• Fig. 1.10 Free Technetium Pertechnetate. On this 99mTc-MAA
(macroaggregated albumin) lung scan, unexpected activity in the
thyroid (top arrows) and stomach (bottom arrows) indicates the pres-
ence of unlabeled free technetium pertechnetate.
only one in common use that is produced without reduc-
tion or chelation by tin is sulfur colloid. The compounds
in which the presence of hydrolyzed technetium (Tc
dioxide) may need to be checked are DTPA, phosphate
compounds, glucoheptonate, and iminodiacetic acid (IDA)
derivatives.
Excessive stannous agents can cause quality control prob-
lems during radiopharmaceutical preparation that become
evident in the actual clinical images. Excess stannous ions
(tin) may cause liver uptake on bone scans by formation of
a tin colloid (Fig. 1.11). Residual stannous ions in the blood
may also cause red blood cell labeling. Stannous ions may
remain in the blood after a bone scan, so that a 99mTc
pertechnetate thyroid or Meckel diverticulum scan attempted
within 1 week may result in red blood cell labeling.
Particle size of certain compounds may be checked by a
hemocytometer as part of the quality control procedure.
The USP maximum diameter recommendation for MAA is
150 µm, with 90% of particles between 10 and 90 µm. This
range is intended to target the precapillary arterioles in the
lung and prevent larger particle blockade of the greater
diameter pulmonary arterioles and smaller ones slipping
through the capillaries into the reticuloendothelial system
(liver, spleen, bone marrow). Most physicians prefer parti-
cles less than 100 µm in size for pulmonary perfusion
imaging.

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 CHAPTER 1
• Fig. 1.11 Excess Tin. Images from a bone scan show unexpected hepatic activity because of poor
quality control and excess tin causing formation of colloid-size particles.
UNSEALED RADIONUCLIDES USED
FOR THERAPY
Radionuclides can be administered to patients for therapeu-
tic purposes in sealed or unsealed form. These procedures
account for about 1% to 1.5% of all nuclear medicine
procedures. Unsealed radionuclides may be given orally,
administered intravenously, or placed directly into a body
cavity (such as a knee joint or peritoneum). Most unsealed
radionuclides are predominantly beta and alpha emitters
with very limited range of travel beyond the patients treated
with them. As such, they usually present little external
hazard to the public or family members or caretakers of
patients. A few of these radionuclides also emit energetic
gamma photons, which can be helpful in imaging the local-
ization of the material; however, a large amount of gamma
emissions will present a radiation hazard and give a signifi-
cant radiation dose to nontarget tissues as well as to those
nearby. Some of these agents are referred to as “theranostics”
since they can be used for therapy and diagnosis.
Issues related to the release of patients in accordance with
USNRC regulations are included in Appendix G. Sealed
radionuclides are administered to patients in an encapsu-
lated form for regional radiotherapy. Because they are gener-
ally used in the practice of radiation oncology, sealed
radionuclides will not be discussed in this text.
Phosphorus-32, Yttrium-90, and Gold-198
All three of these radionuclides have been used for radioiso-
topic therapy. Currently, they are rarely used in colloidal
form for intracavitary administration for abdominopelvic
serosal metastases or knee joint synovectomy. Yttrium-90
(90Y) can be coupled with a localization agent to deliver
antineoplastic therapy. Yttrium-90 labeled microspheres,
injected through a transfemoral catheter into the hepatic
artery, lodge in the small blood vessels of liver neoplasms to
mebooksfree.net
Radioactivity, Radionuclides, and Radiopharmaceuticals 17
deliver a therapeutic dose. 90Y-labeled monoclonal antibod-
ies can be injected intravenously to treat some non-Hodgkin
lymphomas.
Iodine-131
Iodine-131 is discussed earlier in the section on imaging
radionuclides; however, large administered activities of
sodium 131I are commonly used for treatment of hyperthy-
roidism and thyroid cancer. Although 131I is a beta emitter,
there is a predominant energetic gamma emission (364 keV),
which can be used to image the biodistribution. This gamma
photon also can result in measurable absorbed radiation
doses to persons near the patient. Because excretion is via
the urinary tract and, to a lesser extent, via saliva and sweat,
special radiation protection precautions need to be taken
for days after these patients are treated. These are discussed
further in Chapter 4 in the section on thyroid therapy and
in Appendixes H-1 and H-2.
Strontium-89, Samarium-153,
Rhenium-186, and Radium-223
All four of these radionuclides are administered intrave-
nously and used to treat painful osseous metastases (usually
from prostate and breast cancer). Strontium-89 (89Sr) is
essentially a pure beta emitter and poses virtually no hazard
to medical staff or patient families, except for urinary pre-
cautions for a few days. Both samarium-153 (153Sm) and
rhenium-186 (186Re) also emit small amounts of relatively
low-energy gamma photons, which can be used to image
distribution. Radium-223 has recently been approved for
use in treating prostate cancer skeletal metastases. Unfortu-
nately, it is very expensive, which limits its use. Radium-223
(11.4 days) is primarily an alpha emitter (94% 5–7.5 MeV).
These agents are discussed in more detail at the end of
Chapter 8.
18 C HA P T E R 1 Radioactivity, Radionuclides, and Radiopharmaceuticals
PEARLS & PITFALLS
• The superscript before a radionuclide symbol or the
number following in regular text is the mass number (A),
which is the sum of the number of neutrons (N) and
protons (Z). Thus, 131I (iodine-131) has 53 protons and 78
neutrons to equal 131.
• All isotopes of a given element have the same number of
protons and only differ in the number of neutrons.
• Effective half-life of a radionuclide is always less than either
the physical or biologic half-life.
• A becquerel is 1 disintegration per second. A curie is 3.7 ×
1010 disintegrations per second.
• Cyclotron-produced isotopes are often carrier free (do not
contain any of the stable element) because the process
involves transmutation. Isotopes produced by neutron
bombardment are not usually carrier free because they
involve bombardment of the same element. Radionuclides
produced by fission in a reactor can be carrier free because
they are produced by splitting other elements.
• A generator system for producing radionuclides uses a
long-lived parent that decays into another shorter-lived
element that can be chemically separated.
• In most generators used, there comes a time when the
ratio of the daughter to the parent becomes constant
(transient equilibrium), and for 99Mo-99mTc generators, the
99m
Tc activity is slightly less than the 99Mo activity. This takes
several days. Once eluted, a 99Mo-99mTc generator will reach
95% of maximal 99mTc activity in about 23 hours.
• Once produced, most excited states of an atom decay
almost instantaneously to a more stable configuration. The
“m” in technetium-99m refers to “metastable,” meaning that
there is an excited state of the isotope that persists for an
extremely short time before there is emission of a gamma
ray.
• If using unit doses, you must either measure the activity or
calculate the decay from the radiopharmacy calibration and
you must check the photopeak (often automatic on new
cameras).
Suggested Readings
Bushberg JT, Seibert JA, Leidholdt EM, et al. The Essential Physics of
Medical Imaging. 3rd ed. Philadelphia: Lippincott, Williams &
Wilkins; 2012:[Chapters 15–19].
mebooksfree.net
• Severe adverse reactions of radiopharmaceuticals are
extremely rare (about 2 per 100,000). Adverse reactions to
nonradioactive pharmaceuticals used in nuclear medicine
are much more common.
• Technetium-99m as eluted is in a +7 valence state. Tin
(stannous ion) is used as a reducing agent to allow labeling
of other compounds.
• Molybdenum breakthrough in a generator eluate is detected
by the penetration of 740- and 780-keV photons through a
lead shield that attenuates the 140-keV photons of
technetium. The limit is 0.15 µCi of 99Mo activity per 1 mCi
of administered 99mTc.
• Aluminum ion breakthrough in the eluate from a 99Mo-99mTc
generator is detected by using a special test paper that
changes color. Excessive aluminum indicates the lack of
stability of the generator column. The USP limits the
amount of aluminum ion to 10 µg Al3+/mL 99mTc eluate from
a generator using fission produced 99Mo.
• Radionuclide purity is the percent of the total radioactivity
being assayed that is the desired radionuclide. It is
performed by examining the energy of the photons emitted
and comparing it with those expected for a given
radionuclide.
• Radiochemical purity is the percentage of wanted versus
unwanted radiolabeled chemical in the preparation. It is
tested by using thin-layer chromatography with either
acetone or saline as the solvent. Usually, 95% tagging is
required.
• For traditional 99mTc diagnostic agents, there are three
common radiochemical impurities that may be measured by
thin-layer chromatography: (1) Free 99mTc pertechnetate
(99mTc04-; soluble), (2) hydrolyzed-reduced 99mTc (99mTc02;
insoluble), and (3) 99mTc bound to other chemical
compounds (either chemical impurities or secondary
chemicals needed for the labeling process).
• Free 99mTc pertechnetate is usually seen as unexpected
activity in the stomach, thyroid, and salivary glands.
Silberstein EB. Prevalence of adverse events to radiopharmaceuticals
from 2007-2011. J Nucl Med. 2014;55(8):1308–1310.
Simpkin DJ. The AAPM/RSNA Physics Tutorial for Residents:
Radiation interactions and internal dosimetry in nuclear
medicine. Radiographics. 1999;19:155–167.
2
Instrumentation and Quality Control
CHAPTER OUTLINE
Geiger-Mueller Counter Data Acquisition
Ionization Chamber Tomographic Image Production
Sodium Iodide Well Counter SPECT/CT
Single Probe Counting Systems Positron Emission Tomography (PET)
Dose Calibrator Overview of PET Cameras
PET Scintillation Detectors
Gamma Scintillation Camera
PET Detector Geometry
Collimator
Attenuation Correction
Crystal and Other Photon Detector Devices
System Sensitivity and Resolution
Photon Transducers
PET Image Acquisition and Processing
Solid-State Photon Detectors
Pulse Height Analyzer PET/CT
Console Controls PET/MRI
Resolution Instrumentation Quality Control
Count Rate and Dead Time Gamma Cameras
Field Uniformity SPECT Quality Control
Image Acquisition: Memory and Matrix Size Detector Head Alignment With the Axis of Rotation
Image Display and Processing Collimator Evaluation
Frame Manipulation System Performance
Operator Interaction PET/CT Quality Control
Dedicated Molecular Breast Imaging Cameras Technical Artifacts
Single-Photon Emission Computed Tomography (SPECT) Areas of Decreased Activity
Instrumentation Areas of Increased Activity
Dedicated Cardiac SPECT Cameras

GEIGER-MUELLER COUNTER
Geiger-Mueller (GM) counters are handheld, very sensitive,
inexpensive survey instruments used primarily to detect
small amounts of radioactive contamination. The detector
is usually pancake shaped, although it may be cylindrical
(Fig. 2.1). The detector is gas filled and has a high applied
voltage from the anode to the cathode. This causes one
ionization to result in an “avalanche” of other electrons,
allowing high efficiency for detection of even a single
gamma ray. The avalanche of electrons takes some time to
dissipate; as a result, “dead time” must occur before the next
ionization can be detected. This precludes use of GM coun-
ters in high radiation fields. They are usually limited to
exposure rates of up to about 100 mR (2.5 × 10-5 C/kg)/hr.
Most GM counters are equipped with a thin window that
also allows detection of most beta rays. Very weak beta rays
(such as those from tritium) cannot be detected.
Advantages of GM counters include their durability, por-
tability, and ability to detect many types of radiation with
high sensitivity. Limitations include that they can neither
differentiate which type of radiation is being detected nor
determine the exact energy of the detected radiation. Thus
their primary use is simply to survey for the presence of
radiation and radioactivity.
IONIZATION CHAMBER
Ionization chambers are handheld survey instruments used
to measure low or high exposure rates (Fig. 2.2). They have

19

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obliged to adhere in communion. And consequently, this witness of
the Spirit, which shews that we christians are the sons of God,
cannot possibly be applied to the mere private testimony of the Spirit
given to our own consciences, to prove that we, or private christians,
are the sons of God and heirs of salvation, as is pretended by
modern enthusiasts.”

But does not his Lordship here argue from a mistaken

supposition, that the Apostle, in the 8th of the Romans, is speaking
of the miraculous power our Lord gave to his first Apostles to work
miracles, in confirmation that their doctrine was of God? Is there any
such thing so much as hinted at through the whole chapter? Is not
the whole scope of it to shew the privileges of those, who “being
justified by faith” alone, chapter 5th, “have peace with God through
our Lord Jesus Christ?” Does not the Apostle therefore at the first
verse say, “That there is no condemnation to them who are in
Christ Jesus?” Does he not say, verse the 9th, that “the Spirit of
God dwelt in them?” Does not his Lordship allow, page 16, &c. That
the Apostle in this and the preceding verses treats of that “spiritual
principle in christians which enables them to mortify the deeds of the
body, and overcome carnal inclinations?” And what shadow of a
reason can be given to prove that the same spiritual principle is not
spoken of in verse 16th, as bearing witness with believer’s spirits
that they were the children of God? Is it not said, verse 15th, to be
something that they had received? “But ye have received the spirit of
adoption, whereby ye cry Abba, Father.” And is not the obvious
sense of these verses put together plainly this, “That true believers,
those who are christians indeed, have the Spirit of God dwelling in
them, verse 9th; are led by this Spirit, verse 14th; have gotten an
inward witness from this same Spirit, that they are God’s children,
and therefore need not be brought into bondage, and fear, lest God
would reject them, but may have free access, and with a full
assurance of faith, and a holy child-like simplicity, draw near unto
him, crying Abba, Father?”

His Lordship, to prove that this is not the sense of this passage,
but that the testimony of the Spirit here spoken of, is a public gift of
working miracles, refers, page 19th, to Galatians iii. 2. where the
Apostle puts this question to them: “Received ye the Spirit, (i. e.
according to his Lordship, the power of working miracles) by the
works of the law, or by the hearing of faith?” which (says his
Lordship) the same Apostle presently after explains, when he says at
verse 5th, “He therefore that ministereth to you the Spirit, and
worketh miracles among you, doth he it by the works of the law, or
by the hearing of faith?” But is not here a plain antithesis between
administring the Spirit and working miracles? Do they not evidently
imply two distinct things? And can it be supposed, that the Spirit
which the Apostle asks, verse 2d, “Whether they had received by the
works of the law, or the hearing of faith,” was a power to perform
such miracles, at least that only? Would it not then follow, since he
declares in the 8th of the Romans, “that if any man have not the
Spirit of Christ he is none of his,” that either all believers did receive
his Spirit in his miraculous gifts, or that no one is a believer that has
them not? And doth not the Apostle in this very epistle make it
appear, that the Spirit here spoken of is not this miraculous outward
testimony? For what says he, Galatians iv. 6. “And because ye are
sons, God hath sent forth the Spirit of his Son into your hearts
(whereby it is plain the Spirit was received into the heart) crying,
Abba, Father?” And does not this quite clear up that passage of
Romans, chapter viii. verse 15. about the witnessing Spirit and the
Spirit of adoption, viz. that believers (besides seeing the miracles
which the Apostles wrought) had an inward testimony of the Holy
Ghost, he making an inward application of the merits of Christ to
their souls, and giving them an inward testimony that they were
indeed the adopted sons of God, and therefore in a holy confidence
they might cry, Abba, Father? Is there any thing forced in this
interpretation? And consequently (notwithstanding what appears to
the contrary from his Lordship’s explanation) may not persons
assert, that there is such a thing as a witness or testimony of the
Spirit given to our own consciences, to prove that private christians
are the Sons of God and heirs of salvation, without being censured
for so doing as modern enthusiasts?
 May I not likewise venture to affirm, that his Lordship is equally
mistaken in his interpretation of the 26th and 27th verses of the
same chapter, which runs thus: “Likewise the Spirit also helpeth our
infirmities: for we know not what we should pray for as we ought, but
the Spirit itself maketh intercession for us with groanings which
cannot be uttered. And he that searcheth the heart, knoweth what is
the mind of the Spirit, because he maketh intercession for the saints
according to the will of God?”

The Spirit here spoken of, according to his Lordship, was the
Spirit acting in the inspired person, who in the apostolical age, says
his Lordship, page 24th, “had the gift of prayer, and interceded for
the whole congregation; so that what is here said of the Spirit, is ♦by
an easy figure transferred to the spiritual or inspired person, who
prayed in that capacity, for the whole christian assembly. It is he that
maketh intercession with God for private christians, with vehement
and inexpressible groanings or sighs.” But however easy it may be to
find out a figure to transfer what is here said of the Spirit, to the
spiritual or inspired person, yet how will it be easy to find a figure to
interpret this of the spiritual or inspired person at all? For has it not
already been shewn, that this whole chapter is no where speaking of
any such spiritual inspired person, but of the Spirit of God dwelling in
all believers?

♦ “hy” replaced with “by”

His Lordship goes on, page ibid. to comment upon the 27th
verse: “And he that searcheth the hearts, knoweth what is the mind
of the spirit, (i. e. of the spiritual or inspired person) because he
maketh intercession for the saints according to the will of God.” That
is, says his Lordship, “God knows the intentions of the spiritual
person, and judges of the vehemence of his desires in prayer for the
whole assembly, for whom he makes intercession, with regard to the
immediate subject of affliction; literally indeed, according to God
(kata Theon) or relatively to him, but by construction, conformably to
the will of God; namely, that in a most fervent manner, the person
that has the inspired gift of prayer, which he uses for the benefit of
the whole assembly, he, I say, leaves it entirely to God, whether it be
best that christians should suffer afflictions for the gospel, or be
delivered from them. And such an intention of his prayer cannot but
be highly acceptable to God, who searches his heart, and approves
of such an act of profound resignation to his will.”

Thus far his Lordship. But where is there through the whole
chapter any mention made of an assembly, or of any spiritual
inspired person praying in its behalf? Does it not require a very
profound understanding to search it out? Is it not more agreeable to
the whole scope of the apostle in this chapter, to believe, that this
spirit here mentioned as helping infirmities, or distresses, and
assisting in prayer, is the common privilege of all believers? Is he not
said to make intercession for the saints in general? And does not his
Lordship, page 22d, in effect own this? For what says his Lordship?
“Now on this occasion, he, the apostle, adds another proof of the
truth of christianity, and that christians are the adopted sons of God,
and more especially with regard to their sufferings at that time, for
the sake of their religion, says he, verse 26th. Likewise the Spirit
also, (or rather even, kai) helpeth our infirmities (or our distresses,
for the word Astheneiais signifies both.) And then he mentions in
what instances he does so, viz. in prayers to God about bearing
afflictions, or being delivered from them; and which of these two is
most profitable for us, the Spirit knows better than we ourselves, and
therefore instructs christians how to pray with regard to their
sufferings. We know not, says he, what we should pray for as we
ought; that is, whether it be best for us to bear afflictions, or to be
delivered from them according to our natural inclinations.” And after
writing thus, how inconsistent is it in his Lordship to say, that this is
done by the Spirit acting in the inspired person only, who made
intercession for the whole assembly? Is not the quite contrary, I
could almost say, self-evident? And how then can those who, from
this passage of the 8th of the Romans, humbly claim the gift and
grace of prayer now, as well as formerly, for so doing, be justly
termed modern enthusiasts.
 May we not further enquire, whether his Lordship’s interpretation
of the 4th and 5th verses of the 2d chapter of the first epistle to the
Corinthians be sound and consistent? The words are these, page
27th. “And my speech and my preaching were not with the enticing
words of man’s wisdom, but in demonstration of the Spirit and of
power, that your faith should not stand in the wisdom of men, but in
the power of God,” As to the former part of these words, “My speech
and my preaching were not with the enticing words of man’s
wisdom,” his Lordship seems to agree with the interpretation put
upon them by those whom he is pleased to term enthusiasts; but the
latter, “The demonstration of the Spirit and of power,” his Lordship, in
pages 29th, 30th, 31st, and 32d, would fain shew, means no more,
than that the Apostle proved Jesus to be the Messiah by proofs out
of the prophecies of the Old Testament, and evinced the truth of
christianity by performing miracles.

And supposing this may be one sense of the words, yet if this be
the sole meaning of the Apostle’s expression, would it not have
better become such a scholar as Paul was, to have said, “He came
to them in the demonstration of the scriptures, rather than of the
Spirit?” Can any parallel passage be produced, where the word Spirit
is thus put for the scriptures? And therefore, by the demonstration of
the Spirit, may we not understand, that the Spirit of God himself,
whilst the Apostle was preaching, wrought a demonstrative
conviction in the souls of his hearers, not only that what he spake
was of God, but also that he was assisted in speaking by the Spirit
of God? Does not this agree with what he says, 2d epistle
Corinthians iii. 2, 3. “Ye are our epistle, written in our hearts, known
and read of all men: forasmuch as ye are manifestly declared to be
the epistle of Christ ministered by us, written not with ink, but with
the Spirit of the living God, not in tables of stone, but in fleshly tables
of the heart.” And though it should be allowed that the word Dunamis
(as his Lordship observes, page 30th) “in its ordinary sense in the
New Testament, must signify the power exerted in miraculous
operations:” yet how is it foreign to the Apostle’s purpose to interpret
it also of a divine power or energy, which ordinarily attended the
word preached by him; I mean such a power as accompanied the
word when the Lord opened the heart of Lydia, and when so many
were pricked to the heart, and made to cry out, “Men and brethren,
what shall we do to be saved?” Does not the word Dunamis seem to
carry this sense with it, 2 Corinthians iv. 7.? “But we have this
treasure in earthen vessels, that the excellency of the power
(Dunameos) may be of God, and not of men.” And is not Apollos
said to be (Dunatos engraphais) mighty, or powerful, in the
scriptures, though we do not hear that he performed any miracles at
all? And though his Lordship is pleased to say, page ibid. “For by this
power of God here spoken of, that it is a power to work miracles
appears expresly,” from the immediately following verse, in which is
assigned the reason for using this method of proving christianity to
be true, “that your faith should not stand in the wisdom of men, but in
the power of God:” yet will it not equally hold good, that their faith
stood not in the wisdom of men, but in the power of God? If by the
power we understand a divine power attending the word preached in
convincing the conscience, and changing the hearts of men,
exclusive or besides a power of working miracles.

His Lordship in the same page proceeds thus. “By the power of
God therefore must necessarily be understood the miraculous
operations performed by Jesus Christ and his Apostles, as a divine
testimony of their authority.” He goes on in the 7th, 10th, and
following verses, to explain this “demonstration of the Spirit and of
power;” and tells us, “That this wisdom of God is a mystery, or
wisdom formerly hidden from the world, which was couched in the
types and prophecies of the Messiah in the Old Testament, under the
title of the Law of Moses, the Psalms, and all the prophets that were
actually fulfilled in Jesus Christ. For, says he, ‘the Spirit searcheth
all things, even the deep things of God. Now we have not received
the spirit of the world, (viz. of oratory and philosophy) but the spirit
which is of God, that we might know the things that are freely given
to us of God.’ That is, that we might learn of the Spirit the true
meaning of those writings which he dictated himself, and which none
but the Spirit of God could know, since the gospel is the contrivance
of God alone for man’s salvation; and the benefits of it are freely and
of his mere grace conferred upon us.”
 But in all these passages, where is there a shadow of a proof,
that by the word power, the Apostle meant only that he worked
miracles among them? Is there any such thing so much as hinted at
in those verses? Or what greater reason is there to infer from hence,
that the demonstration of the Spirit means no more than proving
Christ to be the Messiah, from the books of the Old Testament?

His Lordship goes on, page 31st, to comment upon the 13th
verse of the 1st Corinthians 2d. thus: “The apostle adds, ‘Which
things also we speak not in the words which man’s wisdom teacheth,
(viz. as before by oratory and philosophy) but which the Holy Ghost
teacheth; comparing spiritual things with spiritual.’ From which last
passage it appears that the words which the Holy Ghost is said to
teach, must be prophetical revelations made of Jesus Christ in the
Old Testament, which were clearly discovered to the Apostles, and
explained by them to the world by the same Holy Spirit, that perfectly
knew those deep or mysterious things of God in the holy scriptures,
which related to and were fulfilled in Jesus Christ; and whose
expositions of his doctrine were authorized by the miracles they
wrought in confirmation of it.”

But supposing this be in part true, have not the words a further
meaning? And by “Words which the Holy Ghost teacheth,” may we
not understand, words which the Holy Ghost did immediately put into
this and other Apostles minds whilst they were preaching, speaking,
or writing? Was there not such assistance promised to the Apostles?
Did they not speak as the Spirit gave them utterance? And since
Jesus Christ has promised in an especial manner to be with his
ministers, even to the end of the world, may they not humbly claim
the divine influence to assist them in a degree in preaching now, as
well as formerly, by bringing to their remembrance the words and
things he had taught them in the holy scriptures before, and so
opening a door of utterance to them, without being, for so doing,
justly stiled modern enthusiasts.

His Lordship, in order to give a sanction to these his several

interpretations, quotes Chrysostom, Origen, and Athanasius: but
does his Lordship deal candidly or simply in this matter? For though
they may in some respects agree with his Lordship’s literal
interpretation, do they not give a spiritual one also? Does not his
Lordship himself, page 42d, citing the authority of Athanasius, that
great light of the christian church, in effect confess this? Does he not
say, that he interprets the unction of the Holy One not merely of
divine grace? But does it therefore follow that he did not interpret it at
all of divine grace? Nay, does it not follow, that he did interpret it of
the divine grace of the Spirit of God dwelling in all believers, as well
at least as of the miraculous gifts of the Spirit? Does not Ignatius,
one of the most early writers, stile himself Theophoros, and the
people to whom he writes Theophoroi? And can it be supposed, that
Origen in particular, (who his Lordship professes again and again, in
his treatises against Woolston, to be such a spiritual interpreter of
scripture,) has in these passages so tenaciously cleaved to the literal
interpretation, as utterly to deny the indwelling and inward witness of
the Spirit? Is not this entirely opposite to the whole tenor of his
writings, as well as the writings of the most ancient fathers? And has
not his Lordship, out of his great zeal against enthusiasm, by writing
thus, unwarily run into an extreme? And as he justly charged the
infamous Woolston with sticking too close to the spirit, and not
minding the letter, has he not in this performance so closely adhered
to the letter, and so sadly neglected the spirit, as almost totally (if his
interpretations be true) to exclude the Holy Ghost in his operations,
since the primitive times, out of the christian world?

Is not this matter of fact? Are not these words of truth and
soberness? Be not angry therefore, but bear with me a little, if like
Elihu, “I speak that I may refresh myself. For behold my belly is as
wine which hath no vent, it is ready to burst like new bottles.” Let his
Lordship write what he pleases to the contrary, “there is a Spirit in
man, and a holy Spirit in believers, and an ordinary inspiration of the
Almighty, which now, as well as formerly, giveth them spiritual
understanding.” But supposing it was not so, and all his Lordship’s
glosses upon the forementioned passages, were as right as in my
opinion they are wrong, could you, Reverend Brethren, (I appeal to
your consciences) in your own hearts even wish that they were so? If
you should answer, Yes, (as your requesting his Lordship to print this
charge, gives me too great reason to think you would,) “Tell in it not
in Gath, publish it not in the streets of Ascalon, lest the daughters of
the Philistines rejoice, lest the daughters of the uncircumcised
triumph.” For if this be the case, in what a poor benighted condition
has the Lord Jesus left his church in these last days? And what
avails it to have his doctrines and divine mission evinced formerly by
gifts and miracles, if we are deprived of the inward teachings and
indwelling of the Holy Spirit? It is true, his Lordship does talk here
and there of the Blessed Spirit, and of his ordinary influences: but
what are his ordinary operations, if he is neither to dwell in us, nor to
give us an inward testimony in our hearts, that we are born of God?
What signifies talking of his assistances, and at the same time
declare, that they can neither be inwardly felt, or perceived, nor
believers be supernaturally assured thereby of their salvation? Or if
we are to expect no operations of the Spirit that are supernatural, as
his Lordship again and again intimates, what are the natural
operations that we are to look for? Or can there possibly be any
operation of the Holy Spirit which is not supernatural? What can
deists and the whole tribe of unbelievers wish for more than such
doctrine? Does not his Lordship, by writing thus, greatly hurt the
cause he would defend; and out of a zeal to prove christianity no
enthusiasm, unwittingly run into that fault which he would throw upon
these against whom his charge is levelled, page 2d; I mean, “does
he not act in concert with infidelity against our established religion,
our great common salvation?” How must the church of Rome also
glory in such a charge? Is it not after their own heart? Is not the
denying the witness of the Spirit in believers hearts, one of the main
pillars of Popery? Are not papists kept in slavery, and taught to trust
to the absolution of their priest; because it was one of the
determinations of the council of Trent, that none can here below
attain from the Spirit a certainty of their being finally saved? His
Lordship has done well in signalizing himself by writing against the
papists and infidels. But what will it avail, or how can his Lordship
flatter himself that the efforts of the latter, page 2d, “have been
sufficiently opposed:” since by writing against the witness of the
Spirit, he so nearly symbolizes with the one, and by crying down all
supernatural operations of the Holy Ghost, joins hands with the
other? Besides, “If there are no proofs of the truth of our religion by
the inward testimony of the Spirit, as his Lordship affirms, page 52d.
or even by the infallible application of the several marks of truth in it
by the Holy Spirit, to the minds of men, and his making so strong and
violent an impression on them, as to form (horresco referens) a new
unintelligible sort of divine faith, page 53.” how shall we distinguish
true and divine faith, from that which is false and barely historical?
Are not the devils capable of such a faith? Nay, have they not as real
faith as christians themselves, if there be no other faith but what is
wrought by external revelation and outward miracles? Do they not
thus believe and tremble? And can it be supposed, that all the
miracles that the Apostles wrought, and the glorious sermons that
they were enabled to preach, were only to shew people what
communion they were to be of? Is not this bringing the gospel down
to a mere history, which one may read of the exploits of an
Alexander; and making faith to be a bare assent of the
understanding, which a person may have, and yet be no more
benefited by the death of Christ, than Simon Magus was in
believing that he was crucified?

But further; supposing his Lordship had shewn, that every one of
those passages he has commented upon, had been misapplied by
modern enthusiasts; yet are there not besides a great cloud of
witnesses to be fetched from the lively oracles, to prove that the
indwelling, and inward witness of the Spirit, are the privileges of all
believers? Will you permit me to instance only in a few? What think
you of that passage in St. John’s gospel, chapter vii. 37, 38, 39. “In
the last day, that great day of the feast, Jesus stood up and cried,
saying, If any man thirst, let him come unto me and drink. He that
believeth on me, as the scripture hath spoken, out of his belly shall
flow rivers of living waters. But this spake he of the Spirit, which they
that believe on him should receive?” How, I pray you, are we to
understand that petition of our Lord for his disciples, just before his
passion, in the same evangelist, chapter xvii. 20, 21. “Neither pray I
for these alone, but for them also which shall believe on me through
their word: that they all may be one, as thou, Father, art in me, and I
in thee; that they also may be one:” And again, verses 22, 23. “That
they all may be one, even as we are one, I in them, and thou in me,
that they may be made perfect in one?” How would you explain that
question of the Apostle’s to the Corinthians, (a church famous for its
gifts above any church under heaven) “Know ye not that Christ is in
you, unless you be reprobates?” How do you explain that assertion
of the evangelist John, in his 1st epistle v. 10. “He that believeth hath
the witness in himself?” Or that of the Apostle Paul to the Ephesians,
chapter i. 13, 19. And again, chapter iv. 30? How do you interpret
that passage, 2 Corinthians xvi. 16? Or what say you to that
exhortation of St. Jude, verse 20. “But ye, beloved, building up
yourselves in your most holy faith, praying in the Holy Ghost, keep
yourselves in the love of God?” Can any of these passages, with
any manner of consistency, be interpreted of the miraculous gifts of
the Holy Ghost, or be confined to the primitive church? Do they not
speak of an indwelling witnessing spirit, which all believers in all
ages have a right to expect, till time shall be no more?

And now, my Reverend Brethren, if these things be so, may not

that question be very justly put to you, which our Lord on a like
occasion asked Nicodemus, a ruler of the Jews: “Are ye masters of
Israel? Are ye ministers of the Church of England, and know not
these things?” What has his Lordship been doing so many years, in
professing to confer the Holy Ghost by imposition of hands on so
many ministers, saying unto them, “Receive the Holy Ghost by
imposition of our hands,” if there are none of those assistances from
the Blessed Spirit to be expected now, which were conferred when
our Saviour first spoke these words to his disciples? How can his
Lordship in conscience make use of the ordination office? Or how
could you, before many witnesses, publicly confess that you were
inwardly moved by the Holy Ghost to take upon you the
administration of the church? when you openly deny him in his most
powerful, and as to believers, in his common operations. Should you
not tremble to think, how much this looks like belying the Holy Ghost,
and acting the dreadful crime of Ananias and Sapphira over again, or
lying not only unto man, but unto God? And why are you so zealous
for the church, and continually crying out, “The temple of the Lord,
the temple of the Lord,” and yet trample her offices, collects and
articles in effect under your feet? With what consistency can you use
the baptismal office, and ♦ solemnly say unto God, “We yield thee
hearty thanks, most merciful Father, that it hath pleased thee to
regenerate this infant with thy Holy Spirit,” and yet agree with his
Lordship, page 61, in asserting, “to that ♠ federal rite of baptism is
annexed the preventing or preparatory grace of God, as is likewise
(on a due improvement) that of the assisting kind?” Is this all that is
implied in the baptismal office? And is regeneration no more than
this? What a miserable condition then are those in, who have only
their baptismal regeneration to depend on? For who is there that has
improved, nay who is there that has not sinned away this preparatory
grace? Is not this directly contrary to the whole baptismal office? And
are not those to be reckoned friends to mankind, who bid them look
for a better regeneration than this amounts to? Again, with what
propriety can his Lordship, in the office of confirmation, pray unto
God to give the persons to be confirmed “the Spirit of wisdom and
♣understanding, the Spirit of counsel and ghostly strength?” Or how
can ministers in general, in the collect for Whit-sunday, say, “Grant
us by the same Spirit to have a right judgment in all things, and
evermore to rejoice in his holy comforts?” Why are the passages,
wherein these blessings are promised to the first Apostles, appointed
to be read at this festival, if we are not in our degree to expect the
same mercies? And if these things are not to be inwardly felt, and we
are not to be supernaturally assured of our salvation, wherefore do
you make use of those words in the visitation of the sick? “The
Almighty Lord, who is a most strong tower to all them that put their
trust in him, to whom all things in heaven, in earth, and under the
earth, do bow and obey, be now and evermore thy defence, and
make thee know and feel, that there is none other name under
heaven given to man, in whom and through whom thou mayest
receive health and salvation, but only the name of our Lord Jesus
Christ:” Or with what propriety can you subscribe to the 17th article,
wherein we are told, “That the godly consideration of predestination,
and our election in Christ, is full of sweet, pleasant, and
unspeakable comfort to godly persons, and such as feel in
themselves the working of the Spirit of Christ?” And if there be no
such thing as inspiration at all, how can you, consistent with your
principles, use the church collect before the communion office, and
pray “Almighty God to cleanse the thoughts of our hearts by the
inspiration of his Holy Spirit?” Or how can you agree with the 13th
article, which affirms, “That works done before the grace of Christ,
and the inspiration of the Spirit, are not pleasant to God?” Are not all
these things against you? Do they not all concur to prove, that you
are the betrayers of that church which you would pretend to defend?
Alas, what strangers must you be to a life hid with Christ in God,
and the blessed fruits of the Spirit, such as love, joy, peace, long-
suffering, gentleness, goodness, faith, meekness, temperance; when
you know of no other first-fruits of the Spirit, than the miraculous gifts
of the Holy Ghost conferred on some particular persons in the
primitive church, which a man might have, so as to prophesy and
cast out devils in the name of Christ, and yet be commanded to
depart from him in the last day? How miserable must the
congregations be, of which you are made overseers? And how little
of the divine presence must you have felt in your administrations,
that utterly deny the spirit of prayer, and the Spirit’s helping you to
preach with power, and consider them as things that have long since
ceased? Is not this the reason why you preach as did the scribes,
and not with any divine pathos and authority, and see so little good
effect of your sermons? Have not your principles a direct tendency to
lull poor souls asleep? For if they are not to look for the supernatural
operations of the Spirit of God, or any inward feeling or perceptions
of this Spirit, may not all that are baptized, and not notoriously
wicked, flatter themselves that they are christians indeed? But is not
this the very quintessence of Pharisaism? Is not this the dark,
benighted state the great Apostle of the Gentiles confesses he was
in, before he was experimentally acquainted with Christ, or knew or
felt the power of his resurrection? Is not this a prophesying falsely, to
say unto people, “Peace, peace,” when there is no true solid
scriptural ground for peace? And are not you then properly the
persons his Lordship speaks of, page 1st, as “betraying whole
multitudes into an unreasonable presumption of their salvation?” For
is it not the highest presumption, for any to hope to be saved without
the indwelling of the Spirit, since the Apostle declares, in the most
awful manner, “If any man have not the Spirit of Christ, he is none
of his?” Is it not high time for somebody to rouze the sleepy world out
of this state, though it should cost them some melancholy thoughts?
May they not justly despond and despair too of being saved in such
a condition? For how can they possibly be good christians, or indeed
christians at all, unless they some time or other feel the Spirit of God
in their hearts? Or how can any justly be stiled enthusiastical
pretenders to immediate inspiration and new revelation, page 3d,
who only claim what is promised in the will of God already revealed,
and exhort all to add diligence to make their calling and election
sure? And why should that great man of God, Dr. Owen, be so
particularly mentioned by his Lordship, page 15th? Has there a more
solid critical learned divine appeared for many ages in the christian
world? Being dead, doth he not yet speak? Do not his works praise
him? Or supposing he was an enthusiast, as his Lordship calls him,
how can he be a modern one? Has he not been dead now above
fifty years? And why is he mentioned with an &c.? Would his
Lordship have us understand Dr. Goodwin, Mr. Baxter, and writers of
the Puritan stamp? But in reproaching them, does not his Lordship
equally brand Archbishop Usher, Bishop Hall, Bishop Davenant,
Bishop Hopkins, and others, nay all the godly reformers and martyrs,
and the compilers of our articles, homilies, and liturgy also? Were
they not equally enthusiastical with those, which his Lordship in this
charge would condemn; and may I not therefore say, if they were
enthusiasts, would to God you were not only almost, but altogether
such as they were? Has not his Lordship undesignedly put an
honour upon the Methodists, by joining them in such company?
Might not his Lordship easily foresee, that such a procedure as this,
would rather increase than diminish the progress of Methodism,
which his Lordship seems to have unwittingly prophesied of three
years ago, when this charge was first delivered? See margin of page
60. For what in an human way can have a more natural tendency to
strengthen the Methodists hands, than their having a public occasion
to shew, that they preach up the great doctrines of the reformation,
and are thrust out of the synagogues for no other reason, than
because they preach articles of faith, to which they have subscribed,
as the expression is in the literal and grammatical sense?
 ♦ “solemny” replaced with “solemnly”

♠ “fedral” replaced with “federal”

♣ “undestanding” replaced with “understanding”

O my reverend brethren, my heart is in pain for you: indeed I

could weep over you. Surely you are not all of his Lordship’s mind.
And yet the title-page of this Charge seems at least to imply, that it
was printed at the request of the generality of you. O be not angry if I
entreat you, if there be any consolation in Christ, or fellowship of
the Spirit, to think of these things, and lay them to heart. Remember,
I beseech you, remember the good confession you made before
many witnesses, when you professed that you were inwardly moved
by the Holy Ghost to take upon you the administration of the church.
And consider with yourselves, what a horrid prevarication it must be
in the sight of God and man, to subscribe to articles in the literal and
grammatical sense, which you do not believe? Reflect on what is
spoken by the Prophet, “They have run, and I have not sent them,
therefore shall they not profit this people at all.” Think what a
dreadful thing it is to preach an unknown, an unfelt Christ; and how
awful it will be to have the blood of thousands required at your hands
at the great day? As you have received an apostolical commission,
labour after an apostolical spirit. And do not set yourselves to
oppose or run down his blessed operations in others, because you
do not feel them in yourselves. Beware of thus doing despite to the
Spirit of grace: and be not like the Pharisees, who “neither entered
into the kingdom of God themselves, and those that were entering in
they hindered.” Seek you after a righteousness which exceeds
theirs. Call to mind, I beseech you, that ye are the lights of the world.
If therefore that light which is in you be darkness, how great must
that darkness be? “Ye are the salt of the earth; but if the salt hath
lost its savour, wherewith shall it be salted? It is thenceforth good for
nothing, but to be cast out and to be trodden under foot of men.”
God seems now about to rise to shake terribly the earth. We hear of
wars and rumours of wars. O let your loins be girt, your lamps
trimmed, and be ye like unto servants that are waiting for the
bridegroom: that if he should come at the second or third watch, he
may find you so doing. Smite not your fellow-servants; but rather
take ye Gamaliel’s advice: “Refrain from these men, and let them
alone. For if this counsel or work be of men, it will come to nought;
but if it be of God, ye cannot overthrow it, lest haply ye be found to
fight against God.” The harvest is great, very great, and souls are
every where perishing for lack of knowledge. Why should the
labourers be so few? Think of that awful saying of the angel of the
Lord, “Curse ye Meroz, curse ye bitterly the inhabitants thereof,
because they came not to the help of the Lord, to the help of the
Lord against the mighty.” Shew that you love Christ above all
things, by feeding his lambs and his sheep; by being instant in
season and out of season. That so when the great Shepherd and
Bishop of souls shall appear, you may give up your accounts with
joy, and not with grief.

Suffer me also (as undoubtedly you requested his Lordship to

publish this charge for their instruction) to give a word of exhortation
to your Parishioners. You see, Sirs, that I have used great plainness
of speech in my remarks upon this charge of your Right Reverend
Diocesan. Do not without examination contradict and blaspheme, but
be noble, as the Bereans were, and “search the scriptures whether
these things be so or not: to the law, and to the testimony.” Let that
determine who are the seducers, who are the enthusiasts, and the
enemies to the Church; those who preach up the doctrine of
justification by faith alone in the imputed righteousness of Jesus
Christ, and the indwelling and witnessing of the Spirit; or those who
tell you, that they were the miraculous gifts of the Holy Ghost, and
not to be expected in these last days. Say not within yourselves, “We
have Jesus for our saviour, we have been born again in baptism, we
are members of the Church of England, we do nobody any harm, we
will do what we can, and Jesus Christ will do the rest;” but seek ye
after a better righteousness than your own, even that “righteousness
which is by faith;” and earnestly press after that indwelling of the
Spirit, and that true inward holiness and purity of heart, without which
no man living shall see the Lord. Get acquainted with the collects,
homilies, articles and old writers of that Church whereof you profess
yourselves members, and let not ignorance be the mother of your
devotion. Remember that “God is a spirit, and they that worship him
must worship him in spirit and in truth.” See that your zeal be
according to knowledge: and count not those to be troublers of
Israel, nor like the misguided Jews, irritated thereto by the high
priests, raise mobs against them, as turners of the world upside
down, who out of love to your souls, have put their lives in God’s
hands, and shew unto you the true way of eternal salvation. Place
not holiness in outward buildings, nor reject the gospel because
preached to you in the fields, in the streets and lanes of the city. See,
hear, and judge for yourselves, and beware lest that come upon you
which is spoken by a Prophet: “Behold, ye despisers, and wonder
and perish: for I work a work in your days, which a man shall not
believe, though one declare it unto him.”

As for those among you, who in derision are termed Methodists,

be you thankful to that God, who I trust has made you wise unto
everlasting salvation, and given you not only to believe on the Lord
Jesus, but also to suffer for his name. You have lately been enabled
joyfully to bear the spoiling of your goods ¹. Think it not strange, if you
should hereafter be called to resist unto blood. Fear not the faces of
men, neither be afraid of their revilings. Having believed on the Lord
Jesus, with your hearts, in spite of all opposition from men and
devils, make confession of him with your mouths unto eternal
salvation. Contend earnestly for the faith once delivered to the
saints, and sealed by the blood of your martyrs: at the same time,
“be ready to give a reason of the hope that is in you with meekness
and fear.” If you were of the world, the world would love its own; but
because you are not of the world, but the Lord Jesus hath chosen
and redeemed you out of the world, therefore the world hateth you.
Follow him therefore chearfully without the camp, bearing his
reproach. The more you are afflicted, the more you shall multiply and
grow. For verily no man hath lost houses or lands for Christ’s sake,
and the gospel, who shall not receive a hundred-fold in this life with
persecution, and in the world to come life everlasting. Persecution is
your privilege: it is a badge of your discipleship: it is every christians
lot in some degree or other. Only be ye careful to give no just
offence, either to Jew or Gentile, or the church of God. And as you
profess to have received the Holy Ghost in his sanctifying gifts and
graces, and to have the Spirit of God dwelling in you, be ye studious
to bring forth the fruits of the Spirit in your lives; that all who are
acquainted with you may take knowledge that you have been with
Jesus. Call no man master but Christ. Follow others only as they
are followers of him. Be fond of no name but that of Christian.
Beware of making parties, or calling down fire from heaven to
consume your adversaries. “Bless them that curse you, and pray for
them that despitefully use you.” Labour to shine in common life, by a
due conscientious discharge of all relative duties, and study to adorn
the gospel of our Lord in all things. If you are good christians, you
will fear God, and for his sake honour the King. Be thankful for the
many blessings you enjoy under the government of his present
Majesty King George, and continue to pray to Him, by whom kings
reign, and princes decree justice, to keep a popish Pretender from
ever sitting on the English throne. Be cloathed with humility: and
always count yourselves beginners in religion. Let it be your meat
and drink to do and suffer the will of your Master, and forgetting the
things which are behind, reach forward to the things which are
before, and never cease striving, till you are filled with all the fulness
of God. Determine to know nothing but Jesus, and him crucified.
Remember his agony and bloody sweat, his shameful cross and
passion. Chearfully pledge him in his bitter cup, and as he was, so
be ye in this world. Think of his last and new commandment, and
“love one another with a pure heart fervently;” looking and preparing
for that blessed hour, when he shall come and call you to sit down
with him at the marriage-feast in the realms of light and love, where
the wicked shall cease from troubling, and where your weary souls
shall be at rest.

¹ N. B. The Methodists in Staffordshire were mobbed the

Shrove-Tuesday before, and plundered of their substance
to the amount of seven hundred pounds sterling.
 Finally, I would drop a word to you, who have been lately called
out into the highways and hedges, and have been honoured as
instruments to compel many poor sinners to come in. Against you,
my brethren, his Lordship’s charge seems to be particularly levelled.
But I am persuaded you will be nothing terrified thereby, since you
know, I believe, by happy experience, what it is to have the hidden
mysteries of the kingdom of God opened to your souls, and to have
the Comforter come and abide with you. You have often felt his
blessed influences, whilst you have been praying to that God whom
you serve, dealing out the bread of life in his name to the people. Ye
are highly favoured. Having believed, ye speak, and in your degree
can say with our Saviour, “We speak the things that we know.” God,
who hath commanded the light to shine out of darkness, hath shone
into your hearts with the light of the glorious gospel. Put not therefore
this light under a bushel, but preach the word; “Be ye instant in
season and out of season; rebuke, reprove, exhort with all long-
suffering and doctrine. Do the office of evangelists, and make full
proof of your ministry.” And whilst others are calling for miracles from
you, to prove that you are sealed and sent by the Spirit, do you
labour after the conversion of precious souls as seals of your
mission, who shall be your joy and crown of rejoicing in the day of
the Lord Jesus. Whilst others are approving themselves ministers
of Christ, by dignities and great preferments, do you approve
yourselves as the ministers of God in much patience, &c. See 2
Corinthians vi. 4‒8. Set the glorious company of the Apostles, the
goodly fellowship of the Prophets, and the noble army of martyrs
always before you. O think how ♦abundant they were in labours, in
stripes above measure, in deaths oft, and how they rejoiced when
they were counted worthy to suffer shame for Jesus Christ’s sake.
Above all, look ye unto Jesus the author and finisher of your faith;
consider him who endured such contradiction of sinners against
himself, lest ye be weary and faint in your minds. Are you esteemed
mad? So was he. Are you termed deceivers of the people? So was
he. Are ye looked upon as actuated by an evil spirit? He was called
Beelzebub, the very chief of the devils. Are ye thrust out of the
synagogues? So was he. Do men hunt for your precious lives? So
they did for his. The Jews sought often to kill him, but they could not,
because his hour was not yet come: and so it shall be with you. You
are immortal till your work is done. The witnesses shall not be slain
till their testimony is finished. Set your faces therefore as flints: let
your brows be harder than adamant: fear not the faces of men, lest
God confound you before them. Give not place to those who oppose
the operations of the Spirit, no not for an hour. Go ye forth in the
strength of the Lord, making mention of his righteousness, and his
only. Remember that blessed promise, “Lo, I am with you always,
even to the end of the world.” Jesus is the same now as he was
yesterday. And if you are really thrust out into the harvest by Jesus,
he will give you a mouth and wisdom, which all your adversaries
shall not be able to resist. You see how dreadfully the scriptures are
interpreted. Give yourselves therefore to reading. Search the
scriptures. But above all things, pray that ye may be taught of God:
without which, notwithstanding all critical and human learning, you
will never be scribes well instructed to the kingdom of heaven.
Continue to go out into the highways and hedges. Consider what
multitudes there are around you every where, ready to perish for lack
of knowledge. And though your enemies, for want of arguments,
should so far prevail, as to bring you before governors for so doing,
fear not, for it shall be given you, as well as unto the first preachers
of the everlasting gospel, what ye shall speak. O men, greatly
beloved, my heart is enlarged towards you. Give me leave to say
unto you, as the angel did to Daniel, “Be strong,” yea be strong: quit
yourselves like men: put on the whole armour of God. And then,
though you should be cast into a den of lions, that God whom you
serve, is able, and will deliver you. Though afflicted, destitute,
tormented here on earth, verily great shall be your reward in heaven.

♦ “abundandant” replaced with “abundant”

And now, my reverend brethren, to whom this letter is particularly

inscribed, what shall I say more? I commend it, and you, to the great
God, and to the word of his grace, which is able to build you up, and
give you an inheritance among all them that are sanctified. I have
written to you out of the fulness of my heart; and praying that God