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Biokinetics of Technetium-99m-Tetrofosmin:
Myocardia! Perfusion Imaging Agent:
Implications for a One-Day Imaging Protocol
Diwakar Jam, Frans J.Th. Wackers, Jennifer Mattera, Michael McMahon, Albert J. Sinusas and Barry L. Zaret

Section of Cardiovascular Medicine, Department ofinternal Medicine and Cardiovascular Nuclear Imaging Laboratory,
Yale UniversitySchoolofMedicine, New Haven, Connecticut

known coronary artery disease (CAD) (1—4). Thallium-201

Tetrotosminis a @Fc-labeledmyocardialperfUSiOn imaging has been the traditional myocardial perfusion imaging
agentthat has shownencouragingresuftsin PhaseI and II agent since its clinical introduction in 1976. However, this
dinical tnals. The purpose of this study was to determine the agent has important physical limitations which include a
biokineticsof thisagentfollowingadministration duringexercise low energy emission and a relatively long half-life (73 Kr).
and at rest in order to determine an optimal imaging protocol. These factors result in significant soft-tissue attenuation
Twentypatientswithsuspectedcoronatyartetydiseaseunder and scatter, limitation of allowable dose and technical dif
wentsymptom-limited treadmillexercise.Sixto 8 mCIof °@Tc
tetrofosminwas injectedat peakexerciseand22-24 mCiwas ficulties with both planarand SPECT imaging.
injected4 hr later at rest. Serial 5-mmplanarimageswere To address these issues, @Tc-labeled agents have been
obtainedintheleftanteriorobl,queviewat5,10,15,30,60,120 developed and evaluated over the past 5 yr. Sestamibi
and 180mmafterthe radiotracerir@ection. Regkxisof interest (5—8)and teboroxime (9—11)have been approved for cm
were drawnon the senalimagesaroundthe entireheait and ical use. Sestamibi generally provides good quality images.
portionsof liver,lung,spleen,gallbladderand gastrointestinal However, a high initial hepatic sestamibi activity with rel
tract.Averagedecay-corrected countsper pixelin eachorgan ativehy slow clearance necessitates a delay of 0.5—2hr
were plottedagainsttime. In addftion,heart-to-adjacent organ before imaging can be started after injection (12). This
ratioswerealsodetermined.Onstressimages,thehearthadthe
increases the total time a patient is required to spend in the
highestactivityat all times,withthe exceptionof gallbladderin
thefirst 15 mm.On restimages,the gallbladder,liverandgas imaging laboratory and consequently impacts upon labora
trointestinaltractinitiallyhadhigheractivitythantheheart;butthe tory logistics. Moreover, in some cases residual high he
activityin these organsdeared rapidlyover the subsequent patic and gastrointestinal tract activity can make image
30-60 mm.Heart-to-adjacentorgan ratioswere>1.0atalltimes interpretation impossible. In contrast, teboroxime has a
in the stress images. Heart-to-organ ratios were <1 .0 in the first very short residence time in the myocardium and rapidly
15 mm on the rest images for the liver and gastrointestinal tract. washes out after initial uptake (9,10). There is a very nar
However,30 mmlater,all ratioson the restimageswere 1.0. row time window during which imaging should be corn
Technetiurn-99m-tetrofosmin imageswereconalderedto be of pleted and images are often of suboptimal quality (9). In
goodto excellentqualftywfthgoodmyocardialdelineationand addition, hepatic activity increases progressively within a
adequate contrast between the heart and background. These
few minutes after injection of@Tc-teboroxime which also
Theseobservationsindicatethata convenientone-daytetrofos
interferes with image interpretation.
mm imagingprotocolsimilarin durationto conventional@°ii
imagingis feasible. Tetrofosrnin (Myoviewtm) is a newly developed corn
poundofthe diphosphinegroup labeled with @‘@‘Tc (13—16).
J NucIMed1993;34:1254—1259 The chemical name of this compound is 1,2-bis [bis (2-
ethoxyethyl) phosphino] ethane. After intravenous admin
istration, this compound is rapidly cleared from the blood
and is taken up by the heart, skeletal muscle, liver, spleen
and kidneys in proportion to the blood flow (14—16). The
tress radionucide myocardial perfusion imaging is an biodistributionof this compound suggests its suitabilityfor
integral part of the clinical evaluation of suspected or use as a myocardial perfusion imaging agent. Once it is
taken up by the rnyocardium, there appears to be little, if
any, redistribution over the subsequent 3—4hr (17,18).
ReceivedDec.17,1992; revisionacceptedApr.14,1993.
Forcorrespondence MD,RobertW.BedinerProfessor Initial Phase I and II clinical studies indicate that
contact:BarryL Zaret@ @Tc
of Medidne,ChistSectionof CadovascularMechdne, 3 FMP,YaleUniversity tetrofosmin compares well to @°“fl as far as detection of
SchodofMed@ne, 333CedarSt, NewHavenCT06510.
Forreprintscon@: DiwalcarJwn,MD,Sectionof Cardevascular
Med@ine,3 CAD is concerned (16—17).
FMP,YaleUniversity Schoniof Med@ne, 333CedarSt.,NewHavenCT06510. The purpose ofthis study was to evaluate and define the

1254 TheJournalof NudearMedicine•

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biokinetics of @Tc-tetrofosminat rest and following ex

ercise. To achieve this goal, serial quantitative imaging was ImagingProtocol
performed in patients. Data generated in such a manner
can then be used to define an optimal timing for imaging 6-8 mCiof Tc-99m-TF
under varying physiologic circumstances with this agent. Ex.Ii'Il I I I I
0 5 10 15 30 60 120 180mm.

METhODS 4 hourslater
22-24mCIof Tc-99m-TF
Patient Population ReatII―II I I I I
The studypopulationconsistedof 20 patients(16 menand4 0 5 10 15 30 60 120 180mm.
women; mean ±s.d. age 55 ±12 yr), enteringa Phase III @Tc
tetrofosmin clinical trial who underwent additional serial imaging FIGURE1. Schematicrepresentation of the imagingprotocol.
following stress and rest injections of tetrofosmin (19). Thirteen Imagingwascommenced 5 mmafterbothstressandrest°@Tc
patients had symptomssuggestiveof CAD supportedby at least tetrofosmin
injectionsin theleftanteriorobliqueview.Eachimage
one or more ofthe following: (a) an abnormalexercise test defined wasa@uiredfor5 mm.
by chestpainwithreversibleST-segmentdepressionof >1.5 mm,
(b)evidenceof reversiblemyocardialischemiaon exercise @°‘T1
scintigraphy, (c) presence of 70%or greater occlusion of at least Cardiac ImagIng
one majorcoronaryvessel on coronaryangiographyperformed Patients received an intravenous injection of6—8mCi of@―Tc
within the last 6 mo. The remainingseven patients had atypical tetrofosminat peak exercise through an indweffingintravenous
chestpainsyndromebutwithnegativestress201'flimages. canula and were then encouraged to exercise for an additional 2
Three ofthe 20 patients had diabetes, 8 had hypertension, 9 had mm. Patients received a second injection of 22—24
mCi of ra
prior documented myocardial infarction. Six patients had under diotracerfor rest imaging4 hr later. Serialplanar cardiac imaging
gone priorpercutaneouscoronaryangioplasty,butnonehadUn was begun 5 mm after injection of the radiotracer (see Fig. 1).
dergoneprior coronaryartery bypassgrafting.Patientscontinued Imagingwas performedusingSiemensLEM or PickerCX 240
theirroutinemedicationduringthe test. Five patientswere re smallfieldof view gamma cameras, each equipped with a low
ceivingbeta blockers, 11were receivingcalciumchannelblock energy, all-purpose collimator. For the purpose of the analysis of
cr5, 6 were receiving long-actingnitrates, 8 were receiving diuret organbiokinetics,serialimageswere obtainedin the left anterior
ics and 4 patients were receiving no medications. obliqueview. The samegammacamerawas usedforobtaininga
complete set of serial images in all patients. The heart was posi
Radlopharmaceutlcal Preparation tionedinthecenterofthe fieldofview withoutzoom,so thatparts
Tetrofosminwas suppliedby MediphysicsAmershamHealth of the liver,gallbladder,spleen,gastrointestinaltractand lungs
care (Arlington Heights, IL) as freeze-dried vials, with each vial werealsoincludedinthefieldofview. Theimageswereobtained
containing 0.23 mg of tetrofosmin, 0.32 mg of disodium suipho at 5, 10, 15,30, 60, 120and 180mmafterbothexerciseandrest
salicylate, 0.03 mg stannous chloride dihydrate and 1.00mg of injections. Figure 1 is a schematic representation of the study
sodium D-gluconatesealed under an inert nitrogenatmosphere. protocol and imaging sequence. Each image was obtained for 5
Each vial was reconstituted at room temperature with 4-8 ml of mm. The angle of the camera and position of the cardiac activity
sterile @“Tc
as sodiumpertechnetatecontainingno more than 30 in the fieldofview were kept unchangedfor all the images. The 5-,
mCiof @Tc per ml. The vial was shakento ensureadequate 10-, 15-and 30-mmimages were obtained without moving the
mixing and then allowed to stand at room temperature for 15mm. patientfromthe imagingtable. In the intervalbetweenthe subse
Radiochemicalpurity was determinedby thin-layerchmmatogra quentimages, patientswere allowed to move from the table. They
phy and only preparationswith 90%labelingwere used. The were, however,carefullyrepositionedpriorto imaging.In addi
preparation was stored at room temperature and was used within tion, standard anterior and left lateral views were also acquired in
8 hr of labeling. theintervalbetween15-60mmafterinjectionof the radiotracer,
Study Protocol both followingexerciseand at rest. This providedimagesfor the
This study was designedas a one-day @Tc-tetrofosmin imag analysis of three standardplanar views employed for diagnostic
ingprotocol.Exerciseimagingwas performedfirst,followedby interpretation.Images were stored on magneticdisc for subse
rest imaging4 hr later utilizinga second injectionof the radio quentanalysis.
pharmaceutical(see Fig. 1). The study was approved by the Hu
man Investigation Committee of Yale University School of Med Image Analysis
icine. The imageswere transferredto a PickerPCS 512 computer
using a common format and were displayed on the computer
Exercise Testing screen. Regionsof interest (ROIs)were manuallydrawn around
Patients underwent a symptom-limited treadmill exercise test the entireheart,liver, spleen,gallbladder,gastrointestinaltract
with continuous 12-lead ECG monitoring. Exercise was con and lungs (Fig. 2). The counts per pixel in each organwere
ductedin the morningeitherin the fastingconditionor at least2 determinedin the serialimagesand wereplottedagainsttimeafter
hr after a light breakfast. Exercise was terminated by the appear decaycorrectioninorderto definetheaveragetime-activitycurve
ance of limiting symptoms of angina, dyspnea or fatigue, or if over each organ.In addition,smallROl (3-S pixel wide) were
therewas a dropin bloodpressureor appearanceof significant drawn over the left ventricular myocardium and contiguous parts
arrhythmia, or if maximumage-relatedheart rate was achieved. ofthe liver,lung,spleenandgastrointestinal
tractto determinethe
Standard American Heart Association safety recommendations ratio of average pixel activity between the myocardium and the
for exercisetestingwerefollowed(20). surroundingorgans [i.e., heart to liver, heart to lung, heart to

Tetrotosmmn
BiOkineticS
•
Jamet al. 1255
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@ +@ @—
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Ave Cts

A83
B 101
C 82
D 78
E 51
@‘c@;@ F 119
Tim. (mm.) TIm•(mm.)

FIGURE 4. Mean(±s.d.) decay-correctedorgan actMtiesover

timefollowingir@eCtiOn
of @Tc-tetrofosmin
at peakexerciseandat
rest.MeanorganactivityisnOrmaliZed
toactivityintheheartat5 mm
FIGURE2. ROlsontheleftanterior obliqueviewforassessment postirijection.Fordarity, s.d. barsare only indicatedfor 5-, 15-,60-,
of organ biokinetics.Reg@ns:heat (A), liver (B), gaStrointeStinal 120-and180-mm valuesintheleftventricle(LV)andliver.
tract (C),spleen(D), left lung (E) and gallbladder(F).
shown in Figure 4. It is apparentthat in the stress images,
gastrointestinal tract and heart to spleen ratios (Fig. 3)]. All im
the heart has the highest activity of all organs at all times
ages were also examined visually to assess overall image quality (except the gallbladder in the images acquired during the
and relativeactivitiesin the heartand surroundingorgans.In first 15 min). In comparison, in the rest images, the liver,
addition, the three standardplanarviews were analyzed visually
and quantitativelyfor evidenceof regionalmyocardialperfusion gastrointestinal tract as well as gallbladder initially have
abnormalities (4). higheractivity than the heart. However, tetrofosmin clears
rapidly from the liver, gallbladder and gastrointestinal
Data Analysis tract. At 60 mm after injection, the heart has higher activity
The decay-correctedaveragepixel activityover the different than the remainingorgans. Figure 5 shows the stress and
organs was plotted againsttime. The average activity in the heart redistribution201'fland stress and rest @Tc-tetrofosmin
intheinitial5-mmimagewasarbitrarily assigneda valueof 100% images of a patient with atypical chest pain. Myocardial
andthe activitiesintheheartandotherorgansovertimewereall
expressedrelativeto this maximum.All valuesareexpressedas perfusion is normal with both imaging agents. Stress and
mean ±s.d. rest @Tc-tetrofosmin images were acquired 15 and 30
mm, respectively,after injectionof the radiotracer. There
RESULTS is excellent myocardial delineation with minimal back
ground activity.
All 20 patients in the study group had good quality im Table 1 shows the heart-to-organratios at various time
ages suitable for clinical interpretation, as well as for anal intervals following the stress and rest injections of @Tc
ysis of kinetics. Specifically, there was no interpretative tetrofosmin. Again, the ratio is >1.0 for all organs at all
problem due to subdiaphragmaticuptake in any of the times after the stress injection. For rest images, it is <1.0
patients. Visual analysis of three-view planar stress and for the liver and gastrointestinal tract in the 5-, 10- and
rest @Tc-tetrofosmin images showed reversible ischemia
in 12 patients, a fixed defect in 1 and were normal in the
remaining 7. The average organ activity of @‘@‘Fc-tetrofos
mm over time followingexercise and rest injections are

EM SI@

FIGURE 5. Leftanterioroblique(LAO),leftlateral(Li) and ante

r@r(ANT) @rc-tetrofosmmnstress and rest images and corre
sponding201flstr@ and redistribution imagesin a patientwith
FiGURE3. ROlsontheleftanterioro@ue viawforassessment atypicalchest pain. Both sets of imagesshow normalmyocardiai
of heart-to-ac@acent
organratios.Regions:leftventricularmyocar perfusion.Note the excellentimage quality and low extra cardiac
dium(A),liver(B),gut(C),spleen(D)andleftlung(E). activityof the @Tc-tetrofosminimages.

1256 The Journal of Nuclear Medicine •

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TABLE 1
Ratios Between TetrofosmmnActMty in the Left VentricularMyocardium (H) and Adjacent Organs at Vanous Time Intervals
Following Injectionat Stress and at Rest (Values are expressed as mean ±s.d.)
StressRestH-to

Spleen5mm UverH-to LungH-to-GlH-to SpleenH-to UverH-to LungH-to-GlH-to

10mm 12±0.3 1.9±0.3 1.3±0.3 1.5±0.4 0.7±0.2 1.9±0.2 0.9±0.2 12±0.3

15mm 1.2±0.3 1.9±0.3 1.4±0.4 1.6±0.4 0.7±0.1 1.9±0.2 0.9±0.2 1.2±0.3
30mm 1.4±0.3 2.2±0.5 1.4±0.3 1.9±0.5 1.0±0.2 2.0±0.4 1.3±0.3 1.8±0.4
60mm 1.6±0.4 2.1 ±0.4 1.3±0.3 1.9±0.5 1.3±0.4 2.1 ±0.3 1.5±0.3 1.9±0.4
120mm 1.8±0.4 2.2±0.3 1.4±0.3 2.0±0.6 1.7±0.3 2.1 ±0.3 1.6±0.3 2.0±0.5
2.0±0.41.9±0.3
180mm1.3±0.4 2.1 ±0.31.3±0.3
1.5±0.41.5±0.4 2.1 ±0.41.8±0.2
2.0±0.60.8±0.2 2.1 ±0.40.9±0.2
1.7±0.412±0.3
2.1 ±0.6

15-mm images. In the subsequent images, however, it is heart in the initial images. Nevertheless, activity in the
1.0.For the remainingorgans,it is >1.0 in allimages. liver and gastrointestinaltract clear rapidly, and as early as
Figure 6 shows serial images of a patient with partially 30—45mm after injection it is lower than that in the heart.
reversible perfusion abnormality involving the interven The gallbladderagain accumulates considerably higher ac
tncular septum and apex. The stress images show an ex tivity than the heart, but the activity also clears rapidly.
cellent visualization of the myocardium with low back Serial count density ratios between the heart and adjacent
ground activity. The rest images show significant tracer organs are consistent with the above pattern (Table I).
activity in the liver, gastrointestinal tract and spleen in the These observations on organ kinetics indicate that im
5-mm image. However, there is rapid clearanceof the agingcan be started as soon as 5 mm after injection during
hepatic and splenic activity in the 10-, 15- and 30-mm exercise. For rest imaging, a delay of 30 mm after tracer
images. injection allows adequate hepatic clearance in most pa
tients. However, a delay of 45 mm may be required in a
DISCUSSION small percentage ofpatients. Thus, it is possible to perform
This study indicates that tetrofosmin, a both stress and rest imaging on the same day within a
@‘Fc-labeled
agent, has biokinetics suitable for clinical use as a myocar 4.5-5-Kr time period.
dial perfusion imaging agent. The hepatic uptake is accept For optimal nuclear imaging of an organ, not only is
ably low, even at rest. Following injectionat peak exercise, adequate tracer uptake in that organ required, but also a
hepatic activity is lower than heartactivity as soon as 5 mm relatively low uptake in adjacent organs. High tracer up
postinjection. Moreover, hepatic activity declines further take by the adjacent organs results in scattering and
over time. The gallbladderhas slightly higheractivity than crosstalk of the radiation to the target organ, which makes
the heart in the first 15 mm. However, the gallbladder is not it difficult to clearly delineate the margins of the target
immediately adjacent to the heart and does not interfere organ. From an imaging point of view, an ideal myocardial
with myocardial perfusion interpretation. In comparison, perfusion imaging agent should have the following charac
following the injection of @‘@‘Tc-Tetrofosmin
at rest, the teristics:
liver and gastrointestinaltract have higheractivity than the 1. High first-pass myocardial extraction that is propor
tional to myocardial blood flow.
At7 serialT4TOfOSmIn
mmags@n
LAOV@w 2. A high target-to-background ratio which can be
achieved by relatively low uptake and rapid clearance
from the contiguous organs, particularlythe liver.
3. An adequate time window for obtaining images of the
heart following radiotracer administration.
4. Completionof the entire stress and rest imagingon
the same day in as little time as possible.
The development of@―Fc-Iabeled agents for myocardial
perfusion imaging is a significant advance over 201'flimag
FIGURE6. Serialimagesintheleftantedorobliqueviawfollow ing. To date, three different categories of @Tc-labeled
ing exercise and rest injections of@Tc-tetrofosmin in a patient with agents have been developed for myocardial perfusion
partiallyreversibleseptal and apical perfusionabnormality.Each imaging: (a) cationic isonitriles; (b) boronic acid adducts;
imagewas obtainedfor 5 mm. Notethe low subdiaphragmaticac (c) diphosphines. However, the biokinetics, initial organ
tivityaseMy as5 mmaftertheexerciseir@edtiOn.
Following
therest
injection,the first image shows significanthepaticactivity,which distribution and clearance, as well as the mechanism of
rapkllydears and concentratesin the gal@der. By 30 mm,most myocellular uptake and clearance for agents from each
ofthesubdiaphragmatic
activityhascleared. group are quite different from each other as well as from

TetrofosminBiOkineticS
•
Jamet al. I 257
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2OI'@ These marked differences necessitate unique imaging with appropriate quantities of @Tc,without the need for
protocols for agents from each group. boiling. The present study performed stress imaging first
Of the cationic isonitriles,tertiary-butylisomtrile(TB!) using a smaller dose, followed by rest imaging 4 hr later
(21) and carbomethoxyisopropyl isonitrile (CPI) (22) were using a larger dose. Further studies are needed to see if it
two of the early isonitrile compounds tested in humans. is possible to reduce the interval between the two imaging
They were soon abandoned because of unsatisfactory periods to even less than 4 hr without affecting image
myocardial-to-background ratios. Sestamibi is the cur quality. In addition, it is worth considering performingrest
rently used agent from this group and has been found to imaging first using a small dose, followed immediately
provide good quality images (5—7,12). However, there is thereafter by exercise imaging using a higher dose. More
significant hepatic radiotracer uptake, which is cleared over, further studies are required to investigate the mech
rather slowly over time. This slow hepatic clearance ne anism(s) of tetrofosmin myocellular uptake, the exact site
cessitates a delay of 1—2hr after tracer injection prior to of myocyte localization, its potential for assessing myocar
imaging. This significantly increases the time a patient is dial viability and the biokinetics following pharmacological
required to spend in the imaging laboratory. Since two stress with dipyridamole, adenosine or dobutamine.
separate injections are required for stress and rest images,
it is difficult to obtain satisfactory image sets on the same CONCLUSION
day. The initial studies with this agent were carried out This study indicates that @Tc-tetrofosminmay be an
using two-day protocols where stress and rest imaging additional significant advance in myocardial perfusion im
were carried out on two consecutive days. However, from aging. Tracer organ biokinetics allow imaging to be started
a practical and logistic standpoint, this is inconvenient for as soon as 5 mm after injection during exercise and 30—45
the majority of referralpatients. mm after injectionat rest. This allows a more convenient
A number of strategies have been proposed for same imaging protocol, which is similar in duration to that with
day imaging (6,23—25). Initial rest imaging using a smaller 20111.
dose (7—10mCi) followed by stress imaging using a larger
dose (25—30 mCi) or vice versa have been evaluated in ACKNOWLEDGMENTS
relatively small series ofpatients (6,24). Computersubtrac The authors thank Mark Saaii, CNMT, Donna Natalie,
tion techniques have also been proposed for same-day CNMT, Ed Levine, CNMT and Michael White, CNMT for tech
protocols (23). However, this does not seem to be a widely nical assistance. Supported by a grant from Mediphysics Amer
applicable approach. Combined use of 20―fl and @Tc sham Healthcare, Arlington Heights, IL.
sestamibi has also been advocated to complete rest and
stress imaging on the same day. In this technique, 201'flis REFERENCES
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Biokinetics of Technetium-99m-Tetrofosmin: Myocardial Perfusion Imaging Agent:

Implications for a One-Day Imaging Protocol
Diwakar Jain, Frans J.Th. Wackers, Jennifer Mattera, Michael McMahon, Albert J. Sinusas and Barry L. Zaret

J Nucl Med. 1993;34:1254-1259.

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