Drug Discovery Today

Volume 28, Issue 3, March 2023, 103485

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Rapid progress in neuroimaging technologies fuels central nervous system

translational medicine
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Linghui Kong 1, Qian He 1, Qiu Li 2, Rudy Schreiber 3, Kenneth I. Kaitin 4, Liming Shao 1 2 5

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https://doi.org/10.1016/j.drudis.2023.103485
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Central nervous system (CNS) drug discovery suffers from high attrition rates; translational neuroscience approaches aiming to reduce these high
rates include the use of brain imaging technologies. However, there is a need to better understand what methods are being used and for what diseases
and purposes. Our analysis of the literature found that magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon
emission computed tomography (SPECT) were the neuroimaging techniques used most often in clinical trials for the most prevalent CNS diseases:
Alzheimer’s disease (AD), Parkinson’s disease (PD), depression, and schizophrenia. Moreover, the number of initiated clinical trials using MRI, PET, and
SPECT increased over the period 1981–2021. Such insights indicate that the significant increase in the use of neuroimaging studies could decrease the
attrition of novel drug candidates in late clinical development.

Introduction
The past few decades have witnessed rapid advances in neuroimaging technologies in terms of equipment, methodologies, and the development of
radioligands. Neuroimaging modalities, particularly MRI, PET, and SPECT, are used routinely in most medical institutions and research centers and
have helped to improve our understanding of the neuropathology of various CNS diseases, as well as to aid the selection of appropriate treatments.
The roles of neuroimaging studies in CNS disease clinical research include, but are not limited to, aiding the diagnosis and prevention of disease, as
well as the development of newer, improved therapeutics.

Neuroimaging can optimize CNS drug discovery by providing a key metric that can increase confidence in early decision-making, thereby improving
success rates and reducing risk, development times, and costs [1], [2]. It can help address several challenges contributed to the high attrition rates for
CNS drugs, including difficulties in developing preclinical models and assessing target engagement, the penetration limitation of the blood–brain
barrier, limited understanding of the pathophysiology involved, heterogeneity of clinical phenotypes, and insensitivity of clinical scales [3]. In
preclinical studies, imagings such as PET and MRI are widely used to reflect the biochemical and physiological changes associated with a disease. They
can define the neuroreceptors with which the novel drug interacts, and determine what level of target engagement is needed to produce drug-
induced biological changes expected to give clinical benefit. They also potentially enable the same measures to be used in preclinical and patient
studies and support back-translation from clinical findings to preclinical models to refine these models [2]. In clinical trials, neuroimaging can identify
patients with homogenous underlying pathophysiology to improve the stratification methodology used for the recruitment of patients to a specific
group to evaluate a novel potential drug treatment. It also has the potential to provide a more sensitive imaging marker of drug action compared with
changes in clinical rating scales [2].

As one of the most widely used imaging tools, MRI scanners use strong magnetic fields and radiowaves (radiofrequency energy) to form clear, high-
contrast images of the internal structures of the body, without the use of damaging ionizing radiation and contrast agents. Such a non-invasive and
radiation-free approach is preferred in the studies of brain structure and function in CNS diseases, especially in neurodegenerative disorders caused
by neuronal lesions in brain tissue [4]. MRI can detect the location and degree of brain atrophy in patients with AD and cerebrovascular damage in
patients with PD [5], [6]. Compared with neurodegenerative disorders, psychiatric disorders are characterized by abnormalities in brain networks,
which tend to be more heterogeneous. Therefore, using neuroimaging in the diagnosis of psychiatric disorders, such as depression and schizophrenia,
can be less accurate. Nonetheless, a large body of functional MRI (fMRI) and PET studies has revealed correlations between mood/behavioral
disturbances and functional abnormalities in certain brain structures and connections in patients with psychiatric disorders [7], [8], [9], [10], [11]. For
example, the fMRI measure of ventral striatum activation acted as the primary outcome in a randomized proof-of-mechanism trial to evaluating κ-
opioid antagonism as a treatment for anhedonia. Notably, the results of exploratory analysis indicated that the changes with treatment in the primary
outcome (fMRI measure) were statistically significantly correlated with the change in a self-report measure (the SHAPS score) [11].

Molecular imaging modalities with PET or SPECT measure physiological indicators (such as the distribution of metabolic biomarkers, occupation of
receptors, and activities of neurotransmitters) using radiolabeled tracer molecules and are valued for their high specificity and sensitivity [12].
Separately, SPECT uses radionuclides that emit gamma rays, whereas PET relies on the positron nuclides, such as 11C, 13N, 15O, and 18F. As the basic
elements of human tissue, these positron nuclides can label biologically active molecules involved in the metabolism of the living body [13]. Thus, PET
can result in images reflecting the metabolism in the body at the molecular level and is used more widely compared with SPECT. As an application in
CNS diseases, 18F-fluorodeoxyglucose PET (FDG-PET) is able to detect regional glucose metabolism, which is well established and widely recognized as
an important auxiliary examination method for the diagnosis of AD [14], [15]. A few radioactive tracers, such as 18F-florbetapir, 18F-flutemetamol, and
18F-florbetaben, have already been approved in the European Union (EU), USA, and other countries for use in brain PET imaging of β-amyloid (βA)

plaques in patients with AD [16]. Regional cerebral blood flow imaging using SPECT could provide useful information about brain perfusion in the
diagnoses of AD [17]. 123I-ioflupane (DaTscan™) SPECT has been approved in the EU and USA to evaluate patients with suspected Parkinsonian
syndromes (PS) [18].

The important therapeutic targets of the dopaminergic system in psychiatric disorders, among others, have been justified by a large amount of
evidence from in vivo imaging studies [19]. These studies used radiolabeling of drugs or drug candidates with PET/SPECT radioisotopes to determine
the biodistribution characteristics of compounds. Labeling of molecular targets with PET/SPECT radiotracers allowed measurement of the target
occupancy of a new medication, which is used to aid dose finding in early clinical trials [20]. The neuropathological mechanisms of CNS diseases
revealed by neuroimaging have also facilitated the recent discovery and development of novel therapeutics. For example, cariprazine, a dual
dopamine D3/D2 receptor partial agonist, was approved to treat bipolar I disorder and schizophrenia [21]. However, the development of PET tracers
for new targets remains challenging, with intensive screening processes required in development phases. Factors impeding or reducing the ability of
PET tracers to accurately report on a target could severely limit their applicability or render them unusable [22]. Moreover, efforts have been made to
explore new synthetic reagents and reactions with radionuclides to develop higher-performing radioligands to implement successful labeling
strategies for PET studies [23], [24].

In addition to advancing the development of CNS drugs, neuroimaging also has potential clinical translational value for individualized and accurate
diagnoses. For instance, the new tau tracer 18F-APN-1607 displayed better binding properties, and was able to bind to some extent to tau deposits in
AD and other tauopathies, such as progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), in vivo with high contrast [25]. It allowed
individual-based identification of primary AD and non-AD tauopathies. Imaging technologies also foster constructs that attempt to link psychological
aspects of disorders with biological systems. A fMRI-based test revealed a continuum of cognitive control dysfunction and its neural underpinnings
across bipolar disorder and schizophrenia [26]. Bipolar disorder showed intermediate levels of cognitive control relative to controls and
schizophrenia. The fMRI-based test provided validation of the approach of examining dimensional measures across diagnostic boundaries, supporting
a Research Domain Criteria (RDoC)-based framework of understanding this important aspect of these illnesses [27].

Uppoor et al. reviewed all imaging studies for New Drug Applications (NDAs) for CNS drugs approved from 1995 through 2004 by the US Food and
Drug Administration (FDA) [28]. Of the 106 NDAs that were approved, 15 were supported by imaging studies, predominantly PET. Imaging was
primarily conducted for drugs used in schizophrenia, depression, multiple sclerosis, and migraine. Most of the studies evaluated receptor occupancy
or proof of concept [22]. However, despite various reviews of advances in neuroimaging for CNS drug development, less is known about the
characteristics and changes over time of neuroimaging use in relevant clinical studies [29]. Therefore, in this study, we investigated the use of
neuroimaging techniques (MRI, PET, and SPECT) in clinical trials for the most prevalent CNS diseases (AD, PD, depression, and schizophrenia) based on
data accessed from https://clinicaltrials.gov/ . We analyzed the neuroimaging-use trends and primary purposes of the imaging studies by disease
type and imaging technique. Our goal was to characterize the use of neuroimaging in CNS diseases clinical trials with supportive data and provide
insight into the role of neuroimaging in translational studies.

Section snippets

Statistical analysis
We performed a systematic review of clinical trials on https://clinicaltrials.gov/ with a closing date of December 31, 2021, for AD, PD, depression, and
schizophrenia. The inclusion of trials that used neuroimaging techniques was decided through a keywords search using ‘MRI’, ‘PET’, and ‘SPECT’
combined with the above four disease names. Furthermore, we conducted a detailed analysis of interventional clinical trials based on the start dates,
phases, primary purposes, and conditions of the…

Time trends of initiated CNS clinical trials involving neuroimaging

In total, 16 513 CNS clinical trials, including 13 641 interventional studies and 2872 observational studies, targeting AD, PD, depression, or
schizophrenia were initiated and registered on https://clinicaltrials.gov from January 19, 1981, to December 31, 2021. Among the interventional and
observational studies, 1631 (12.0% of 13 641) and 524 (18.2% of 2872) trials used neuroimaging (PET, SPECT, or MRI), respectively. In clinical trials using
neuroimaging technology, interventional studies were …

Discussion
There was a general trend of a substantial increase in the use of neuroimaging modalities (MRI, PET, and SPECT) in clinical trials for four CNS diseases
over the past two decades. Moreover, several important findings were identified from our investigation of neuroimaging techniques in clinical trials.

First, the three neuroimaging techniques were often used in CNS clinical trials to different extents and for different purposes. Their use has been
linked to progress in our understanding of their…

Concluding remarks
The past two decades have witnessed a rapid growth in the application of translational neuroimaging in clinical settings for CNS diseases.
Translational imaging tools are also widely used in other therapeutic areas, such as oncology and cardiovascular diseases. The emergence and
successful commercialization of the latest image fusion technology has further accelerated the development of imaging technologies. In short,
imaging technologies as a translational tool have bridged the gap between…

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