The training will augment my experience in Positron Emission Tomography (PET) instrumentation and image analyses of breast cancer to enable me to become an independent investigator of PET methodology for neuroimaging addiction and establish a neuroimaging analysis laboratory patterned after the neuroimaging analysis laboratory established by my co-mentor Dr. Dean F. Wong at John Hopkins University. My interest in neuroimaging addiction work is an outgrowth of my exposure to addiction research since moving to Penn as a faculty member, and an understanding of what molecular neuroimaging can bring to bear on this important public health problem. I now want to study addiction, but first must fill 3 training gaps in (1) novel radiotracer imaging, (2) human addictio neuroscience, and (3) advanced computer-based quantitative image analysis. Dopamine D3 receptors are localized in reward-relevant brain regions; imaging them will elucidate their role in addiction relapse, leading to more effective cessation therapy, including D3-selective agents. Until now, determining the role of D3 receptors in addiction and relapse has not been feasible, as current PET radioligands are not sufficiently selective for distinguishing D2 versus D3 receptor subtypes. In response to this need, my mentor Dr. Robert Mach has created the first D3-specific tracer, [18F]fluortriopride ([18F]FTP). Preliminary data from our recent first-in-human PET scan of [18F]FTP uptake shows concentration in the expected D3-rich thalamus, putamen, and caudate regions and in brain regions involved in memory. This new tracer stimulates Aim 1, and addresses my first training gap: I will devise methods for quantitating [18F]FTP uptake for first-in-human studies of controls under mentor Dr. Mach and co-mentor Dr. Wong. Though there is no FDA-approved drug for stimulant addiction, co-mentor Dr. Anna Rose Childress was recently funded to study whether a new D3-targeted drug engages relapse-relevant brain targets (with fMRI). This study offers a natural opportunity to address training gap 2: Dr. Childress will provide mentored experience in human addiction neuroscience in the context of adding D3-specific [18F]FTP scans to her human study - allowing us in Aim 2 to examine D3-receptor occupancy in cocaine patients before and during D3- targeted medication. These D3 studies would be the first of their kind in cocaine patients. Dr. Caryn Lerman will mentor training on other forms of addiction (i.e. nicotine), for which the role of D3 receptor is also relevant. Training in deformable atlas computational methods for localization of brain structures and multivariate pattern analysis identification of imaging markers by co-mentor Dr. Christos Davatzikos will fill training gap 3 and through Aim 3's mentored research allow refinement of image markers of addiction via pattern analyses. The mentored research will create valuable tools for quantitating in vivo availability of dopamine D3 receptors to study efficacy of a cocaine cessation therapy and reveal underlying mechanisms of addiction.

Public Health Relevance

Discovering the role of dopamine D3 receptors, a key component of addiction biology and target for novel addiction therapy, by Positron Emission Tomography (PET) brain imaging will explain mechanisms of addiction and lead to more effective cessation therapy2-6. Understanding the role of D3 receptors in addiction is not feasible using the current PET tracers for dopamine receptors because they are not sufficiently selective between dopamine D2 and D3 receptor subtypes7-9. The proposed mentored research will use the first D3- specific PET tracer, [18F]fluortriopride ([18F]FTP), to study the role of dopamine D3 receptors in healthy human controls and in cocaine dependent (CD) patients and will employ [18F]FTP imaging to quantitate the response of CD patients to a new medication for cocaine addiction that targets D3 receptors.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Scientist Development Award - Research & Training (K01)
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Special Emphasis Panel (ZRG1)
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Grant, Steven J
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University of Pennsylvania
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Doot, Robert K; Dubroff, Jacob G; Scheuermann, Joshua S et al. (2018) Validation of gallbladder absorbed radiation dose reduction simulation: human dosimetry of [18F]fluortriopride. EJNMMI Phys 5:21
Doot, Robert K; Dubroff, Jacob G; Labban, Kyle J et al. (2018) Selectivity of probes for PET imaging of dopamine D3 receptors. Neurosci Lett :