The dopamine D3 receptor has continued to be one of the most challenging targets for PET radiotracer development in the field of CNS receptor research. This difficulty has been largely based on the high degree of sequence homology between D2 and D3 receptors in the ligand binding region of each receptor. Although the past decade has witnessed a number of compounds having a high affinity and selectivity for D3 vs. D2 receptors, and many of these have been labeled with either carbon-11 or fluorine-18, none has proven to be successful in imaging the D3 receptor without the cross-over labeling of the D2 receptor. As described in the progress report, we have developed a D3-selective radiotracer, [18F] Fluortriopride (FTP) that has shown promising results in preliminary first-in-human PET studies. One of the conclusions reached in the progress report is that [18F]FTP binds to the orthosteric site in the D3 receptor, which results in a competition between dopamine (DA) and radiotracer for binding to the D3 receptor. Therefore, [18F] FTP measures D3 availability, which represents the number of D3 receptors that does not have DA bound to the orthosteric site. The first goal of the research described in this competing renewal is to conduct a detailed first- in-man study to fully characterize the ability of [18F] FTP to measure D3 receptor availability. A second goal is to identify a PET radiotracer that is insensitive to endogenous dopamine levels so that it is capable of imaging the density of D3 receptor in vivo. The project described in this grant proposal involves the continuation of a long-standing collaboration with the P.I. (RH Mach) and an expert in the field of dopamine receptor pharmacology (R.R. Luedtke). These investigators have a total of 38 joint publications in the field of dopamine receptor pharmacology. This project consists of five Specific Aims. The first Specific Aim consists of the first-in-human studies of [18F] FTP. The second Specific Aim describes a detailed structure-activity relationship study that will be conducted on two series of compounds with the goal of identifying the properties needed to develop a D3- selective probe whose in vivo binding is not influenced by synaptic dopamine levels. The compounds synthesized in Aim 2 will be screened in a series of in vitro binding studies described in Specific Aim 3.
Specific Aim 4 involves the development of the radiosynthetic methods needed to conduct the rodent and nonhuman primate imaging described in Specific Aim 5. We anticipate generating one PET radiotracer that displays the affinity, specificity, and in vivo kinetics needed for translational imaging studies i human subjects by the completion of this 5-year research project.

Public Health Relevance

The goal of the research described in this competing renewal is to conduct first-in-human studies with a novel D3 positron emission tomography (PET) radiotracer which was developed over the previous funding period. This radiotracer, [18F] FTP, measures D3 receptor availability, which is the number of receptors that are not occupied by dopamine. A second goal of this research project is to develop a D3-selective radiotracer for imaging the density of D3 receptors in vivo with PET. The development of a PET radiotracer for imaging D3 density will provide valuable information on the change in receptor levels in the brain as a consequence of disease and will serve as a complement to our PET radiotracer that measures D3 receptor availability.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Rapaka, Rao
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Medicine
United States
Zip Code
Reilly, Sean W; Griffin, Suzy; Taylor, Michelle et al. (2017) Highly Selective Dopamine D3 Receptor Antagonists with Arylated Diazaspiro Alkane Cores. J Med Chem 60:9905-9910
Reilly, Sean W; Mach, Robert H (2016) Pd-Catalyzed Synthesis of Piperazine Scaffolds Under Aerobic and Solvent-Free Conditions. Org Lett :
Peng, Xin; Wang, Qi; Mishra, Yogesh et al. (2015) Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands. Bioorg Med Chem Lett 25:519-23
Rangel-Barajas, Claudia; Malik, Maninder; Taylor, Michelle et al. (2014) Characterization of [(3) H]LS-3-134, a novel arylamide phenylpiperazine D3 dopamine receptor selective radioligand. J Neurochem 131:418-31
Li, Aixiao; Mishra, Yogesh; Malik, Maninder et al. (2013) Evaluation of N-phenyl homopiperazine analogs as potential dopamine D3 receptor selective ligands. Bioorg Med Chem 21:2988-98
Sun, J; Cairns, N J; Perlmutter, J S et al. (2013) Regulation of dopamine D? receptor in the striatal regions and substantia nigra in diffuse Lewy body disease. Neuroscience 248:112-26
Sun, Jianjun; Kouranova, Evguenia; Cui, Xiaoxia et al. (2013) Regulation of dopamine presynaptic markers and receptors in the striatum of DJ-1 and Pink1 knockout rats. Neurosci Lett 557 Pt B:123-8
Tu, Zhude; Li, Shihong; Li, Aixiao et al. (2013) Synthesis and in vitro pharmacological evaluation of indolyl carboxylic amide analogues as D3 dopamine receptor selective ligands. Medchemcomm 4:1283-1289
Sun, Jianjun; Xu, Jinbin; Cairns, Nigel J et al. (2012) Dopamine D1, D2, D3 receptors, vesicular monoamine transporter type-2 (VMAT2) and dopamine transporter (DAT) densities in aged human brain. PLoS One 7:e49483
Mach, Robert H; Tu, Zhude; Xu, Jinbin et al. (2011) Endogenous dopamine (DA) competes with the binding of a radiolabeled D? receptor partial agonist in vivo: a positron emission tomography study. Synapse 65:724-32

Showing the most recent 10 out of 14 publications