Antagonists used for positron emission tomographic (PET) studies of dopamine D2/D3 receptors do not distinguish between the high-affinity (HA) and low-affinity (LA) states of the receptors. We and others have now accomplished imaging only the HA-state of dopamine D2/D3 receptors using aminotetralin-based and apomorphine-based PET radiotracers. These studies confirm that some of the D2/D3 receptors in the striatum of the living rodent and monkey are present in the HA-state. The ability to image and reliably quantitate the amount of receptors present in the HA-state has a number of applications. These include: (a), the study of etiology of disease states such as schizophrenia, manic depression and Parkinson's disease; (b). study of dopamine release since dopamine now competes with a more sensitive PET radiotracer that is bound only (or predominantly) to the HA-state; (c). study of therapeutic drugs that may shift population of affinity states, from HA- to LA-state. Our goal is this application is two-fold: 1. Develop and evaluate agents that are suitable for HA-state imaging of striatal and extrastriatal receptors; and 2. Evaluate HA-state radiotracers that will be able to discriminate between D2 and D3 receptor subtypes. We have optimized 5- hydroxyaminotetralins for imaging dopamine D2 receptors which has resulted in the development of 18F-5- OH-FPPAT as a suitable imaging agent. We propose to optimize radiosynthesis of the more active isomer S-18F-5-OH-FPPAT and carry out in vitro and in vivo binding properties of both R- and S-isomers. The high- affinity agent 11C-PPHT will be studied for extrastriatal HA-states. Both, R- and S-isomers will be evaluated. Quantitative microPET studies to measure amphetamine-induced dopamine release in striatal and extrastriatal regions will be carried out. In order to direct the tetralins to the D3 receptor, the 7-hydroxy analogs of FPPAT and PPHT will be investigated. Specifically we will synthesize R- and S-isomers of 18F-7- OH-FPPAT and 11C-7-OH-PPHT that may have potential as D3 selective agents. Fluorine-18 analog of PPHT, 18F-FPPHT (both 5- and 7-hydroxy) will also be prepared for extrastriatal imaging of HA-states. Pharmacological characterization of these agents using D3 cell lines, brain homogenates, autoradiographic studies, D2 and D3 receptor knock-out mice microPET studies will be carried out. Finally PET studies will be carried out in monkeys with these agents to demonstrate HA-state binding and receptor subtype selectivity. ? ? ?

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
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Medical Imaging Study Section (MEDI)
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Haller, John W
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University of California Irvine
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Mukherjee, Jogeshwar; Majji, Divya; Kaur, Jasmeet et al. (2017) PET radiotracer development for imaging high-affinity state of dopamine D2 and D3 receptors: Binding studies of fluorine-18 labeled aminotetralins in rodents. Synapse 71:
Mukherjee, Jogeshwar; Constantinescu, Cristian C; Hoang, Angela T et al. (2015) Dopamine D3 receptor binding of (18)F-fallypride: Evaluation using in vitro and in vivo PET imaging studies. Synapse 69:577-91
Tahara, Nobuhiro; Mukherjee, Jogeshwar; de Haas, Hans J et al. (2014) 2-deoxy-2-[18F]fluoro-D-mannose positron emission tomography imaging in atherosclerosis. Nat Med 20:215-9
Pithia, Neema; Gulati, Neal; Pandey, Suresh et al. (2013) Synthesis and biological evaluation of 18F-Norfallypride in the rodent brain using PET imaging. Nucl Med Biol 40:697-704
Constantinescu, Cristian C; Coleman, Robert A; Pan, Min-Liang et al. (2011) Striatal and extrastriatal microPET imaging of D2/D3 dopamine receptors in rat brain with [¹?F]fallypride and [¹?F]desmethoxyfallypride. Synapse 65:778-87
Vandehey, Nicholas T; Moirano, Jeffrey M; Converse, Alexander K et al. (2010) High-affinity dopamine D2/D3 PET radioligands 18F-fallypride and 11C-FLB457: a comparison of kinetics in extrastriatal regions using a multiple-injection protocol. J Cereb Blood Flow Metab 30:994-1007
Nguyen, Vivien L; Pichika, Rama; Bhakta, Paayal H et al. (2010) (R)-N-Methyl-3-(3'-[F]fluoropropyl)phenoxy)-3-phenylpropanamine (F-MFP3) as a potential PET imaging agent for norepinephrine transporter. J Labelled Comp Radiopharm 53:172-177
Constantinescu, Cristian C; Mukherjee, Jogeshwar (2009) Performance evaluation of an Inveon PET preclinical scanner. Phys Med Biol 54:2885-99
Airaksinen, Anu J; Nag, Sangram; Finnema, Sjoerd J et al. (2008) [11C]cyclopropyl-FLB 457: a PET radioligand for low densities of dopamine D2 receptors. Bioorg Med Chem 16:6467-73