The ultimate goal of this project is to develop a Positron Emission Tomography (PET) radiotracer for brain imaging of the cyclic nucleotide phosphodiesterase 10A (PDE10A). PDE10A is specifically expressed in the brain with high levels in striatal medium-sized spiny projection neurons (MSN) where it plays a critical role in the regulation of both cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP). Abnormal striatal levels of PDE10A affect striatal output and may contribute substantially to the pathophysiology of schizophrenia, Huntington's disease (HD) and other mental disorders. Decreased striatal PDE10A level has been correlated with the severity of HD, while inhibition of PDE10A has been proposed as a novel therapeutic strategy for treating schizophrenia and related conditions. Thus, a PET radiotracer for PDE10A would be a valuable tool for clinical neuroscience research. To achieve the goal of this project, we first radiolabeled a representative PDE10A compound, 2-((4-(1-[11C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3- yl)phenoxy)-methyl)quinoline ([11C]MP-10) with C-11. MP-10 is a high potency PDE10A inhibitor (IC50 = 0.37 nM) with high selectivity (1000 fold) for PDE10A vs. other PDEs and CNS receptors. We also successfully modified the structure of MP-10 to make a fluorine analogue, TuJF103 (IC50 = 0.27 nM). Preliminary biodistribution evaluation of [11C]MP-10 and [18F]TUJF103 in rats, and microPET imaging studies of both radiotracers in monkeys displayed good contrast between the target (striatal) and the reference (cerebellum) region. However, analysis of the time-activity curves of striatum and cerebellum and subsequent metabolite analysis of rat brain and blood indicated the presence of lipophilic radiolabeled metabolites that accumulate non-specifically in the brain. Such metabolites could limit the clinical utility of either [11C]MP-10 or [18F]TUJF103 as novel PET tracers for imaging PDE10A. To overcome such concerns, this proposal will optimize the structure of MP-10 to synthesize new analogues with high affinity and selectivity for PDE10A;radiolabel lead candidates with C-11 or F-18 and then use in vivo methods to validate optimal PET radiotracers for imaging PDE10A in the brain. Consequently, the specific aims of the R21 component include: (1) synthesize new analogues by structural optimization of MP-10;(2) measure the affinities of new analogues in vitro;(3) radiolabel the ligands having high affinities (IC50<15 nM) and high selectivity (>100 fold) with C-11 or F-18;(4) conduct biodistribution and brain uptake studies of radiotracers in rats to identify at least two promising candidates.
The specific aims of the R33 component will be the continued evaluation of these candidate radiotracers in primates with the goal of identifying a PET tracer suitable for translational clinical evaluation for imaging PDE10A in the brain with PET.

Public Health Relevance

Huntington's disease is a progressive neurological disorder of motor, cognitive, and psychiatric disturbances. It was reported more than 15,000 Americans have HD. At least other 150,000 have a 50% risk of developing the disease and thousands more of their relatives live with the possibility that they might develop HD. A PET radiotracer of PDE10A may help physician to quantify the progression of Huntington Disease based on the PET measurement of PDE10A level in patients with the Huntington disease patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33MH092797-04
Application #
8661060
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Brady, Linda S
Project Start
2011-02-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
$462,180
Indirect Cost
$158,114
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Jin, Hongjun; Zhang, Xiang; Yue, Xuyi et al. (2016) Kinetics modeling and occupancy studies of a novel C-11 PET tracer for VAChT in nonhuman primates. Nucl Med Biol 43:131-9
Rosenberg, Adam J; Liu, Hui; Jin, Hongjun et al. (2016) Design, Synthesis, and In Vitro and In Vivo Evaluation of an (18)F-Labeled Sphingosine 1-Phosphate Receptor 1 (S1P1) PET Tracer. J Med Chem 59:6201-20
Jin, Hongjun; Yang, Hao; Liu, Hui et al. (2016) A promising carbon-11-labeled sphingosine-1-phosphate receptor 1-specific PET tracer for imaging vascular injury. J Nucl Cardiol :
Liu, Hui; Jin, Hongjun; Yue, Xuyi et al. (2016) Comparison of [(11)C]TZ1964B and [(18)F]MNI659 for PET imaging brain PDE10A in nonhuman primates. Pharmacol Res Perspect 4:e00253
Yue, Xuyi; Bognar, Christopher; Zhang, Xiang et al. (2016) Automated production of [¹⁸F]VAT suitable for clinical PET study of vesicular acetylcholine transporter. Appl Radiat Isot 107:40-6
Yue, Xuyi; Jin, Hongjun; Liu, Hui et al. (2015) A potent and selective C-11 labeled PET tracer for imaging sphingosine-1-phosphate receptor 2 in the CNS demonstrates sexually dimorphic expression. Org Biomol Chem 13:7928-39
Yang, Hao; Murigi, Francis N; Wang, Zhijian et al. (2015) Synthesis and in vitro characterization of cinnoline and benzimidazole analogues as phosphodiesterase 10A inhibitors. Bioorg Med Chem Lett 25:919-24
Tu, Zhude; Zhang, Xiang; Jin, Hongjun et al. (2015) Synthesis and biological characterization of a promising F-18 PET tracer for vesicular acetylcholine transporter. Bioorg Med Chem 23:4699-709
Karimi, Morvarid; Tu, Zhude; Yue, Xuyi et al. (2015) Radiation dosimetry of [(18)F]VAT in nonhuman primates. EJNMMI Res 5:73
Liu, Hui; Jin, Hongjun; Li, Junfeng et al. (2015) In vitro and ex vivo characterization of (-)-TZ659 as a ligand for imaging the vesicular acetylcholine transporter. Eur J Pharmacol 752:18-25

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