Radiosyntheses and in vivo evaluation of carbon-11 PET tracers for PDE10A in the brain of rodent and nonhuman primate |
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| Institution: | 1. Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA;2. Department of Neurology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA;1. Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan;2. SHI Accelerator Service Co. Ltd, 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan;1. Department of Life Sciences, National University of Kaohsiung, Kaohsiung 811, Taiwan;2. Department of Microbiology, Kaohsiung Medical University, Kaohsiung 807, Taiwan;3. Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan;4. Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan;1. Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States;2. Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States;3. Department of Cardiometabolic Diseases, Merck Research Laboratories, Kenilworth, NJ 07033, United States;4. Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, Kenilworth, NJ 07033, United States;5. Department of Safety Assessment & Laboratory Animal Resources, Merck Research Laboratories, Kenilworth, NJ 07033, United States;1. School of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, Brisbane 4072, Australia;2. School of Pharmacy, University of Queensland, St. Lucia, Brisbane 4072, Australia |
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| Abstract: | The radiosyntheses and in vivo evaluation of four carbon-11 labeled quinoline group-containing radioligands are reported here. Radiolabeling of 11C]1–4 was achieved by alkylation of their corresponding desmethyl precursors with 11C]CH3I. Preliminary biodistribution evaluation in Sprague-Dawley rats demonstrated that 11C]1 and 11C]2 had high striatal accumulation (at peak time) for 11C]1 and 11C]2 were 6.0-fold and 4.5-fold at 60 min, respectively. Following MP-10 pretreatment, striatal uptake in rats of 11C]1 and 11C]2 was reduced, suggesting that the tracers bind specifically to PDE10A. MicroPET studies of 11C]1 and 11C]2 in nonhuman primates (NHP) also showed good tracer retention in the striatum with rapid clearance from non-target brain regions. Striatal uptake (SUV) of 11C]1 reached 1.8 at 30 min with a 3.5-fold striatum:cerebellum ratio. In addition, HPLC analysis of solvent extracts from NHP plasma samples suggested that 11C]1 had a very favorable metabolic stability. Our preclinical investigations suggest that 11C]1 is a promising candidate for quantification of PDE10A in vivo using PET. |
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| Keywords: | PDE10A Carbon-11 PET imaging MP-10 CNS |
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