Journal Article Developing new PET tracers to image the growth hormone secretagogue receptor 1a (GHS-R1a)

Kawamura, Kazunori  ,  Fujinaga, Masayuki  ,  Shimoda, Yoko  ,  Yamasaki, Tomoteru  ,  Zhang, Yiding  ,  Hatori, Akiko  ,  Xie, Lin  ,  Wakizaka, Hidekatsu  ,  Kumata, Katsushi  ,  Ohkubo, Takayuki  ,  Kurihara, Yusuke  ,  Ogawa, Masanao  ,  Nengaki, Nobuki  ,  Ming-Rong, Zhang

52pp.49 - 56 , 2017-06 , Elsevier
Introduction: `The growth hormone secretagogue receptor 1a (GHS-R1a) is the orphan G-protein-coupled receptor,and its endogenous ligand is ghrelin. GHS-R1a contributes to regulation of glucose homeostasis,memory and learning,food addiction, and neuroprotection. Several PET tracers for GHS-R1a have been developed, but none have been reportedto be clinically applicable to GHS-R1a imaging. In this study, we developed three new PET tracers for GHSR1a:18F-labeled 6-(4-chlorophenyl)-3-((1-(2-fluoroethyl)piperidin-3-yl)methyl)-2-(o-tolyl)quinazolin-4(3H)-one(1), 11C-labeled 6-(4-chlorophenyl)-3-((1-(2-methoxyethyl)piperidin-3-yl)methyl)-2-(o-tolyl)quinazolin-4(3H)-one (2), and 11C-labeled (S)-(4-(1H-indole-6-carbonyl)-3-methylpiperazin-1-yl)(4′-methoxy-[1,1′-biphenyl]-4-yl)methanone (3).Methods: [18F]1was synthesized by the 18F-fluoroethylation; [11C]2 or [11C]3 was synthesized by the 11C-methylation.Biodistribution studies and PET studies were conducted in mice.Results:Wesuccessfully radiosynthesized [18F]1, [11C]2, and[11C]3 with appropriate radioactivity for the animal study.In the ex vivo biodistribution study, 60 min following injection, the radioactivity level of [18F]1 was relatively high inthe small intestine, that of [11C]2was high in the liver, and that of [11C]3was high in the pancreas. The radioactivitylevels of the three PET tracerswere relatively low in the brain. Under pretreatmentwith YIL781 (a selective and highaffinity antagonist for GHS-R1a), the pancreas radioactivity level at 30min following [11C]3 injectionwas significantlyreduced to 55% of control, but the radioactivity in the brain was not changed. In the PET study under control conditions,high radioactivity levels in the liver and pancreas were observed following [11C]3 injection. With YIL781 pretreatment,the accumulated radioactivity in the pancreas 15–60 min after [11C]3 injection was significantlydecreased to 78% of control.Conclusion: [11C]3 exhibited relatively high uptake and in vivo specific binding to GHS-R1a in the mouse pancreas.[11C]3 may be a useful PET tracers for in vivo imaging of GHS-R1a in the pancreas.

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