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

Abstract 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 reported to be clinically applicable to GHS-R1a imaging. In this study, we developed three new PET tracers for GHS-R1a: 18 F-labeled 6-(4-chlorophenyl)-3-((1-(2-fluoroethyl)piperidin-3-yl)methyl)-2-(o-tolyl)quinazolin-4(3 H )-one ( 1 ), 11 C-labeled 6-(4-chlorophenyl)-3-((1-(2-methoxyethyl)piperidin-3-yl)methyl)-2-(o-tolyl)quinazolin-4(3 H )-one ( 2 ), and 11 C-labeled ( S )-(4-(1 H -indole-6-carbonyl)-3-methylpiperazin-1-yl)(4′-methoxy-[1,1′-biphenyl]-4-yl)methanone ( 3 ). Methods [ 18 F] 1 was synthesized by the 18 F-fluoroethylation; [ 11 C] 2 or [ 11 C] 3 was synthesized by the 11 C-methylation. Biodistribution studies and PET studies were conducted in mice. Results We successfully radiosynthesized [ 18 F] 1, [ 11 C] 2 , and [ 11 C] 3 with appropriate radioactivity for the animal study. In the ex vivo biodistribution study, 60 min following injection, the radioactivity level of [ 18 F] 1 was relatively high in the small intestine, that of [ 11 C] 2 was high in the liver, and that of [ 11 C] 3 was high in the pancreas. The radioactivity levels of the three PET tracers were relatively low in the brain. Under pretreatment with YIL781 (a selective and high affinity antagonist for GHS-R1a), the pancreas radioactivity level at 30 min following [ 11 C] 3 injection was significantly reduced 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 [ 11 C] 3 injection. With YIL781 pretreatment, the accumulated radioactivity in the pancreas 15–60 min after [ 11 C] 3 injection was significantly decreased to 78% of control. Conclusion [ 11 C] 3 exhibited relatively high uptake and in vivo specific binding to GHS-R1a in the mouse pancreas. [ 11 C] 3 may be a useful PET tracers for in vivo imaging of GHS-R1a in the pancreas.