Presentation Synthesis and evaluation of a new 11C-labeled growth hormone secretagogue receptor 1a probe

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

Objectives: Growth hormone secretagogue receptor 1a (GHS-R1a) is a G protein-coupled receptor and expressed predominantly in the pituitary gland, at lower levels in the brain regions including hypothalamus that regulate feeding behavior and glucose sensing, and at even lower level in the pancreas. Therefore, GHSR1a is a promising drug target for complex neuroendocrine disorders that involve in both the central nervous system and the endocrine system. Recently, we developed PET probes for imaging of GHS-R1a ([18F]FEGRL1 and [11C]GRL2). These PET probes showed moderate uptake and low specific binding in the brain and pancreas. To improve uptake of radioactivity and specific binding in the brain and pancreas, we searched new candidate agents for a useful PET probe. Among the investigated compounds, (S)-(4-(1H-indole-6-carbonyl)-3-methylpiperazin-1-yl)(4’-methoxy-[1,1’-biphenyl]-4-yl)methanone (GRL3) has a high selective affinity for GHS-R1a (IC50 = 7.0 nmol/L)[1], and is possible for 11C labeling. Thus, we developed [11C]GRL3 as a new PET probe for imaging of GHS-R1a in the brain and pancreas.Methods: [11C]GRL3 was synthesized by the methylation of its precursor (1.0 mg) with [11C]methyl iodide in the presence of 0.5 mol/L sodium hydroxide solution (5 μL) at 80ºC for 5 min. Biodistribution studies were conducted in mice.Results: In the radiosynthesis, the decay-corrected radiochemical yield from 11CO2 was 43±8% (n = 10) at the end of radionuclide production, the molar radioactivity was 104±64 GBq/μmol (n = 15) at the end of synthesis, the radiochemical purity was >99%, and the synthesis time was approximately 30 min. In the biodistribution, radioactivity level of pancreas was highest (6.5 %ID/g) and that of brain was lowest (0.4 %ID/g) among all investigated tissues at 60 min after the injection. The radioactivity level in pancreas was gradually increased until 30 min after the injection, and maintained for 60 min after the injection. By pretreatment with YIL-781, which has high and selective affinity for GHS-R1a, the radioactivity level of pancreas at 30 min after the injection was significantly reduced to 55% of control, but that of brain was not changed.Conclusions: [11C]GRL3 was successfully synthesized as an injection, and showed relatively high uptake and specific binding of the pancreas in mice. [11C]GRL3 may be a useful PET probe for imaging of GHS-R1a in the pancreas.
22nd International symposium on radiopharmaceutical science (ISRS)

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