Igawa Hideyuki, Stepanov Vladimir, Tari Lenke, Okuda Shoki, Yamamoto Syunsuke, Kasai Shizuo, Nagisa Yasutaka, Haggkvist Jenny, Svedberg Marie, Toth Miklos, Takano Akihiro, Halldin Christer
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., 26-1, Muraoka-Higashi 2- Chome, Fujisawa, Kanagawa 251-8555. Japan.
Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, SE-171 76, Stockholm. Sweden.
Curr Radiopharm. 2017;10(1):35-40. doi: 10.2174/1874471009666161230113630.
Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents and many drug discovery programs have been dedicated to identify smallmolecule antagonists of melanin-concentrating hormone receptor 1 (MCHR1). The aim of this study was to develop a positron emission tomography (PET) tracer for MCHR1 for translation of preclinical pharmacology to clinic to enhance success rate of drug discovery programs.
We identified 4-(cyclopropylmethoxy)-N-[8-methyl-3-({[(1-methyl-1H-pyrrol-2-yl)methyl] amino}ethyl)quinolin-7-yl]benzamide (Compound II) from Takeda MCHR1 antagonist library by utilizing binding affinity, log D value, physicochemical parameters ideal for a central nerve system agent, and synthetic feasibility of corresponding carbon-11 labeled radioligands as selection parameters for tracer candidates.
In the rat PET study, [11C] Compound II showed clear uptake in the caudate/putamen with the pretreatment of cyclosporine A and its uptake was higher than that in the cerebellum where expression of MCHR1 was reported to be low.
In summary, [11C]Compound II is a promising lead compound for developing a suitable MCHR1 PET radioligand. [11C]Compound II, in combination with cyclosporine A, could be used as a research tool to visualize and quantify MCHR1 in rodents.
黑色素浓缩激素（MCH）是抗肥胖药物的一个有吸引力的靶点，许多药物研发项目致力于寻找黑色素浓缩激素受体1（MCHR1）的小分子拮抗剂。本研究的目的是开发一种用于MCHR1的正电子发射断层扫描（PET）示踪剂，将临床前药理学转化到临床，以提高药物研发项目的成功率。
我们从武田MCHR1拮抗剂文库中鉴定出4-（环丙基甲氧基）-N-[8-甲基-3-({[(1-甲基-1H-吡咯-2-基)甲基]氨基}乙基)喹啉-7-基]苯甲酰胺（化合物II），利用结合亲和力、log D值、作为中枢神经系统药物理想的物理化学参数以及相应碳-11标记放射性配体的合成可行性作为示踪剂候选物的选择参数。
在大鼠PET研究中，[11C]化合物II在环孢素A预处理后在尾状核/壳核中显示出明显摄取，其摄取高于据报道MCHR1表达较低的小脑。
总之，[11C]化合物II是开发合适的MCHR1 PET放射性配体的有前景的先导化合物。[11C]化合物II与环孢素A联合使用，可作为一种研究工具来可视化和定量啮齿动物体内的MCHR1。
