Department of Biomedical Imaging and Image-guided Therapy, Divison of Nuclear Medicine, Radiopharmacy and Experimental Nuclear Medicine, Medical University of Vienna, 1090 Vienna, Austria; Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, 1090 Vienna, Austria.
Department of Biomedical Imaging and Image-guided Therapy, Divison of Nuclear Medicine, Radiopharmacy and Experimental Nuclear Medicine, Medical University of Vienna, 1090 Vienna, Austria.
Eur J Pharmacol. 2014 Jul 15;735:177-83. doi: 10.1016/j.ejphar.2014.04.020. Epub 2014 Apr 26.
The MCHR1 is an interesting pharmacological and pharmaceutical target, due to its involvement in pathologies as diabetes, gut inflammation and adiposity. in vivo PET-studies of the MCHR1 in energy homeostasis and diabetes could be of great value for deeper understanding of endocrinological hormone status and consequential pharmacological interactions. Furthermore, PET-tracers would facilitate compound dose selection of MCHR1 antagonists for treatment. Therefore, we developed two potential PET-tracers, [(11)C]SNAP-7941 and [(18)F]FE@SNAP, for the in vivo visualization of this receptor. Aim of this study was a preclinical in vitro evaluation of both unlabeled ligands. Therefore, a comparative autoradiographic investigation on CNS (coronal rat brain and 4 different human brain regions) and peripheral tissues (rat tongue as target and rat testes as non-target region) was conducted. Competition experiments, using the two radioligands [(125)I]-MCH and [(125)I]-S36057, were performed with selective and specific MCHR1 ligands as PMC-3886, a MCHR1 agonist, SNAP-7941 and FE@SNAP, two MCHR1 antagonists. Additionally, immunohistochemical staining with a specific MCHR1 antibody was performed. Specific binding was found in all tissues known to express the MCHR1 as human and rat CNS and peripheral rat tongue tissue. No specific binding was found in the non-target region of rat testes. MCHR1 antibody staining complemented the outcome of the autoradiographic experiments. The compounds SNAP-7941 and FE@SNAP were generally comparable with PMC-3886. Hence, the in vitro autoradiographic study of the unlabeled compounds SNAP-7941 and FE@SNAP further qualifies the potential of the PET-tracers [(11)C]SNAP-7941 and [(18)F]FE@SNAP as useful MCHR1 PET-tracers.
MCHR1 是一个有趣的药理学和药物学靶点，因为它参与了糖尿病、肠道炎症和肥胖等疾病。MCHR1 在能量平衡和糖尿病中的体内 PET 研究对于深入了解内分泌激素状态和随之而来的药物相互作用可能非常有价值。此外，PET 示踪剂将有助于选择 MCHR1 拮抗剂的化合物剂量用于治疗。因此，我们开发了两种潜在的 PET 示踪剂，[(11)C]SNAP-7941 和 [(18)F]FE@SNAP，用于该受体的体内可视化。本研究的目的是对两种未标记配体进行临床前体外评估。因此，对中枢神经系统（冠状大鼠脑和 4 个不同的人脑区域）和外周组织（大鼠舌作为靶标和大鼠睾丸作为非靶标区域）进行了比较放射自显影研究。使用两种放射性配体[(125)I]-MCH 和 [(125)I]-S36057 进行了竞争实验，使用选择性和特异性 MCHR1 配体作为 MCHR1 激动剂 PMC-3886、SNAP-7941 和 FE@SNAP 进行了实验。此外，还进行了特异性 MCHR1 抗体的免疫组织化学染色。在已知表达 MCHR1 的所有组织中均发现了特异性结合，包括人中枢神经系统和大鼠中枢神经系统以及外周大鼠舌组织。在大鼠睾丸的非靶标区域未发现特异性结合。MCHR1 抗体染色补充了放射自显影实验的结果。化合物 SNAP-7941 和 FE@SNAP 通常与 PMC-3886 相当。因此，未标记化合物 SNAP-7941 和 FE@SNAP 的体外放射自显影研究进一步证明了 PET 示踪剂[(11)C]SNAP-7941 和 [(18)F]FE@SNAP 作为有用的 MCHR1 PET 示踪剂的潜力。
