Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Mol Pharm. 2020 Apr 6;17(4):1293-1299. doi: 10.1021/acs.molpharmaceut.9b01309. Epub 2020 Mar 23.
The deposition of islet amyloid is associated with β-cell mass dysfunction in type 2 diabetes mellitus (T2DM). Since the amylin aggregate is the main component of islet amyloid, imaging of amylin may be useful for diagnosis and elucidation of the pathogenic mechanism of T2DM. In the present study, we newly designed, synthesized, and evaluated two F labeled compounds ([F]DANIR-F 2b and [F]DANIR-F 2c) as positron emission tomography (PET) probes targeting amylin aggregates. In an binding study, DANIR-F 2b and DANIR-F 2c showed binding affinity for amylin aggregates ( = 160 and 29 nM, respectively). In addition, [F]DANIR-F 2b and [F]DANIR-F 2c clearly labeled islet amyloids in autoradiography of T2DM pancreatic sections. In the biodistribution study using normal mice, [F]DANIR-F 2b and [F]DANIR-F 2c displayed favorable pharamacokinetics in the pancreas and some organs located near the pancreas. Furthermore, in an autoradiographic study, [F]DANIR-F 2c also bound to amylin aggregates in the pancreas of the amylin transplanted mice. The results of this study suggest that [F]DANIR-F 2c shows fundamental properties as a PET imaging probe targeting amylin aggregates in the T2DM pancreas.
胰岛淀粉样沉积与 2 型糖尿病（T2DM）中的β细胞功能障碍有关。由于胰岛淀粉样蛋白的主要成分是淀粉样蛋白，因此淀粉样蛋白的成像可能有助于 T2DM 的诊断和发病机制的阐明。在本研究中，我们新设计、合成并评估了两种 F 标记的化合物（[F]DANIR-F 2b 和 [F]DANIR-F 2c）作为针对淀粉样蛋白聚集体的正电子发射断层扫描（PET）探针。在结合研究中，DANIR-F 2b 和 DANIR-F 2c 对淀粉样蛋白聚集体表现出结合亲和力（分别为 160 和 29 nM）。此外，[F]DANIR-F 2b 和 [F]DANIR-F 2c 在 T2DM 胰腺切片的放射自显影中清楚地标记了胰岛淀粉样蛋白。在使用正常小鼠的生物分布研究中，[F]DANIR-F 2b 和 [F]DANIR-F 2c 在胰腺和靠近胰腺的一些器官中显示出良好的药代动力学特性。此外，在放射自显影研究中，[F]DANIR-F 2c 还与淀粉样蛋白转染小鼠胰腺中的淀粉样蛋白聚集体结合。这项研究的结果表明，[F]DANIR-F 2c 显示出作为针对 T2DM 胰腺中淀粉样蛋白聚集体的 PET 成像探针的基本特性。
