Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences , Kyoto University , 46-29 Yoshida Shimoadachi-cho , Sakyo-ku, Kyoto 606-8501 , Japan.
Division of Clinical Radiology Service , Kyoto University Hospital , 54 Shogoin Kawahara-cho , Sakyo-ku, Kyoto 606-8507 , Japan.
Mol Pharm. 2018 Dec 3;15(12):5574-5584. doi: 10.1021/acs.molpharmaceut.8b00756. Epub 2018 Nov 8.
Deposition of islet amyloid consisting of amylin constitutes one of pathological hallmarks of type 2 diabetes mellitus (T2DM), and it may be involved in the development and progression of T2DM. However, the details about the relationship between the deposition of islet amyloid and the pathology of T2DM remain unclear, since no useful imaging tracer enabling the visualization of pancreatic amylin is available. In the present study, we synthesized and evaluated six novel F-labeled phenoxymethylpyridine (PMP) derivatives as amylin imaging probes. All F-labeled PMP derivatives showed not only affinity for islet amyloid in the post-mortem T2DM pancreatic sections but also excellent pharmacokinetics in normal mice. Furthermore, ex vivo autoradiographic studies demonstrated that [F]FPMP-5 showed intense labeling of islet amyloids in the diabetes model mouse pancreas in vivo. The preclinical studies suggested that [F]FPMP-5 may have potential as an imaging probe that targets amylin aggregates in the T2DM pancreas.
胰岛淀粉样沉积由胰岛淀粉样多肽组成，是 2 型糖尿病（T2DM）的病理学特征之一，可能参与了 T2DM 的发生和发展。然而，由于缺乏可用于可视化胰岛淀粉样多肽的有用成像示踪剂，关于胰岛淀粉样沉积与 T2DM 病理学之间关系的细节仍不清楚。在本研究中，我们合成并评价了 6 种新型 F 标记的苯氧甲基吡啶（PMP）衍生物作为胰岛淀粉样多肽成像探针。所有 F 标记的 PMP 衍生物不仅对死后 T2DM 胰腺切片中的胰岛淀粉样沉积具有亲和力，而且在正常小鼠中也表现出良好的药代动力学特性。此外，离体放射性自显影研究表明，[F]FPMP-5 在糖尿病模型小鼠胰腺中对胰岛淀粉样沉积具有强烈的标记作用。这些临床前研究表明，[F]FPMP-5 可能具有作为一种成像探针的潜力，用于靶向 T2DM 胰腺中的淀粉样多肽聚集物。
