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Development of Novel PET Imaging Probes for Detection of Amylin Aggregates in the Pancreas.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-03-23 , DOI: 10.1021/acs.molpharmaceut.9b01309
Hiroyuki Watanabe 1 , Kiyoshiro Kawano 1 , Yoichi Shimizu 2 , Shimpei Iikuni 1 , Yuji Nakamoto 2 , Kaori Togashi 2 , Masahiro Ono 1
Affiliation  

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, in vivo 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 18F labeled compounds ([18F]DANIR-F 2b and [18F]DANIR-F 2c) as positron emission tomography (PET) probes targeting amylin aggregates. In an in vitro binding study, DANIR-F 2b and DANIR-F 2c showed binding affinity for amylin aggregates (Ki = 160 and 29 nM, respectively). In addition, [18F]DANIR-F 2b and [18F]DANIR-F 2c clearly labeled islet amyloids in in vitro autoradiography of T2DM pancreatic sections. In the biodistribution study using normal mice, [18F]DANIR-F 2b and [18F]DANIR-F 2c displayed favorable pharamacokinetics in the pancreas and some organs located near the pancreas. Furthermore, in an ex vivo autoradiographic study, [18F]DANIR-F 2c also bound to amylin aggregates in the pancreas of the amylin transplanted mice. The results of this study suggest that [18F]DANIR-F 2c shows fundamental properties as a PET imaging probe targeting amylin aggregates in the T2DM pancreas.

中文翻译:

用于检测胰腺胰岛淀粉样多肽聚集体的新型PET成像探针的开发。

胰岛淀粉样蛋白的沉积与2型糖尿病(T2DM)中的β细胞质量异常有关。由于胰岛淀粉样多肽聚集体是胰岛淀粉样蛋白的主要成分,因此胰岛淀粉样多肽的体内成像可用于诊断和阐明T2DM的致病机制。在本研究中,我们新设计,合成和评估了两种18 F标记的化合物([ 18 F] DANIR-F 2b和[ 18 F] DANIR-F 2c)作为针对胰岛淀粉样多肽聚集体的正电子发射断层扫描(PET)探针。在体外结合研究中,DANIR-F 2b和DANIR-F 2c显示出对胰岛淀粉样多肽聚集体的结合亲和力(分别为K i = 160和29 nM)。此外,[ 18F] DANIR-F 2b和[ 18 F] DANIR-F 2c在T2DM胰腺切片的体外放射自显影中清楚地标记了胰岛淀粉样蛋白。在使用正常小鼠进行的生物分布研究中,[ 18 F] DANIR-F 2b和[ 18 F] DANIR-F 2c在胰腺和位于胰腺附近的一些器官中显示出良好的超声动力学。此外,在离体放射自显影研究中,[ 18 F] DANIR-F 2c还与胰岛淀粉样多肽移植小鼠胰腺中的胰岛淀粉样多肽聚集体结合。这项研究的结果表明[ 18 F] DANIR-F 2c作为针对T2DM胰腺中胰岛淀粉样多肽聚集体的PET成像探针显示出基本特性。
更新日期:2020-04-24
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