Zhao Austin Y, Brooks Allen F, Raffel David M, Stauff Jenelle, Arteaga Janna, Scott Peter J H, Shao Xia
Department of Radiology, University of Michigan, Ann Arbor Michigan 48109, United States.
Departments of Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor Michigan 48109, United States.
ACS Med Chem Lett. 2020 Oct 5;11(11):2325-2330. doi: 10.1021/acsmedchemlett.0c00479. eCollection 2020 Nov 12.
Radiolabeled guanidines such as -iodobenzylguanidine (MIBG) find utility in nuclear medicine as both diagnostic imaging agents and radiotherapeutics and, over the years, numerous methods for incorporating radionuclides into guanidines have been developed. In connection with a project developing new positron emission tomography (PET) radiotracers for cardiac sympathetic nerve density, we had cause to prepare [C]3F-PHPOG. However, it quickly became apparent that radiolabeling of guanidine scaffolds with carbon-11 has remained challenging, and historical methods lack compatibility with modern automated radiochemistry synthesis platforms and current Good Manufacturing Practice (cGMP) requirements. To address this challenge, we report a new automated method for radiolabeling guanidines with carbon-11. The method was used to prepare a series of [C]guanidines in good radiochemical yield (8-76% by radio-HPLC) and was found to have broad substrate scope and tolerance of unprotected OH and NH functional groups. The method was used to synthesize [C]3F-PHPOG for preclinical imaging, and suitability of the radiotracer for preclinical use was demonstrated through preliminary cardiac PET in New Zealand white rabbits which revealed good cardiac uptake and expected retention in the heart.
放射性标记的胍类化合物，如碘苄胍（MIBG），在核医学中作为诊断成像剂和放射治疗剂都有应用，多年来，已经开发出许多将放射性核素引入胍类化合物的方法。在一个开发用于心脏交感神经密度的新型正电子发射断层扫描（PET）放射性示踪剂的项目中，我们有必要制备[C]3F-PHPOG。然而，很快就发现用碳-11对胍类骨架进行放射性标记仍然具有挑战性，而且传统方法与现代自动化放射化学合成平台以及当前的药品生产质量管理规范（cGMP）要求不兼容。为应对这一挑战，我们报告了一种用碳-11对胍类化合物进行放射性标记的新自动化方法。该方法用于以良好的放射化学产率（通过放射性高效液相色谱法测定为8-76%）制备一系列[C]胍类化合物，并且发现该方法具有广泛的底物范围以及对未保护的OH和NH官能团的耐受性。该方法用于合成用于临床前成像的[C]3F-PHPOG，通过在新西兰白兔身上进行的初步心脏PET实验证明了该放射性示踪剂适用于临床前使用，实验显示心脏摄取良好且预期在心脏中保留。
