Five Eleven Pharma Inc., Philadelphia, Pennsylvania 19104, United States.
College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China.
J Med Chem. 2022 Oct 13;65(19):13001-13012. doi: 10.1021/acs.jmedchem.2c00852. Epub 2022 Sep 14.
Prostate-specific membrane antigen (PSMA) is a promising target for the diagnosis and radionuclide therapy of prostate cancer. This study reports conversion of a previously reported Ga-imaging agent, [Ga]Ga-P16-093, to a Lu-177 radionuclide therapeutic agent. Substitution of the HBED-CC metal chelating group with DOTA(GA) led to P17-087 () and P17-088 (). Both agents showed excellent PSMA binding affinity (IC = 10-30 nM) comparable to that of recently FDA-approved [Lu]Lu-PSMA-617 (Pluvicto). Biodistribution studies in PSMA expressing tumor bearing mice showed that [Lu]Lu- exhibited very high tumor uptake and a fast blood clearance similar to those of [Lu]Lu-PSMA-617. Conversely, [Lu]Lu-, containing an albumin binder, extended its blood half-life and exhibited significantly higher uptake and longer tumor residence time than [Lu]Lu- and [Lu]Lu-PSMA-617. The switch from chelator HBED-CC to DOTA(GA) and the switch from the imaging isotope gallium-68 to the therapeutic isotope lutetium-177 have successfully transformed a PSMA-targeting agent from diagnosis to promising radionuclide therapeutic agents.
前列腺特异性膜抗原（PSMA）是诊断和放射性核素治疗前列腺癌的有前途的靶点。本研究报告了先前报道的 Ga 成像剂[Ga]Ga-P16-093 向 Lu-177 放射性核素治疗剂的转化。用 DOTA(GA)替代 HBED-CC 金属螯合剂得到了 P17-087（）和 P17-088（）。这两种试剂均表现出与最近获得 FDA 批准的[Lu]Lu-PSMA-617（Pluvicto）相当的优异 PSMA 结合亲和力（IC=10-30 nM）。在表达 PSMA 的肿瘤荷瘤小鼠中的生物分布研究表明，[Lu]Lu-表现出非常高的肿瘤摄取和与[Lu]Lu-PSMA-617 相似的快速血液清除率。相反，[Lu]Lu-，含有白蛋白结合物，延长了其血液半衰期，并表现出比[Lu]Lu-和[Lu]Lu-PSMA-617 更高的摄取和更长的肿瘤滞留时间。从螯合剂 HBED-CC 到 DOTA(GA)的转变以及从成像同位素镓-68 到治疗同位素镥-177 的转变，成功地将 PSMA 靶向剂从诊断转化为有前途的放射性核素治疗剂。
Nucl Med Biol. 2017-12-27
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