Development of Tc-99m-labeled asymmetric urea derivatives that target prostate-specific membrane antigen for single-photon emission computed tomography imaging

作者：Kimura Hiroyuki; Sampei Sotaro; Matsuoka Daiko; Harada Naoya; Watanabe Hiroyuki; Arimitsu Kenji; Ono Masahiro; Saji Hideo^*

来源：Bioorganic & Medicinal Chemistry, 2016, 24(10): 2251-2256.

DOI：10.1016/j.bmc.2016.03.051

• Prostate-specific membrane antigen
• Single-photon emission computed tomography
• Anionic Tc-99m-tricarbonyl complex

Prostate-specific membrane antigen (PSMA) is expressed strongly in prostate cancers and is, therefore, an attractive diagnostic and radioimmunotherapeutic target. In contrast to previous reports of PMSA-targeting Tc-99m-tricarbonyl complexes that are cationic or lack a charge, no anionic Tc-99m-tricarbonyl complexes have been reported. Notably, the hydrophilicity conferred by both cationic and anionic charges leads to rapid hepatobiliary clearance, whereas an anionic charge might better enhance renal clearance relative to a cationic charge. Therefore, an improvement in rapid clearance would be expected with either cationic or anionic charges, particularly anionic charges. In this study, we designed and synthesized a novel anionic Tc-99m-tricarbonyl complex ([Tc-99m] TMCE) and evaluated its use as a single-photon emission computed tomography (SPECT) imaging probe for PSMA detection. Direct synthesis of [Tc-99m] TMCE from dimethyl iminodiacetate, which contains both the asymmetric urea and succinimidyl moiety important for PSMA binding, was performed using our microwave-assisted one-pot procedure. The chelate formation was successfully achieved even though the precursor included a complicated bioactive moiety. The radiochemical yield of [Tc-99m] TMCE was 12-17%, with a radiochemical purity greater than 98% after HPLC purification. [Tc-99m] TMCE showed high affinity in vitro, with high accumulation in LNCaP tumors and low hepatic retention in biodistribution and SPECT/CT studies. These findings warrant further evaluation of [Tc-99m] TMCE as an imaging agent and support the benefit of this strategy for the design of other PSMA imaging probes.

• 出版日期2016-5-15