Prostate-specific membrane antigen (PSMA)-targeted radio ligand therapeutics (RLTs), such as [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto), have been shown to accumulate in salivary glands and kidneys, potentially leading to undesired side effects. As unwanted accumulation in normal organs may derive from the cross-reactivity of PSMA ligands to glutamate carboxypeptidase III (GCPIII), it may be convenient to block this interaction with GCPIII-selective ligands. Parallel screening of a DNA-encoded chemical library (DEL) against GCPIII and PSMA allowed the identification of GCPIII binders. Structure–activity relationship (SAR) studies resulted in the identification of nanomolar GCPIII ligands with up to 1000-fold selectivity over PSMA. We studied the ability of GCPIII ligands to counteract the binding of [¹⁷⁷Lu]Lu-PSMA-617 to human salivary glands by autoradiography and could demonstrate a partial radioprotection.

中文翻译：

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发现谷氨酸羧肽酶 III 配体以竞争健康器官对 [177Lu]Lu-PSMA-617 的摄取


前列腺特异性膜抗原 (PSMA) 靶向放射配体疗法 (RLT)，例如 [ ¹⁷⁷ Lu]Lu-PSMA-617 (Pluvicto)，已被证明会在唾液腺和肾脏中积聚，可能会积聚在唾液腺和肾脏中。导致不良的副作用。由于正常器官中不需要的积累可能源自 PSMA 配体与谷氨酸羧肽酶 III (GCPIII) 的交叉反应性，因此用 GCPIII 选择性配体阻断这种相互作用可能会很方便。针对 GCPIII 和 PSMA 的 DNA 编码化学文库 (DEL) 的并行筛选允许鉴定 GCPIII 结合物。构效关系 (SAR) 研究鉴定出纳摩尔 GCPIII 配体，其选择性比 PSMA 高 1000 倍。我们通过放射自显影研究了 GCPIII 配体抵消 [ ¹⁷⁷ Lu]Lu-PSMA-617 与人唾液腺结合的能力，并证明了部分辐射防护作用。