Discovery of Glutamate Carboxypeptidase III Ligands to Compete the Uptake of [Discovery of Glutamate Carboxypeptidase III Ligands to Compete the Uptake of [¹⁷⁷Lu]Lu-PSMA-617 in Healthy OrgansLu]Lu-PSMA-617 in Healthy Organs
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Date
2024-05-23
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Journal Article
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Abstract
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.
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67 (10)
Pages / Article No.
8247 - 8260
Publisher
American Chemical Society
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Subject
Cancer; Fluorescence; Ligands; Monomers; Peptides and proteins