Discovery of Glutamate Carboxypeptidase III Ligands to Compete the Uptake of [177Lu]Lu-PSMA-617 in Healthy Organs

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 cros...

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Bibliographic Details
Published inJournal of medicinal chemistry Vol. 67; no. 10; pp. 8247 - 8260
Main Authors Müller, Marco, Lucaroni, Laura, Favalli, Nicholas, Bassi, Gabriele, Neri, Dario, Cazzamalli, Samuele, Oehler, Sebastian
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 23.05.2024
Amer Chemical Soc
Subjects
Antigens, Surface
Autoradiography
Chemistry, Medicinal
Dipeptides - chemistry
Dipeptides - metabolism
Glutamate Carboxypeptidase II
Heterocyclic Compounds, 1-Ring - chemistry
Heterocyclic Compounds, 1-Ring - metabolism
Humans
Life Sciences & Biomedicine
Ligands
Lutetium - chemistry
Lutetium - metabolism
Pharmacology & Pharmacy
Prostate-Specific Antigen
Radioisotopes - chemistry
Radioisotopes - metabolism
Radiopharmaceuticals - chemistry
Radiopharmaceuticals - metabolism
Radiopharmaceuticals - pharmacokinetics
Salivary Glands - metabolism
Science & Technology
Structure-Activity Relationship
Tissue Distribution
RADIOLIGAND THERAPY
BOTULINUM TOXIN
MEMBRANE ANTIGEN
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Summary: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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ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.4c00332