Construction of the Bioconjugate Py-Macrodipa-PSMA and Its In Vivo Investigations with Large 132/135 La 3+ and Small 47 Sc 3+ Radiometal Ions

• Published in: European journal of inorganic chemistry Vol. 26; no. 35
• Main Authors: Hu, Aohan, Martin, Kirsten E, Śmiłowicz, Dariusz, Aluicio-Sarduy, Eduardo, Cingoranelli, Shelbie J, Lapi, Suzanne E, Engle, Jonathan W, Boros, Eszter, Wilson, Justin J
• Format: Journal Article
• Language: English
• Published: Germany Wiley Blackwell (John Wiley & Sons) 12.12.2023
• Subjects: PSMA; Anticancer agents; Rare earth; Radiopharmaceuticals; Chelate
• ISSN: 1434-1948; 1099-0682
• DOI: 10.1002/ejic.202300457

To harness radiometals in clinical settings, a chelator forming a stable complex with the metal of interest and targets the desired pathological site is needed. Toward this goal, we previously reported a unique set of chelators that can stably bind to both large and small metal ions, via a conformational switch. Within this chelator class, py-macrodipa is particularly promising based on its ability to stably bind several medicinally valuable radiometals including large La , Bi , and small Sc . Here, we report a 10-step organic synthesis of its bifunctional analogue py-macrodipa-NCS, which contains an amine-reactive -NCS group that is amenable for bioconjugation reactions to targeting vectors. The hydrolytic stability of py-macordipa-NCS was assessed, revealing a half-life of 6.0 d in pH 9.0 aqueous buffer. This bifunctional chelator was then conjugated to a prostate-specific membrane antigen (PSMA)-binding moiety, yielding the bioconjugate py-macrodipa-PSMA, which was subsequently radiolabeled with large La and small Sc , revealing efficient and quantitative complex formation. The resulting radiocomplexes were injected into mice bearing both PSMA-expressing and PSMA-non-expressing tumor xenografts to determine their biodistribution patterns, revealing delivery of both La and Sc to PSMA+ tumor sites. However, partial radiometal dissociation was observed, suggesting that py-macrodipa-PSMA needs further structural optimization.