Construction of the Bioconjugate Py‐Macrodipa‐PSMA and Its In Vivo Investigations with Large 132/135La3+ and Small 47Sc3+ 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: Weinheim Wiley Subscription Services, Inc 12.12.2023
• Subjects: anticancer agents; chelates; Chelating agents; Complex formation; In vivo methods and tests; PSMA; radiopharmaceuticals; rare earths; Stability analysis; Tumors; Xenotransplantation
• 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 132/135La3+, 213Bi3+, and small 44Sc3+. 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 132/135La3+ and small 47Sc3+, 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 132/135La3+ and 47Sc3+ to PSMA+ tumor sites. However, partial radiometal dissociation was observed, suggesting that py‐macrodipa‐PSMA needs further structural optimization. A bifunctional chelator py‐macrodiap‐NCS was prepared over 10 steps. Py‐macrodipa‐NCS shows adequate hydrolytic stability and was conjugated to a PSMA‐targeting vector, yielding a bioconjuate py‐macrodipa‐PSMA. Py‐macrodipa‐PSMA delivered both large radiometal 132/135La3+ and small 47Sc3+ to PSMA+ tumors, but further structural optimization is needed to improve its in vivo radiocomplex stability.