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.

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 ^132/135 La ³⁺ , ²¹³ Bi ³⁺ , and small ⁴⁴ Sc ³⁺ . 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 ^132/135 La ³⁺ and small ⁴⁷ Sc ³⁺ , 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 ^132/135 La ³⁺ and ⁴⁷ Sc ³⁺ to PSMA+ tumor sites. However, partial radiometal dissociation was observed, suggesting that py-macrodipa-PSMA needs further structural optimization.
Competing Interests: Conflict of Interest J.J.W. holds equity in Ratio Therapeutics (Boston, MA), which has licensed parts of this technology.