Construction of the Bioconjugate Py‐Macrodipa‐PSMA and Its In Vivo Investigations with Large <sup>132/135</sup>La<sup>3+</sup> and Small <sup>47</sup>Sc<sup>3+</sup> Radiometal Ions
Aohan Hu, Kirsten Martin, Dariusz Śmiłowicz, Eduardo Aluicio‐Sarduy, Shelbie J. Cingoranelli, Suzanne E. Lapi, Jonathan W. Engle, Eszter Boros, Justin J. Wilson
Abstract
Abstract 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.