biostudies-literatureHu AU.S. Department of EnergyNIBIB NIH HHSNIGMS NIH HHSNational Science Foundatione202300457https://www.ebi.ac.uk/biostudies/studies/S-EPMC10939043biostudies-literatureUnknown26(35)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.European journal of inorganic chemistryConstruction 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.PMC10939043DESC0020197CHE-1531632T32 GM136572R01 EB029259R21 EB027282Boros EWilson JJEngle JWMartin KESmilowicz DHu ACingoranelli SJLapi SEAluicio-Sarduy EfalseConstruction 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.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.2023-01-01T00:00:00Z2023 Dec2025-04-04T02:32:47.025Z2025-04-04T02:32:47.025ZS-EPMC109390433849559610.1002/ejic.202300457