H 3 TPAN-Triazole-Bn-NH 2 : Tripicolinate Clicked-Bifunctional Chelate for [ 225 Ac]/[ 111 In] Theranostics.

A new, high-denticity, bifunctional ligand─H 3 TPAN-triazole-Bn-NH 2 ─has been synthesized and studied in complexation with [ 225 Ac]Ac 3+ and [ 111 In]In 3+ for radiopharmaceutical applications. The bifunctional chelator is readily synthesized, using a high-yielding four-step prep, which is highly adaptable and allows for straightforward incorporation of different covalent linkers using Cu I -catalyzed alkyne-azide cycloaddition (click) chemistry. Nuclear magnetic resonance (NMR) studies of H 3 TPAN-triazole-Bn-NH 2 with La 3+ and In 3+ metal ions show the formation of a single, asymmetric complex with each ion in solution, corroborated by density functional theory (DFT) calculations. Radiolabeling studies with [ 225 Ac]Ac 3+ and [ 111 In]In 3+ showed highly effective complexation, achieving quantitative radiochemical conversions at low ligand concentrations (<10 -6 M) under mild conditions (RT, 10 min), which is further accompanied by high stability in human serum. The bioconjugate─H 3 TPAN-triazole-Bn-Aoc-Pip-Nle-CycMSH hex ─was prepared for targeting of MC1R-positive tumors, and the corresponding 111 In-radiolabeled tracer was studied in vivo . SPECT/CT and biodistribution studies in C57BL/6J mice bearing B16-F10 tumors were performed, with the radiotracer showing good in vivo stability; tumor uptake was achieved. This work highlights a new promising and versatile bifunctional chelator, easily prepared and encouraging for 225 Ac/ 111 In theranostics.