HTPAN-Triazole-Bn-NH: Tripicolinate Clicked-Bifunctional Chelate for [Ac]/[In] Theranostics.

A new, high-denticity, bifunctional ligand─HTPAN-triazole-Bn-NH─has been synthesized and studied in complexation with [Ac]Ac and [In]In 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-catalyzed alkyne-azide cycloaddition (click) chemistry. Nuclear magnetic resonance (NMR) studies of HTPAN-triazole-Bn-NH with La and In 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 [Ac]Ac and [In]In showed highly effective complexation, achieving quantitative radiochemical conversions at low ligand concentrations (<10 M) under mild conditions (RT, 10 min), which is further accompanied by high stability in human serum. The bioconjugate─HTPAN-triazole-Bn-Aoc-Pip-Nle-CycMSH─was prepared for targeting of MC1R-positive tumors, and the corresponding In-radiolabeled tracer was studied . SPECT/CT and biodistribution studies in C57BL/6J mice bearing B16-F10 tumors were performed, with the radiotracer showing good stability; tumor uptake was achieved. This work highlights a new promising and versatile bifunctional chelator, easily prepared and encouraging for Ac/In theranostics.