Research & Teaching Faculty

H3TPAN-Triazole-Bn-NH2: Tripicolinate Clicked-Bifunctional Chelate for [225Ac]/[111In] Theranostics

TitleH3TPAN-Triazole-Bn-NH2: Tripicolinate Clicked-Bifunctional Chelate for [225Ac]/[111In] Theranostics
Publication TypeJournal Article
Year of Publication2022
AuthorsWharton, L, Zhang, C, Zeisler, J, Rodríguez-Rodríguez, C, Osooly, M, Radchenko, V, Yang, H, Lin, K-S, Bénard, F, Schaffer, P, Orvig, C
JournalBioconjugate Chem.

A new, high-denticity, bifunctional ligand─H3TPAN-triazole-Bn-NH2─has been synthesized and studied in complexation with [225Ac]Ac3+ and [111In]In3+ 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 CuI-catalyzed alkyne–azide cycloaddition (click) chemistry. Nuclear magnetic resonance (NMR) studies of H3TPAN-triazole-Bn-NH2 with La3+ and In3+ 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 [225Ac]Ac3+ and [111In]In3+ 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─H3TPAN-triazole-Bn-Aoc-Pip-Nle-CycMSHhex─was prepared for targeting of MC1R-positive tumors, and the corresponding 111In-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 225Ac/111In theranostics.

Refereed DesignationRefereed