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

• Published in: Bioconjugate chemistry Vol. 33; no. 12; pp. 2381 - 2397
• Main Authors: Wharton, Luke, Zhang, Chengcheng, Zeisler, Jutta, Rodríguez-Rodríguez, Cristina, Osooly, Maryam, Radchenko, Valery, Yang, Hua, Lin, Kuo-Shyan, Bénard, François, Schaffer, Paul, Orvig, Chris
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.12.2022; Amer Chemical Soc
• Subjects: Alkynes; Antifungal agents; Biochemical Research Methods; Biochemistry & Molecular Biology; Chelating agents; Chemistry; Chemistry, Multidisciplinary; Chemistry, Organic; Complexation; Cycloaddition; Density functional theory; In vivo methods and tests; Life Sciences & Biomedicine; Ligands; Metal ions; NMR; Nuclear magnetic resonance; Pharmaceuticals; Physical Sciences; Precision medicine; Radioactive tracers; Radiochemistry; Radioisotopes; Radiolabelling; Science & Technology; Single photon emission computed tomography; Stability; Synthesis; Triazoles; Tumors; PSEUDOPOTENTIALS; GENERATOR; AC-225; THERAPY; LIGAND
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/acs.bioconjchem.2c00465

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.