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

Abstract

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.

Construction of the Bioconjugate Py‐Macrodipa‐PSMA and Its In Vivo Investigations with Large 132/135La3+ and Small 47Sc3+ Radiometal Ions

“…Because we had previously observed excellent stability of both complexes of unfunctionalized py-macrodipa in human serum, this result demonstrates how radiometal complex stability can be substantially different when incorporated into targeted agents, consistent with similar observations in the literature. [36,37] In any case, this study provides another recent example of leveraging the same construct for targeted nuclear medicine applications with two chemically disparate radiometals, [10][11][12] like 132/135 La 3 + and 47 Sc 3 + in this case. We further note that these initial in vivo studies are limited by the lack of additional time points and the lower molar activity of the 47 Sc used.…”

“…Recent studies have revealed that a bispidine ligand can rapidly and stably bind to both 225 Ac 3+ and 177 Lu 3+ [10] . Likewise, some acyclic picolinate ligands were also found to mutually stabilize 225 Ac 3+ and 111 In 3+ [11,12] . In our contribution to this area, we recently reported a unique class of chelators that possess dual size selectivity, a property that confers good affinity for both the large and small metal ions.…”

“…[10] Likewise, some acyclic picolinate ligands were also found to mutually stabilize 225 Ac 3 + and 111 In 3 + . [11,12] In our contribution to this area, we recently reported a unique class of chelators that possess dual size selectivity, a property that confers good affinity for both the large and small metal ions. This unusual selectivity pattern arises from a significant change in ligand binding mode to afford two distinct complex conformations that maximally stabilize both large and small metal ions.…”

Click Chemistry and Radiochemistry: An Update

“…Structure of H 3 TPAN-triazole-Bn-NH 2 (A) as well as DFT-calculated structures of H 3 TPAN-triazole-Bn-NH 2 bound to (B) Ac 3+ and (C) In 3+ . Panels (B,C) were reproduced with permission from ref . Copyright 2022 American Chemical Society.…”

“…108 Finally, this approach has recently been extended beyond the realm of 99m Tc and its congeners by Wharton et al In this case, the investigators used the CuAAC reaction to create a bifunctional chelator, H 3 TPAN-triazole-Bn-NH 2 , in which the 1,2,3-triazole both coordinates the radiometal and attaches the chelator to the vector in question (Figure 9). 109 This acyclic chelator offers several advantages over extant options, including its synthetic accessibility, lack of steric hindrance, and compatibility with both 225 Ac and 111 In.…”