Bispidine Chelators for Radiopharmaceutical Applications with Lanthanide, Actinide, and Main Group Metal Ions

Octadentate and specifically nonadentate ligands with a bispidine scaffold (3,7-diazabicyclo[3.3.1]nonane) are known to be efficiently coordinated to a range of metal ions of interest in radiopharmaceutical chemistry and lead to exceedingly stable and inert complexes. Nonadentate bispidine L² (with a tridentate bipyridine acetate appended to N3 and a picolinate at N7) has been shown before to be an ideal chelator for ¹¹¹In³⁺, ¹⁷⁷Lu³⁺, and ²²⁵Ac³⁺, nuclides of interest for diagnosis and therapy, and a proof-of-principle study with an SSTR2-specific octreotate has shown potential for theranostic applications. We now have extended these studies in two directions. First, we present ligand derivative L³, in which the bipyridine acetate is substituted with terpyridine, a softer donor for metal ions with a preference for more covalency. L³ did not fulfill the hopes because complexation is much less efficient. While for Bi³⁺ and Pb²⁺ the ligand is an excellent chelator with properties similar to those of L², Lu³⁺ and La³⁺ show very slow and inefficient complexation with L³ in contrast to L², and ²²⁵Ac³⁺ is not fully coordinated, even at an increased temperature (92% radiochemical yield at 80 °C, 60 min, [L³] = 10^-4 M). These observations have led to a hypothesis for the complexation pathway that is in line with all of the experimental data and supported by a preliminary density functional theory analysis, which is important for the design of further optimized bispidine chelators. Second, the coordination chemistry of L² has been extended to Bi³⁺, La³⁺, and Pb²⁺, including solid state and solution structural work, complex stabilities, radiolabeling, and radiostability studies. All complexes of this ligand (La³⁺, Ac³⁺, Lu³⁺, Bi³⁺, In³⁺, and Pb²⁺), including nuclides for targeted α therapy (TAT), single-photon emission computed tomography, and positron emission tomography, are formed efficiently under physiological conditions, i.e., suitable for the labeling of delicate biological vectors such as antibodies, and the complexes are very stable and inert. Importantly, for TAT with ²²⁵Ac, the daughter nuclides ²¹³Bi and ²⁰⁹Pb also form stable complexes, and this is important for reducing damage to healthy tissue.