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 L 2 (with a tridentate bipyridine acetate appended to N3 and a picolinate at N7) has been shown before to be an ideal chelator for 111 In 3+ , 177 Lu 3+ , and 225 Ac 3+ , 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 L 3 , in which the bipyridine acetate is substituted with terpyridine, a softer donor for metal ions with a preference for more covalency. L 3 did not fulfill the hopes because complexation is much less efficient. While for Bi 3+ and Pb 2+ the ligand is an excellent chelator with properties similar to those of L 2 , Lu 3+ and La 3+ show very slow and inefficient complexation with L 3 in contrast to L 2 , and 225 Ac 3+ is not fully coordinated, even at an increased temperature (92% radiochemical yield at 80 °C, 60 min, [ L 3 ] = 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 L 2 has been extended to Bi 3+ , La 3+ , and Pb 2+ , including solid state and solution structural work, complex stabilities, radiolabeling, and radiostability studies. All complexes of this ligand (La 3+ , Ac 3+ , Lu 3+ , Bi 3+ , In 3+ , and Pb 2+ ), 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 225 Ac, the daughter nuclides 213 Bi and 209 Pb also form stable complexes, and this is important for reducing damage to healthy tissue.