Publications Repository - Helmholtz-Zentrum Dresden-Rossendorf

Octa- 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. The 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. Firstly, we present the ligand derivative L3, where 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 similar properties to 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 elevated temperature (92% radiochemical yield (RCY) 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 experimental data and supported by a preliminary DFT analysis, which is of importance for the design of further optimized bispidine chelators. Secondly, 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+, Pb2+), including nuclides for targeted alpha therapy (TAT), single photon emission computed tomography (SPECT), and positron emission tomography (PET) are formed efficiently at 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 of importance to reduce damage to healthy tissue.