Toward Personalized Medicine: One Chelator for Imaging and Therapy with Lutetium-177 and Actinium-225

We report a nonadentate bispidine (3,7-diazabicyclo[3.3.1]nonane) that unveils the potential to bind theranostically relevant radionuclides, including indium-111, lutetium-177, and actinium-225 under mild labeling conditions. This radiopharmaceutical candidate allows the simultaneous application of imaging and treatment (radionuclide theranostics) without changing the type of the bioconjugate; that is, it allows the strong binding to an imaging and a therapeutic radionuclide by the same chelator. Since sophisticated coordination chemistry is required to achieve high thermodynamic and kinetic stability (inertness), it is not surprising that only a few chelators have been reported that are able to strongly bind several radionuclides to a satisfactory extent. Bispidine-derived ligands have proven to be ideal for di-and trivalent metal ions with generally fast complexation kinetics and high in vitro and in vivo stabilities. The presented (radio)complexes are formed under mild conditions (pH 6, <40 degrees C) and exhibit thermodynamic stability and inertness in human serum comparable to the corresponding DOTA complexes. The bispidine-based complexing agent was conjugated to a peptide, targeting somatostatin type 2 receptors (SSTR2), overexpressed on neuroendocrine tumors. The 177Lu-and 225Ac-labeled conjugates were investigated, considering their binding to two different SSTR2-positive cell lines, including the human pancreatic carcinoid tumor (BON-SSTR2+) and the murine pheochromocytoma cell line (MPC). The biodistribution and accumulation pattern in MPC tumor-bearing mice was also evaluated. The LuIII and AcIII complexes studied show how ligand structures can be optimized in general by extending the denticity and varying the donor set in order to allow for fast complex formation and medically relevant inertness.

Automated summary

We report a nonadentate bispidine compound that can bind theranostically relevant radionuclides under mild labeling conditions. The compound shows high stability and inertness in human serum, allowing for simultaneous imaging and treatment without changing the type of bioconjugate. The compound, when conjugated to a peptide, can target and treat neuroendocrine tumors. The study also investigates the biodistribution and accumulation pattern in cell lines and mouse models.