Speaker
Description
A detailed understanding of the coordination chemistry of heavy group 2 metal ions, particularly barium as a surrogate for radium, is essential for advancing radiopharmaceutical applications of radium. This is of particular importance as radium-223 is currently the only clinically approved therapeutic alpha-emitter (by EMA and FDA). However, its clinical applications remains limited. To date, radium-223 is exclusively administered as Xofigo® for the treatment of bone metastases. Macropa represents a promising chelator capable of coordinating Ba2+ and Ra2+. Nevertheless, the stability of the formed complexes is insufficient, leading to partial dissociation, release of Ra2+ and an accumulation in the bones.
To address these limitations, cage-like chelating systems based on the macropa aza-crown-ether skeleton containing a diester bridge were synthesized Three nicotinate-based diesters with varying chain lengths were prepared and reacted with diaza-18-crown-6 (Kryptofix® K22) under high-dilution conditions to ensure 1:1 macrocyclization, affording the desired cryptands in yields of 28–59%. The complex formation of these cryptands with Ba2+ was tested by 1H NMR showing a fast and quantitative complexation at room temperature. The pKa values were determined by NMR titration, and stability constants (logK) were obtained by isothermal titration calorimetry The solid-state structures of the complexes were elucidated by single-crystal X-ray diffraction analysis.
Based on these promising results, a radiolabeling protocol was established using the gamma emitter barium-131, which is suitable for SPECT imaging. All ligands were evaluated in a serial dilution (10-3 – 10-5 M) using 100 kBq of in-house produced 131Ba (TR-Flex cyclotron). As a result, a quantitative radiochemical conversion at a ligand concentration of 10-3 M was achieved for all new chelators as confirmed by radio-TLC analyses. A certain degree of transchelation is found in challenge experiments with EDTA in excess.
F. Reissig, et al. Nucl. Med. Biol. 2021, 98, 59
F. Reissig, et al. Pharmaceuticals 2020, 13, 272