Exploring the use of rigid 18-membered macrocycles with amide pendant arms for Pb(II)-based radiopharmaceuticals

Abstract

[Abstract]: We report a detailed investigation on the use of chelators PYTAM, H4PYTAMGly, CHX-PYTAM and H4CHX-PYTAMGly for the complexation of Pb(II)-radioisotopes with potential use in the preparation of radiopharmaceuticals. The macrocyclic backbones from which the chelators are prepared, PYAN (3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane) or CHX-PYAN ((41R,42R,101R,102R)-3,5,9,11-tetraaza-1,7(2,6)-dipyridina-4,10(1,2)-dicyclohexanacyclododecaphane), are readily synthesized in high yields using a Ba(II) template synthesis. The single difference between the two backbones is that while PYAN contains ethylene spacers, CHX-PYAN incorporates more rigid cyclohexyl spacers. The pendant arms incorporated into the backbone were strategically chosen, selecting amide pendants of different nature, compatible with the borderline Lewis acid character of Pb(II). To study the complexation of Pb(II), first, a detailed characterization of the non-radioactive complexes was carried out, including X-ray crystallography, NMR, and the determination of chelator protonation and stability constants of the complexes. Once the complexes were fully characterized and showed favourable properties towards Pb(II), a radiochemical study using the SPECT compatible radioisotope lead-203 was performed. Although all tested chelators sufficiently complexed lead-203 and presented excellent complex stability in human serum, it was found that novel chelator CHX-PYTAM was superior over the others due to its high kinetic inertness. This effect is due to increased rigidity of the complex with cyclohexyl spacers in the backbone and use of primary amides, over secondary amides, as pendant arms and thus this chelator is a promising candidate for future in vivo studies.