Improving the In Vivo Stability of [⁵²Mn]Mn(II) Complexes with 18-Membered Macrocyclic Chelators for PET Imaging

We report the [^natMn/⁵²Mn]Mn(II) complexes of the macrocyclic chelators PYAN [3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane] and CHXPYAN [(4¹R,4²R,10¹R,10²R)-3,5,9,11-tetraaza-1,7(2,6)-dipyridina-4,10(1,2)-dicyclohexanacyclododecaphane]. The X-ray crystal structures of Mn-PYAN and Mn-CHXPYAN evidence distorted octahedral geometries through coordination of the nitrogen atoms of the macrocycles. Cyclic voltammetry studies evidence reversible processes due to the Mn(II)/Mn(III) pair, indicating that the complexes are resistant to oxidation. CHXPYAN forms a more thermodynamically stable and kinetically inert Mn(II) complex than PYAN. Radiochemical studies with the radioactive isotope manganese-52 (⁵²Mn, t_1/2 = 5.6 days) evidenced better radiochemical yields for CHXPYAN than for PYAN. Both [⁵²Mn]Mn(II) complexes remained stable in mouse and human serum, so in vivo stability studies were carried out. Positron emission tomography/computed tomography scans and biodistribution assays indicated that [⁵²Mn]Mn-PYAN has a distribution pattern similar to that of [⁵²Mn]MnCl₂, showing persistent radioactivity accumulation in the kidneys. Conversely, [⁵²Mn]Mn-CHXPYAN remained stable in vivo, clearing quickly from the liver and kidneys.