Sc(III) Complexes of Pyclen Derivative Ligands as Probes for Hypoxia: Synthesis, Chemical Characterization,...

Rigid pyclen derivative ligands bearing hypoxia-sensitive nitroimidazole (NI) pendants, PC2A-Ph-NI (hexadentate) and PC2AM-NI (heptadentate), were synthesized, radiolabeled with ⁴⁴Sc(III), and evaluated under preclinical circumstances. Physicochemical characterization was carried out using the structurally related model ligand, PC2AM^nBu, by multinuclear NMR, UV-Vis spectroscopy, and pH-potentiometry. Sc(III) ion was found to form a stable complex with PC2AM^nBu (log K_ScL = 19.53(4); pSc = 19.32), in a reasonably fast reaction, with outstanding inertness (t_1/2 = 529 hours in 1 M HClO₄). The [Sc(PC2AM^nBu)]⁺ complex can coordinate fluoride (log K_ScLF = 2.5(2)), and the ternary complex is remarkably inert against fluoride exchange. Based on these results, the PC2A-mono(amide) platform seems to be a promising Sc(III)-binder, paving the way for the labeling of NI-containing ligands with ⁴⁴Sc(III). Followed by successful radiolabeling with the positron-emitting ⁴⁴Sc isotope, labeling yields of 92% and over 99% were evidenced for [⁴⁴Sc][Sc(PC2AM-NI)]⁺ and [⁴⁴Sc][Sc(PC2A-Ph-NI)]⁺; respectively, at 95 °C and 15 minutes; moreover, after purification, the radiochemical purity exceeded 99%. Both radiocomplexes remained stable in rat blood serum for at least 4 hours and exhibited high resistance toward transmetalation and transchelation processes. MicroPET imaging with preclinical models of B16-F10 mouse melanoma was conducted to assess the tumor targeting capability and the in vivo biodistribution pattern of [⁴⁴Sc][Sc(PC2AM-NI)] and [⁴⁴Sc][Sc(PC2A-Ph-NI)]⁺ radiopharmaceuticals. Given the higher tumor uptakes of [⁴⁴Sc][Sc(PC2A-Ph-NI)]⁺ with decreasing off-target activity and related better tumor/noise ratios, we may conclude that the diagnostic potential of the PC2A-Ph-NI derivative outperforms that of the [⁴⁴Sc][Sc(PC2AM-NI)]⁺.