A Comprehensive Study of the Sc(III)–OPC2A–Fluoride Interaction: Equilibrium, Kinetics, and 44Sc-Labeling

Macrocyclic ligands are essential for metal coordination in biomedical applications owing to the high thermodynamic stability and inertness of their complexes. In our current study, we have investigated the Sc(III)-OPC2A2–-F–system for potential diagnostic and theranostic applications (based on18F and44Sc PET, and44Sc/47Sc matched isotopic pair, respectively). Results of equilibrium studies confirmed the formation of a stable [Sc(OPC2A)]+complex (logK[Sc(OPC2A)]= 16.72(4)) in a reaction that proceeds through the formation and rearrangement of an “out of cage” intermediate. The decomplexation reaction follows a kobs= k1[H+] + k2[H+]2rate law returning a t1/2= 0.37 h in 1 M HCl, and an unmeasurable long t1/2at pH = 7.4. The [Sc(OPC2A)F] mixed complex is remarkably stable; logK[Sc(OPC2A)F]= 4.54(8) and moderately inert against F–- exchange, with kd298= 16.5 s–1and activation parameters ΔH‡= 78 ± 1 kJ·mol–1, ΔS‡= 42 ± 4 J·mol–1K–1, and ΔG‡298= 66 ± 1 kJ·mol–1. The [44Sc]Sc(III)-labeled [Sc(OPC2A)]+forms at 95 °C within 10 min but requires purification. The complex is stable in rat blood serum, and toward transmetalation and transchelation processes. Consequently, the OPC2A is an excellent ligand platform for Sc(III) complexation and is recommended for further in vivo studies.