A Comprehensive Study of the Sc(III)–OPC2A–Fluoride Interaction: Equilibrium, Kinetics, and ⁴⁴ Sc-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)-OPC2A^2--F^- system for potential diagnostic and theranostic applications (based on ¹⁸F and ⁴⁴Sc PET, and ⁴⁴Sc/⁴⁷Sc matched isotopic pair, respectively). Results of equilibrium studies confirmed the formation of a stable [Sc(OPC2A)]⁺ complex (log<i>K</i>_[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 <i>k</i>_obs = <i>k</i>₁[H⁺] + <i>k</i>₂[H⁺]² rate law returning a <i>t</i>_1/2 = 0.37 h in 1 M HCl, and an unmeasurable long <i>t</i>_1/2 at pH = 7.4. The [Sc(OPC2A)F] mixed complex is remarkably stable; log<i>K</i>_[Sc(OPC2A)F] = 4.54(8) and moderately inert against F^-- exchange, with <i>k</i>_d²⁹⁸ = 16.5 s^-1 and activation parameters Δ<i>H</i>^‡ = 78 ± 1 kJ·mol^-1, Δ<i>S</i>^‡ = 42 ± 4 J·mol^-1K^-1, and Δ<i>G</i>^‡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 <i>in vivo</i> studies.