Gallium(III) Complexes of DOTA and DOTA−Monoamide: Kinetic and Thermodynamic Studies

Given the practical advantages of the 68Ga isotope in positron emission tomography applications, gallium complexes are gaining increasing importance in biomedical imaging. However, the strong tendency of Ga3+ to hydrolyze and the slow formation and very high stability of macrocyclic complexes altogether render Ga3+ coordination chemistry difficult and explain why stability and kinetic data on Ga3+ complexes are rather scarce. Here we report solution and solid-state studies of Ga3+ complexes formed with the macrocyclic ligand 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, (DOTA)4−, and its mono(n-butylamide) derivative, (DO3AMBu)3−. Thermodynamic stability constants, log K(GaDOTA) = 26.05 and log K(GaDO3AMBu) = 24.64, were determined by out-of-cell pH-potentiometric titrations. Due to the very slow formation and dissociation of the complexes, equilibration times of up to ∼4 weeks were necessary. The kinetics of complex dissociation were followed by 71Ga NMR under both acidic and alkaline conditions. The GaDOTA complex is significantly more inert (τ1/2 ∼12.2 d at pH = 0 and τ1/2 ∼6.2 h at pH = 10) than the GaDO3AMBu analogue (τ1/2 ∼2.7 d at pH = 0 and τ1/2 ∼0.7 h at pH = 10). Nevertheless, the kinetic inertness of both chelates is extremely high and approves the application of Ga3+ complexes of such DOTA-like ligands in molecular imaging. The solid-state structure of the GaDOTA complex, crystallized from a strongly acidic solution (pH < 1), evidenced a diprotonated form with protons localized on the free carboxylate pendants.

鉴于68Ga同位素在正电子发射断层扫描（positron emission tomography）应用中的实用优势，镓配合物在生物医学成像领域的重要性与日俱增。然而，Ga³⁺极强的水解倾向，以及大环配合物缓慢的生成速率与极高的稳定性，共同使得Ga³⁺的配位化学研究极具挑战，这也解释了为何当前关于Ga³⁺配合物的稳定性与动力学数据仍较为匮乏。本研究针对大环配体1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（(DOTA)⁴⁻）及其单正丁基酰胺衍生物(DO3AMBu)³⁻所形成的Ga³⁺配合物，开展了溶液态与固态表征研究。通过胞外pH电位滴定法，测定得到其热力学稳定常数：log K(GaDOTA)=26.05，log K(GaDO3AMBu)=24.64。鉴于该类配合物生成与解离速率均极慢，实验需长达约4周的平衡时间。通过⁷¹Ga核磁共振波谱（⁷¹Ga NMR），在酸性与碱性条件下分别监测了配合物的解离动力学过程。GaDOTA配合物的动力学惰性显著优于GaDO3AMBu类似物：在pH=0时，前者的半衰期τ₁/₂约为12.2天，后者为2.7天；在pH=10时，前者半衰期约为6.2小时，后者仅为0.7小时。尽管如此，两种螯合物的动力学惰性均极高，证实了此类类DOTA配体的Ga³⁺配合物可应用于分子成像领域。从强酸性溶液（pH<1）中结晶得到的GaDOTA配合物的固态结构显示，其为双质子化形式，质子结合于游离的羧酸酯侧臂上。