Gallium(III) Complexes of DOTA and DOTA-Monoamide: Kinetic and Thermodynamic Studies
Gallium(III) Complexes of DOTA and DOTA-Monoamide: Kinetic and Thermodynamic Studies
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DOI：
10.1021/ic101378s
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发表时间：
2010-12-06
影响因子：
4.6
通讯作者：
Lukes, Ivan
中科院分区：
文献类型：
--
作者：
Kubicek, Vojtech;Havlickova, Jana;Lukes, Ivan
鉴于Ga-68同位素在正电子发射断层扫描中的实际应用优势，镓配合物在生物医学成像中正变得越来越重要。然而，由于GA~(3+)强烈的水解性以及大环配合物的缓慢形成和很高的稳定性，使得GA~(3+)配位化学变得困难，并解释了为什么关于GA~(3+)络合物的稳定性和动力学数据相当匮乏。本文报道了大环配体1，4，7，10-tetraazacyclododecane-1，4，7，10-tetraacetic酸(DOTA)(4-)及其单(正丁酰胺)衍生物(DO3AM(Bu))(3-)与GA~(3+)形成的络合物的溶液和固态研究。用胞外pH-电位滴定法测定了其热力学稳定常数，logK(GaDOTA)=26.05，logK(GaDO3AM(Bu))=24.64。由于络合物的形成和解离非常缓慢，需要长达4周的平衡时间。在酸性和碱性条件下，用Ga-71核磁共振研究了络合物的解离动力学。与GaDO3AM(Bu)类似物(在pH=0时，tau(1/2)类似于2.7d，在pH=10时，tau(1/2)类似于0.7h)相比，GaDOTA络合物的惰性更强(在pH=0时，tau(1/2)类似于12.2 d，在pH=10时，tau(1/2)类似于6.2h)。然而，这两种络合物的动力学惰性都非常高，这证实了这类DOTA类配体的GA3+络合物在分子成像中的应用。GaDOTA络合物的固态结构，从强酸性溶液(pH<；1)结晶出来，证明是双质子化的形式，质子定位在游离的羧酸盐侧垂上。
Given the practical advantages of the Ga-68 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, (DO3AM(Bu))(3-). Thermodynamic stability constants, log K(GaDOTA) = 26.05 and log K(GaDO3AM(Bu)) = 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 similar to 4 weeks were necessary. The kinetics of complex dissociation were followed by Ga-71 NMR under both acidic and alkaline conditions. The GaDOTA complex is significantly more inert (tau(1/2) similar to 12.2 d at pH = 0 and tau(1/2) similar to 6.2 h at pH = 10) than the GaDO3AM(Bu) analogue (tau(1/2) similar to 2.7 d at pH = 0 and tau(1/2) similar to 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.