Initial evaluation of new 99mTC(CO)3 renal imaging agents having carboxyl-rich thioether ligands and chemical characterization. of Re(CO)3 analogues
Initial evaluation of new 99mTC(CO)3 renal imaging agents having carboxyl-rich thioether ligands and chemical characterization. of Re(CO)3 analogues
复制标题
DOI：
10.1016/j.nucmedbio.2007.06.007
复制
发表时间：
2007-08-01
影响因子：
3.1
通讯作者：
Taylor, Andrew T.
中科院分区：
文献类型：
--
作者：
He, Haiyang;Lipowska, Malgorzata;Taylor, Andrew T.
前言：首次对一种以~(131)I-马尿酸(I-131-OIH)为核芯的放射性药物Na[(TC)-T-99m(CO)(3)(LAN)]进行了人体研究，结果表明，Na[(TC)-T-99m(CO)(3)(LAN)]是一种很好的肾脏显像剂，但其清除度小于碘-131-马尿酸(I-131-OIH)，且不能直接测量肾脏的有效血浆流量。为了开发具有与I-131-OIH相当的药代动力学性质的~(99m)Tc(CO)(3)/Re(CO)(3)络合物，我们研究了羧甲基硫代琥珀酸(CMSAH(3))与硫代二琥珀酸(TDSAH(4))形成的~(99m)Tc(CO)(3)/Re(CO)(3)络合物。一旦配体通过一个硫醚和两个羧基与99m(CO)(3)结合，配合物中至少有一个未结合的羧基，这是与肾小管转运蛋白相互作用所必需的。方法：用X射线晶体结构分析[NMe4][Re(CO)(3)(CMSAH)]来解释Tc-99m示踪剂的性质。CMSAH(3)和TDSAH4通过在70℃(PH 7)下孵育每个配体和前体[TC-99m(CO)(3)(H2O)(3)](+)30分钟进行放射性标记。结果：用[(TC)-T-99m(CO)(3)(H2O)(3)](+)前驱体放射性标记CMSAH(3)和TDSAH(4)，得到定量产物。对Re(CO)(3)与CMSAH(3)和TDSAH(4)配体的分析表明，配体通过一个硫醚和两个去质子化的羧基(形成三齿双阴离子基团，一般带有两个五元螯合环)结合在Tc-99m/Re(CO)(3)配合物中。在60min时，Na-3[(TC)-T-99m(CO)(3)(TDSA)]的肾脏排泄量(尿中活度占I-131-OIH的百分比)为68+/-1%，而Na-2[(TC)-T-99m(CO)(3()CNISA)]为98+/-1%。结论：在大鼠体内，Na-2[(TC)-T-99m(CO)(3)(CMSA)]被肾脏提取并在尿中排出的速度几乎与I-131-OIH一样快；因此，Na-2[TC-99m(CO)(3)(CMSA)J]可提供有效肾血浆流量的直接测量，并有必要在人体内进行进一步的评估。(C)2007 Elsevier Inc.保留所有权利。
Introduction: The first human studies of a characterized radiopharmaceutical containing a {Tc-99m(CO)(3)}(+) core, Na[Tc-99m(CO)(3) (LAN)], demonstrated that Na[(TC)-T-99m(CO)(3)(LAN)] was an excellent renal imaging agent; however, its clearance was less than that of I-131- orthoiodohippurate (I-131-OIH), and it did not provide a direct measure of effective renal plasma flow. In order to develop a Tc-99m renal agent with pharmacokinetic properties equivalent to those of I-131-OIH, we investigated the Tc-99m(CO)(3)/Re(CO)(3) complexes formed from carboxymethylmercaptosuccinic acid (CMSAH(3)) and thiodisuccinic acid (TDSAH(4)). Once the ligand is bound to Tc-99m(CO)(3) through a thioether and two carboxyl groups, the complexes have at least one unbound carboxyl group, essential for the interaction with the renal tubular transporter.Methods: X-ray crystal structural analysis of [NMe4][Re(CO)(3)(CMSAH)] was performed to interpret the nature of Tc-99m tracers. CMSAH(3) and TDSAH4 were radiolabeled by incubating each ligand and the precursor [Tc-99m(CO)(3)(H2O)(3)](+) at 70 degrees C (pH 7) for 30 min. The products were purified by reversed-phase high-performance liquid chromatography, and biodistribution studies were performed in Sprague-Dawley rats, with (131) I-OIH as an internal control at 10 and 60 min.Results: Radiolabeling CMSAH(3) and TDSAH(4) with the [(TC)-T-99m(CO)(3)(H2O)(3)](+) precursor gave products quantitatively. Analysis of the Re (CO)(3) complexes with the CMSAH(3) and TDSAH(4) ligands demonstrates that ligands are bound in Tc-99m/Re(CO)(3) complexes through a thioether and two deprotonated carboxyl groups (forming tridentate dianionic moieties, generally with two 5-membered chelate rings). Renal excretion at 60 min (activity in the urine as a percentage of I-131-OIH) was 68 +/- 1% for Na-3[Tc-99m(CO)(3)(TDSA)] but was 98 +/- 1% for Na-2 [(TC)-T-99m(CO)(3()CNISA)].Conclusion: In rats, Na-2[(TC)-T-99m(CO)(3)(CMSA)] is extracted by the kidneys and eliminated in the urine almost as rapidly as I-131-OIH; consequently, Na-2[Tc-99m(CO)(3)(CMSA)J may provide a direct measure of effective renal plasma flow, and further evaluation in humans is warranted. (c) 2007 Elsevier Inc. All rights reserved.