Hexadentate Bispidine Derivatives as Versatile Bifunctional Chelate Agents for Copper(II) Radioisotopes
Hexadentate Bispidine Derivatives as Versatile Bifunctional Chelate Agents for Copper(II) Radioisotopes
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DOI：
10.1021/bc800461e
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发表时间：
2009-02-01
影响因子：
4.7
通讯作者：
Comba, Peter
中科院分区：
文献类型：
--
作者：
Juran, Stefanie;Walther, Martin;Comba, Peter
报道了双吡啶衍生物（3，7-二氮杂双环[3.3.1]壬烷）作为诊断（Cu-64）或治疗（Cu-67）用放射性铜同位素的螯合配体的制备和用途。以具有一个酮基和两个酯基取代基的六齿双吡啶基双（胺）四（吡啶）配体I为原料，合成了相应的一元醇2和两个二元酸衍生物3和5。一系列的技术，包括单晶X-射线结构分析，紫外/维斯光谱，循环伏安法，薄层色谱法（TLC），和高效液相色谱法（HPLC），已被用来表征的结构和稳定性的铜（II）-bispidine配合物。已观察到在温和条件（环境温度，水溶液）下快速形成（1分钟内）稳定的铜（II）-bispidine络合物。这些复合物在高过量的竞争配体，如谷胱甘肽，cyclam，或超氧化物歧化酶（SOD）的存在下，以及在大鼠血浆中的挑战实验，没有证据表明脱金属或transchelation。双官能双吡啶衍生物5可以容易地在侧链羧酸酯基团处用生物活性分子官能化。蛙皮素类似物β homo-Glu-β Ala-β Ala-[Cha（13），Nle（14）]BBN（7-14）通过双吡啶骨架的羧酸酯与肽的N-末端缩合而偶联，产生双功能配体6。该蛙皮素-双匹定缀合物的放射性铜（II）络合物具有相当大的亲水性（log D-o/w < -2.4），这导致非常快的血液清除（血液：0.28 +/-0.02SUV，1小时p.i.），肝脏组织蓄积较低（肝脏：1.20 +/- 0.27 SUV，I h p.i.），和快速肾尿排泄（肾脏：6.06 +/- 2.96 SUV，1 h p.i.）如Cu-64-6在Wistar大鼠中的生物分布研究所示。Cu-64-6在携带人前列腺肿瘤PC-3的NMRI nu/nu小鼠中的初步体内研究显示缀合物在肿瘤中的积累（2.25 +/-0.13SUV，12.5min p.i.; 0.94+/- 0.05 SUV，55 min p.i.）并允许通过正电子发射断层扫描（PET）清楚地显示胃泌素释放肽受体分布。
The preparation and use of bispidine derivatives (3,7-diazabicyclo[3.3.1]nonane) as chelate ligands for radioactive copper isotopes for diagnosis (Cu-64) or therapy (Cu-67) are reported. Starting from the hexadentate bispidine-based bis(amine)tetrakis(pyridine) ligand I with a keto and two ester substituents, the corresponding mono-ol 2 and two dicarboxylic acid derivatives 3 and 5 have been synthesized. A range of techniques, including single-crystal X-ray structure analysis, UV/vis spectroscopy, cyclic voltammetry, thin-layer- (TLC), and high-performance liquid chromatography (HPLC), have been used to characterize the structure and stability of the copper(II)-bispidine complexes. A rapid formation (within 1 min) of stable copper(II)-bispidine complexes under mild conditions (ambient temperature, aqueous solution) has been observed. Challenge experiments of these complexes in the presence of a high excess of competing ligands, such as glutathione, cyclam, or superoxide dismutase (SOD), as well as in rat plasma, gave no evidence of demetalation or transchelation. The bifunctional bispidine derivative 5 can be readily functionalized with biologically active molecules at the pendant carboxylate groups. The coupling of a bombesin analogue beta homo-Glu-beta Ala-beta Ala-[Cha(13),Nle(14)]BBN(7-14), by condensation of a carboxylate of the bispidine backbone with the N-terminus of the peptide produced the bifunctional ligand 6. The radiocopper(II) complex of this bombesin-bispidine conjugate has a considerable hydrophilicity (log D-o/w < -2.4), and this leads to a very fast blood clearance (blood: 0.28 +/- 0.02 SUV, 1 h p.i.), low liver tissue accumulation (liver: 1.20 +/- 0.27 SUV, I h p.i.), and rapid renal-urinary excretion (kidneys: 6.06 +/- 2.96 SUV, 1 h p.i.) as shown by biodistribution studies of Cu-64-6 in Wistar rats. Preliminary in vivo studies of Cu-64-6 in NMRI nu/nu mice, bearing the human prostate tumor PC-3 showed an accumulation of the conjugate in the tumor (2.25 +/- 0.13 SUV, 12.5 min p.i.; 0.94 +/- 0.05 SUV, 55 min p.i.) and allowed a clear visualization of the gastrin-releasing peptide receptor distribution by positron emission tomography (PET).