Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Walther-Meissner Strasse 3, 85748 Garching, Germany.
Chemistry. 2013 Jun 10;19(24):7748-57. doi: 10.1002/chem.201300338. Epub 2013 Apr 23.
The cyclen-based tetraphosphinate chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis[methylene(2-carboxyethyl)phosphinic acid] (DOTPI) comprises four additional carboxylic acid moieties for bioconjugation. The thermodynamic stability constants (logK(ML)) of metal complexes, as determined by potentiometry, were 23.11 for Cu(II), 20.0 for Lu(III), 19.6 for Y(III), and 21.0 for Gd(III). DOTPI was functionalized with four cyclo(Arg-Gly-Asp-D-Phe-Lys) (RGD) peptides through polyethylene glycol (PEG4) linkers. The resulting tetrameric conjugate DOTPI(RGD)4 was radiolabeled with (177)Lu and (64)Cu and showed improved labeling efficiency compared with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The labeled compounds were fully stable in transchelation challenges against trisodium diethylenetriaminepentaacetate (DTPA) and disodium ethylenediaminetetraacetic acid (ETDA), in phosphate buffered saline (PBS), and human plasma. Integrin αvβ3 affinities of the non-radioactive Lu(III) and Cu(II) complexes of DOTPI(RGD)4 were 18 times higher (both IC50 about 70 picomolar) than that of the c(RGDfK) peptide (IC50 = 1.3 nanomolar). Facile access to tetrameric conjugates and the possibility of radiolabeling with therapeutic and diagnostic radionuclides render DOTPI suitable for application in peptide receptor radionuclide imaging (PRRI) and therapy (PRRT).
基于环戊二烯的四膦酸盐螯合剂 1,4,7,10-四氮杂环十二烷-1,4,7,10-四[亚甲基（2-羧乙基）膦酸]（DOTPI）包含四个用于生物缀合的额外羧酸部分。通过电位法测定，金属配合物的热力学稳定常数（logK（ML））为 23.11 对于 Cu(II)，20.0 对于 Lu(III)，19.6 对于 Y(III)，21.0 对于 Gd(III)。DOTPI 通过聚乙二醇（PEG4）接头与四个环（精氨酸-甘氨酸-天冬氨酸-D-苯丙氨酸-赖氨酸）（RGD）肽进行功能化。所得四聚体缀合物 DOTPI(RGD)4 用（177）Lu 和（64）Cu 标记，并显示出与 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）相比，标记效率提高。标记化合物在反螯合挑战中对三钠二乙撑三胺五乙酸（DTPA）和二钠乙二胺四乙酸（EDTA）、磷酸盐缓冲盐水（PBS）和人血浆中完全稳定。DOTPI(RGD)4 的非放射性 Lu(III)和 Cu(II)配合物的整联蛋白αvβ3 亲和力均高于 c(RGDfK)肽（IC50=1.3 纳摩尔）的 18 倍（两者的 IC50 均约为 70 皮摩尔）。容易获得四聚体缀合物以及用治疗和诊断放射性核素进行放射性标记的可能性，使得 DOTPI 适合用于肽受体放射性核素成像（PRRI）和治疗（PRRT）。
