New and versatile ternary ligand system for technetium radiopharmaceuticals: Water soluble phosphines and tricine as coligands in labeling a hydrazinonicotinamide-modified cyclic glycoprotein IIb/IIIa receptor antagonist with Tc-99m
New and versatile ternary ligand system for technetium radiopharmaceuticals: Water soluble phosphines and tricine as coligands in labeling a hydrazinonicotinamide-modified cyclic glycoprotein IIb/IIIa receptor antagonist with Tc-99m
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DOI：
10.1021/bc970002h
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发表时间：
1997-03-01
影响因子：
4.7
通讯作者：
Carroll, TR
中科院分区：
文献类型：
--
作者：
Edwards, DS;Liu, S;Carroll, TR
一种肼烟酰胺功能化的环血小板糖蛋白IIb/IIIa （GPIIb/IIIa）受体拮抗剂[cyclo（d - vali - nmearg - gly - asp - mamb（5-（6-（6-肼烟酰胺）己胺）））)(HYNICtide)]用Tc-99m标记，使用三嗪和水溶性膦（TPPTS，三苯基膦-3,3′，3′-三磺酸三钠；TPPDS，三苯基膦-3,3′-二磺酸二钠；或TPPMS，三苯基膦-3-单磺酸钠）作为配体。锝配合物[Tc-99m(HYNICtide)(L)(tricine)] （1, L = TPPTS; 2, L = TPPDS; 3, L = TPPMS）的合成只需一两步，收率高，比活性高（大于或等于20000 Ci/mmol）。例如，HYNICtide， [Tc-99m]高技术酸盐，氯化亚锡和三嗪在pH值4-5和室温下的反应产生配合物[Tc-99m(HYNICtide)（三嗪）(2)]，该配合物与TPPTS（50℃，30分钟）反应，根据放射性高效液相色谱测定，配合物1的产率大于或等于90%。配合物1-3是两种同分异构体形式的相等混合物，在反应混合物和稀溶液中稳定大于或等于6小时。两种异构体形式的复合体1通过血小板结合试验发现含有tc -99m标记的HYNICtide并具有生物活性。通过一系列示踪剂（Tc-99m）水平的混合配体实验，确定了这些配合物的组成为1:1:1:1:Tc:HYNICtide:L:tricine。令人惊讶的是，这种组成在相对配体比例的大范围内保持不变。通过将不同数量的TPPDS或TPPMS加入TPPTS中，确定了三种膦配体与Tc的相对键合能力，其顺序为TPPMS > TPPDS > TPPTS。[Tc-99m]HYNICtide配合物的亲脂性可以通过选择膦和氨基羧酸缀合体而系统地改变。使用三嗪和膦配体的组合，hynici衍生的肽或其他小分子可以用Tc-99m标记，具有高比活性和高稳定性，可作为放射性药物的潜在用途。
A hydrazinonicotinamide-functionalized cyclic platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonist [cyclo(D-Val-NMeArg-Gly-Asp-Mamb(5-(6-(6-hydrazinonicotinamido)hexanamide))) (HYNICtide)] was labeled with Tc-99m using tricine and a water soluble phosphine (TPPTS, trisodium triphenylphosphine-3,3',3''-trisulfonate; TPPDS, disodium triphenylphosphine-3,3'-disulfonate; or TPPMS, sodium triphenylphosphine-3-monosulfonate] as coligands. The synthesis of technetium complexes, [Tc-99m(HYNICtide)(L)(tricine)] (1, L = TPPTS; 2, L = TPPDS; 3, L = TPPMS), can be performed in one or two steps in high yield and with high specific activity (greater than or equal to 20 000 Ci/mmol). For example, the reaction of the HYNICtide, [Tc-99m]pertechnetate, stannous chloride, and tricine at pH 4-5 and room temperature results in the complex [Tc-99m(HYNICtide)(tricine)(2)], which reacts with TPPTS (50 degrees C for 30 min) to give complex 1 in greater than or equal to 90% yield as determined by radio-HPLC. Complexes 1-3 are formed as equal mixtures of two isomeric forms and are stable for greater than or equal to 6 h in the reaction mixture and in dilute solution. Both isomeric forms of complex 1 were found by a platelet-binding assay to contain the Tc-99m-labeled HYNICtide and possess biological activity. The composition of these complexes was determined to be 1:1:1:1 for Tc:HYNICtide:L:tricine through a series of mixed ligand experiments on the tracer (Tc-99m) level. Surprisingly, this composition is maintained over a wide range of relative ligand ratios. The relative bonding capability of the three phosphine coligands to the Tc was determined by spiking various amounts of TPPDS or TPPMS into TPPTS and falls in the order TPPMS > TPPDS > TPPTS. The lipophilicity of the [Tc-99m]HYNICtide complexes can be systematically varied by the choice of the phosphine and aminocarboxylate coligands. Using the combination of tricine and a phosphine ligand, HYNIC-derivatized peptides or other small molecules can be labeled with Tc-99m in high specific activity and with high stability for potential use as radiopharmaceuticals.