Vanbilloen H P, Bormans G M, De Roo M J, Verbruggen A M
Laboratory of Radiopharmaceutical Chemistry, F.F.W., K.U. Leuven, Belgium.
Nucl Med Biol. 1995 Apr;22(3):325-38. doi: 10.1016/0969-8051(94)00110-6.
Tetrapeptides are a class of N4-tetraligands that can efficiently bind 99mTc. In fact, tetrapeptides can be considered as derivatives of mercaptoacetyltriglycine (MAG3) in which the mercaptoacetyl moiety is replaced by a more stable and easier to handle aminoacyl group. Direct labelling of tetrapeptides with 99mTc in alkaline medium (pH > or = 11) in the presence of stannous ions gave a high yield (> 95%) of one or two (probably isomeric) radiochemical species. Exchange labelling at different pH values in the presence of stannous tartrate resulted in lower yields of the same 99mTc-labelled products as those formed during direct labelling. In addition, other radiochemical species were formed of which one was characterized as an oxotechnetium-complex with the cyclisized tetrapeptide. Tetrapeptides with a chiral centre in the first amino acid yield upon labelling with 99mTc two radiochemical species, probably the two diastereomers with an oxotechnetium core respectively syn and anti with respect to the substituent on the amino acid. Only one diastereomer was observed when the chiral carbon atom is located in the second or third amino acid. Electrophoresis indicated that these new 99mTc-labelled complexes are neutral in acidic medium and negatively charged in neutral and alkaline conditions. This correlates with a complex in which an oxotechnetium(V) group is bound to the ligand through three deprotonated nitrogen atoms of the amide functions and the free electron pair of the amine nitrogen atom. Biodistribution in mice showed for all studied 99mTc-labelled tetrapeptides a rapid clearance from the blood mainly by the renal system. The presence of a methyl substituent in the tetrapeptide increased the urinary excretion. 99mTc-labelled L-glycylalanylglycylglycine showed in mice a urinary excretion comparable to that of 99mTc-MAG3. Further rise of lipophilicity by introduction of a dimethyl, isopropyl or isobutyryl group leads to increased hepatobiliary handling. It is concluded that tetrapeptides are an interesting group of technetium complexing agents which can easily be labelled with 99mTc at room temperature in alkaline medium. This class offers the possibility of a wide variety of derivatives, just by substituting one or more amino acids. This group of ligands thus opens a new research field of 99mTc-complexes with potential usefulness in several areas.
四肽是一类能有效结合99mTc的N4 - 四齿配体。事实上，四肽可被视为巯基乙酰三甘氨酸（MAG3）的衍生物，其中巯基乙酰部分被更稳定且更易于处理的氨酰基取代。在碱性介质（pH≥11）中，在亚锡离子存在下用99mTc直接标记四肽，可高产率（>95%）得到一种或两种（可能是异构体）放射化学物质。在酒石酸亚锡存在下于不同pH值进行交换标记，得到的相同99mTc标记产物的产率低于直接标记过程中形成的产率。此外，还形成了其他放射化学物质，其中一种被表征为与环化四肽形成的锝氧络合物。第一个氨基酸中具有手性中心的四肽在用99mTc标记时产生两种放射化学物质，可能是两种非对映异构体，其锝氧核心相对于氨基酸上的取代基分别为顺式和反式。当手性碳原子位于第二个或第三个氨基酸中时，仅观察到一种非对映异构体。电泳表明，这些新的99mTc标记络合物在酸性介质中呈中性，在中性和碱性条件下带负电荷。这与一种络合物相关，其中锝（V）基团通过酰胺官能团的三个去质子化氮原子和胺氮原子的孤对电子与配体结合。小鼠体内的生物分布表明，对于所有研究的99mTc标记四肽，主要通过肾脏系统从血液中快速清除。四肽中甲基取代基的存在增加了尿排泄。99mTc标记的L - 甘氨酰丙氨酰甘氨酰甘氨酸在小鼠体内的尿排泄与99mTc - MAG3相当。通过引入二甲基、异丙基或异丁酰基进一步提高亲脂性会导致肝胆摄取增加。结论是，四肽是一类有趣的锝络合剂，可在室温下于碱性介质中轻松用99mTc标记。通过取代一个或多个氨基酸，这类物质提供了多种衍生物的可能性。因此，这组配体开辟了一个新的99mTc络合物研究领域，在多个领域具有潜在用途。
