COMPLEXES OF TC-99M WITH TETRAPEPTIDES, A NEW CLASS OF TC-99M-LABELED AGENTS

Tetrapeptides are a class of N4-tetraligands that can efficiently bind Tc-99m. 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 Tc-99m in alkaline medium (pH greater than or equal to 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 Tc-99m-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 Tc-99m 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 Tc-99m-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 Tc-99m-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. Tc-99m-labelled L-glycylalanylglycylglycine showed in mice a urinary excretion comparable to that of Tc-99m-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 Tc-99m 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 Tc-99m-complexes with potential usefulness in several areas.