Complexes of technetium-99m with tetrapeptides containing one alanyl and three glycyl moieties

Recently, we have shown that tetrapeptides can be efficiently labelled with technetium-99m by direct labelling at alkaline pH. Tetrapeptides can be considered derivatives of mercaptoacetyltriglycine (MAG3) in which the mercaptoacetyl moiety is replaced by an amino acid residue. In view of the interesting biological properties of some C-methyl substituted derivatives of Tc-99m-MAG3, we have now synthesised and evaluated the complexes of Tc-99m with tetrapeptides containing three glycyl (G) moieties and one D- or L-alanyl (A) moiety. In mice, (TC)-T-99m-L-GAGG, (TC)-T-99m-D-GGAG and Tc-99m-L-GGAG showed a rapid and high renal excretion, comparable to that of Tc-99m-MAG3. Renal handling was somewhat reduced for isomers D and L of Tc-99m-AGGG and Tc-99m-D-GAGG and markedly inferior for Tc-99m-L-GGGA and Tc-99m-D-GGGA. In the baboon, Tc-99m-L-AGGG, Tc-99m-D-AGGG and Tc-99m-L-GAGG showed a comparable or even higher 1-h plasma clearance than Tc-99m-MAG3. Tc-99m-D-GAGG, Tc-99m-L-GGAG and Tc-99m-D-GGAG were characterised by a lower plasma clearance and the clearance of Tc-99m-L-GGGA and Tc-99m-D-GGGA was remarkably low. The three Tc-99m-labelled tetrapeptides with the highest plasma clearance in a baboon were compared with Tc-99m-MAG3 in a human volunteer. Tc-99m-L-AGGG and Tc-99m-L-GAGG had a roughly similar plasma clearance as Tc-99m-MAG3. The clearance of Tc-99m-D-AGGG was significantly lower and liver uptake was clearly visible with this compound. Left kidney renograms of Tc-99m-L-AGGG and Tc-99m-D-AGGG indicated moderate kidney accumulation. On the other hand, the renogram obtained after injection of Tc-99m-L-GAGG had an excellent shape and the maximum kidney concentration was slightly higher than for Tc-99m-MAG3. These results show the importance of the position of the methyl substituent on the Tc-99m-tetrapeptide with respect to its biological behaviour.