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^99mTc-MAG3, we have now synthesised and evaluated the complexes of^99mTc with tetrapeptides containing three glycyl (G) moieties and oned- orl-alanyl (A) moiety. In mice,^99mTc-l-GAGG,^99mTc-d-GGAG and^99mTc-l-GGAG showed a rapid and high renal excretion, comparable to that of^99mTc-MAG3. Renal handling was somewhat reduced for isomersd andl of^99mTc-AGGG and^99mTc-d-GAGG and markedly inferior for^99mTc-l-GGGA and^99mTc-d-GGGA. In the baboon,^99mTc-l-AGGG,^99mTc-d-AGGG and^99mTc-l-GAGG showed a comparable or even higher 1-h plasma clearance than^99mTc-MAG3.^99mTc-d-GAGG,^99mTc-l-GGAG and^99mTc-d-GGAG were characterised by a lower plasma clearance and the clearance of^99mTc-l-GGGA and^99mTc-d-GGGA was remarkably low. The three^99mTc-labelled tetrapeptides with the highest plasma clearance in a baboon were compared with^99mTc-MAG3 in a human volunteer.^99mTc-l-AGGG and^99mTc-l-GAGG had a roughly similar plasma clearance as^99mTc-MAG3. The clearance of^99mTc-d-AGGG was significantly lower and liver uptake was clearly visible with this compound. Left kidney renograms of^99mTc-l-AGGG and^99mTc-d-AGGG indicated moderate kidney accumulation. On the other hand, the renogram obtained after injection of^99mTc-l-GAGG had an excellent shape and the maximum kidney concentration was slightly higher than for^99mTc-MAG3. These results show the importance of the position of the methyl substituent on the^99mTc-tetrapeptide with respect to its biological behaviour.