Synthesis and biological evaluation of the four isomers of 99mTc-cysteinyltriglycine, an amino substituted derivative of 99mTc-MAG3.

Cysteinyltriglycine (CYSG3) is a derivative of MAG3 in which the mercaptoacetyl group is replaced by a cysteinyl moiety. This implies the presence of a primary amino group on the ligand, as in case of p-amino-hippuric acid, the compound with the highest renal tubular secretion known. The present study was undertaken to investigate the influence of this amino group on the biological behaviour of complexes of 99mTc with MAG3-like molecules. The L- and D-isomers of cysteinyltriglycine were synthesized as S-benzyl N1-CBO protected precursors. After removal of the protective groups with Na/NH3, the isomers were labelled with 99mTc. This resulted in the formation of two diastereomeric complexes (A and B in the order of HPLC-elution) for each of them. The biodistribution of the four HPLC-purified isomers was tested in mice. Isomers DA and LB showed slightly superior or similar renal excretion characteristics compared to 99mTc-MAG3, whereas the two other isomers were cleared at a lower rate by the kidneys and more through the liver and the intestines. The results indicate that substitution of 99mTc-MAG3 with an amino function may somewhat improve the rate of renal excretion, but the configuration of the 99mTc-labelled complexes appears to be more important to its biological behaviour.