Synthesis and evaluation of β-homocysteine derivatives of99mTc-L,L-EC and99mTc-L,L-ECD

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Bis-amine bis-thiol tetraligands such as ethylene dicysteine (EC) and its diethylester (ECD) bind 99mTc efficiently at room temperature and neutral to alkaline pH to form stable complexes. The use of bis-amine bis-thiol ligands as bifunctional chelating agents (BCAs) for labelling of bioactive compounds (peptides, diphosphonates, etc.) looks promising. To study the effect of extending the carboxylic side-group in 99mTc-L,L-EC and 99mTc-L,L-ECD, we have synthesised ethylene bis-L-homocysteine (L,L-EhC) and its diethylester derivative L,L-EhCD, incorporating a methylene group between each of the carboxyl groups and the N2S2 tetraligand core. The more distant carboxyl groups could offer reduced steric hindrance in the use of L,L-EhC and L,L-EhCD as BCAs. As for 99mTc-L,L-ECD, 99mTc-L,L-EhCD is neutral on electrophoresis at pH 6.0. In mice, brain uptake of 99mTc-L,L-EhCD is lower than that of 99mTc-L,L–ECD. Blood clearance of the two complexes is similar. The diacid 99mTc-L,L–EhC migrates to the same extent as the corresponding 99mTc-L,L-EC on electrophoresis at pH 3.2, 9.0 and 12 but it migrates 25% further at pH 6. Urine levels for 99mTc-L,L-EhC in mice are lower than those for 99mTc-L,L-EC (65% versus 74% of I.D. at 10 min p.i. and 85% versus 95% at 30 min p.i., respectively). The results show that the β-homocysteine derivatives retain the key characteristics of 99mTc-L,L-EC and 99mTc-L,L-ECD, i.e. easy formation of stable complexes with 99mTc, a high urinary excretion for 99mTc-L,L-EhC, and in the case of 99mTc-L,L-EhCD a neutral compound with appreciable brain uptake. These properties indicate that L,L-EhC and L,L-EhCD merit further evaluation as BCAs with attractive conjugation properties. Copyright © 1999 John Wiley & Sons, Ltd.