Synthesis and renal excretion characteristics of the four stereoisomers present in Tc-99m-bis(mercaptoacetyl)-2,3-diaminopropanoate (Tc-99m-CO/sub 2/-DADS)

Tc-99s-CO/sub 2/-DADS-A has been reported to be a potential replacement for I-131-Hippuran, but its preparation involves an HPLC purification step because of the formation of a second Tc-99m chelate-ring isomer (component B) with less favorable biodistribution. As the starting material in the synthesis of the precursor apparently has been diaminopropionic acid in the racemic DL form, it can be postulated that both separated components A and B of Tc-99m-CO/sub 2/-DADS are actually still constituted of a mixture of optical D(-) and L(+) isomers (enantiomers), that cannot be separated by the described HPLC procedure. It is, however, reasonable to suppose that these isomers can possess a different biological behavior, as it is the case for most optically active compounds. The authors have synthesized the racemic DL form and the L(+) form of the fully protected precursor ethyl N,N''-bis(benzoylmercaptoacetyl)-2.3 diaminopropanoate and isolated the D(-) form by separation of the DL compound in its isomers by HPLC on a chiral stationary phase (R-DNB-Leucine). The three compounds were labeled with Tc-99m at neutral pH after hydrolysis of the ester groups in mild alkaline conditions to avoid racemisation. Labeling of the L(+), D(-) and DL compound yielded each time a similar mixture of two components (chelate-ring isomers A and B), separated by HPLC on Zorbax RP 8 with MeOH-0.05 M acetate buffer pH 6 (15:85). During renal excretion studies in rats, the authors have found that for the three Tc-99m labeled isomers component B was biologically inferior to component A. On the other hand the renal excretion rate clearly decreased from D(-) to DL to L(+) Tc-99m-CO/sub 2/-DADS-A (renal retention after 30 min in % of maximal renal concentration respectively 5, 11 and 25). The D(-) compound is being tested in other animals in order to evaluate this substance as a valuable Hippuran substitute