Synthesis,Rhenium-188 Labeling and Biodistribution Studies of a Phenolic Ester Derivative of Trisuccin

Our previous results indicated that the trihydroxamate ligand, trisuccin, was a promising bifunctional chelating agent (BCA) for radiometal labeling of monoclonal antibodies with rhenium and technetium. An interest was developed to evaluate structural modifications of this compound from both synthetic and biological points of view. In this report we describe the synthesis of an esterified trisuccin (referred to as trisester), and conjugation of this new derivative to MAb CC49, radiolabeling of this conjugate with rhenium-188 (¹⁸⁸Re), and biodistribution of the labeled conjugate in athymic nude mice. Thus, trisuccin (1) was esterified with benzyl 4-hydroxybenzoate in a DCC/DMAP reaction followed by removal of all benzyl protecting groups with catalytic hydrogenation. The resulting product was conjugated to CC49 by the active ester technique, through formation of the 2-nitrophenyl ester 6, and the conjugate was radiolabeled with generator-produced ¹⁸⁸Re. The lead molecule trisuccin 1 was also conjugated to CC49 through the active ester 5 and the conjugate was radiolabeled by the same procedure to serve as the control conjugate. Biodistributions of the labeled conjugates were studied in athymic nude mice, transplanted s.c. with LS174T human colon cancer xenografts. Although an increase in the radiolabeling yield was observed for the esterified ligand-CC49 conjugate, as well as some increase in its immunoreactivity, as compared to those for the parent trisuccin molecule, there were no significant differences in their biodistribution. This new compound therefore may be useful in improving the conjugation and radiolabeling chemistries of this trihydroxamate ligand system.