MALEIMIDO DERIVATIVES OF DIETHYLENETRIAMINEPENTAACETIC ACID AND TRIETHYLENETETRAAMINEHEXAACETIC ACID - THEIR SYNTHESIS AND POTENTIAL FOR SPECIFIC CONJUGATION WITH BIOMOLECULES

Immunoconjugates sometimes suffer changes in immunoreactivity and tumo r targeting because the chelators used interfere with antigen binding. To try to circumvent such problems, two new homobifunctional chelatin g agents, (beta-maleimidopropionyl)amino]benzyl]enetriamine- N,N,N',N '',N ''-pentaacetie acid (MPBz-DTPA) and 2,9-bis[p-[(beta-maleimidopro pionyl)amino]benzyl] triethylenetetraamine-N,N,N',N',N '',N ''-hexaace tic acid (MPBz-TTHA), were synthesized for chelation of In-111 and Y-9 0 metal ions. Each of the new chelators contains two maleimido functio nal groups substituted at the carbon backbone. In this study, the over all chemical yields for MPBz-DTPA and MPBz-TTHA were approximately 5 a nd 4%, respectively. The intermediate and final compounds were purifie d by flash chromatography and fully characterized by H-1-NMR, C-13-NMR , and mass spectroscopy. Chemical modification of the maleimido group on each of these derivatives allowed specific conjugation with a sulfh ydryl group at the hinge region of an antibody molecule and conjugatio n with other peptides. For instance, the two Fab' fragments, through t heir hinge-region sulfhydryl groups, could covalently attach to a homo bifunctional chelator via thioether linkage to generate a Fab'-S-chela tor-S-Fab' immunoconjugate. By design, immunoconjugates containing the se new chelators will contain only one chelator derivative at a known region of antibody away from the antigen binding site, Consequently, t hese chelators may minimize changes in the immunoreactivity and improv e tumor targeting of immunoconjugates that contain them.