Y-90 CHELATION PROPERTIES OF TETRAAZATETRAACETIC ACID MACROCYCLES, DIETHYLENETRIAMINEPENTAACETIC ACID ANALOGS, AND A NOVEL TERPYRIDINE ACYCLIC CHELATOR

Realization of the potential of yttrium-90 for the radioimmunotherapy of cancer depends on rapid and kinetically stable chelation. Condition s were evaluated that influenced the chelation efficiency of these sel ect chelators for yttrium-90: the macrocyclic chelators nitrobenzyl)-1 ,4,7,10-tetraazacyclododecane-N,N',N '',N'''-tetraacetic acid (nitro-D OTA); zacyclododecane-1-acetic-4,7,10-tris(methylacetic) acid (nitro-P ADOTA); itrobenzyl)-1,4,7,10-tetraazacyclotridecane-N,N',N '',N'''-tet raacetic acid (nitro-TRITA); the acyclic chelator diethylenetriaminepe ntaacetic acid (DTPA); its analogues henyl)propyl]-trans-cyclohexane-1 ,2-diamine-N,N',N ''-pentaacetic acid (nitro-CHX-A-DTPA) and l-6-(rho- nitrobenzyl)-1,4,7-triazaheptane-N,N,N',N '',N ''-pentaacetic acid (ni tro-1B4M-DTPA or nitro-MX-DTPA); and a novel acyclic terpyridine chela tor, 6,6 ''-bis[[N,N,N '',N ino]methyl]-4'-(3-amino-4-methoxyphenyl)-2 ,2':6',2 ''-terpyridine-4'-(3-(TMT-amine). The chelators fell into two distinct classes. The acyclic chelators, DTPA, nitro-CHX-A-DTPA, nitr o-MX-DTPA, and TMT-amine, chelated instantaneously in a concentration- independent manner. Chelation efficiency was affected minimally when t he concentrations of trace metal contaminants were increased. In contr ast, the macrocyclic chelators, nitro-DOTA, nitro-TRITA, and nitro-PAD OTA, chelated yttrium-90 more slowly in a concentration-dependent mann er where efficiency was maximal only when the chelator:metal ratio was greater than 3. Their chelation efficiency diminished in a concentrat ion-dependent fashion as the concentrations of trace metal contaminant s were increased. Optimum labeling efficiencies were obtained through application of these principles. Additionally, the kinetic stabilities of these chelator-yttrium-90 complexes were evaluated at low pH, wher e the order of stability was nitro-DOTA, nitro-PADOTA > nitro-CHX-A-DT PA, nitro-MX-DTPA > nitro-TRITA, TMT, DTPA. pH lability stratified the chelators to a conveniently measurable degree and, interestingly, cor related with their in vivo stabilities where known.