RP-0217

The structure-activity relationship in a series of analogues of 99mTc-bicisate (99mTc-N,N'-1,2-ethylenediylbis-L-cysteine diethyl ester dihydrochloride, RP-217) is described using in vivo studies in rodent and primate models and in vitro studies in rodent and primate brain tissue. All analogues investigated were 99mTc-diamine dithiol diesters, which were neutral and lipophilic and had modified brain uptake indexes (> or = 40) suggesting adequate first-pass extraction. All analogues were poorly retained by the rodent brain. In contrast, the stereochemistry and structure of the 99mTc-complexes affected their brain retention in primates. All compounds that demonstrated selective primate brain retention were L-diesters that were metabolized in primate brain tissue to nonlypophilic complexes resulting from ester hydrolysis. Unretained complexes were not metabolized in primate brain tissue. More extensive studies were performed with 99mTc-bicisate, which demonstrated poor brain retention in several nonprimate species (i.e., dogs, ferrets, pigs, and rodents). In rodent and nonhuman primate tissue, 99mTc-bicisate was rapidly metabolized to a monoacid ester (99mTc-N,N'-1,2-ethylenediylbis-L-cysteine monoethyl ester). Therefore, brain metabolism of 99mTc-bicisate results in the formation of an acid product(s) that is selectively trapped in primate brain.