STUDIES OF THE RETENTION MECHANISM OF THE BRAIN PERFUSION IMAGING AGENT TC-99M-BICISATE (TC-99M-ECD)

The structure-activity relationship in a series of analogues of Tc-99m -bicisate (Tc-99m-N,N'-1,2-ethylenediylbis-L-cysteine diethyl ester di hydrochloride, RP-217) is described using in vivo studies in rodent an d primate models and in vitro studies in rodent and primate brain tiss ue. All analogues investigated were Tc-99m-diamine dithiol diesters, w hich were neutral and lipophilic and had modified brain uptake indexes (greater than or equal to 40) suggesting adequate first-pass extracti on. All analogues were poorly retained by the rodent brain. In contras t, the stereochemistry and structure of the Tc-99m-complexes affected their brain retention in primates. Ail compounds that demonstrated sel ective primate brain retention were L-diesters that were metabolized i n primate brain tissue to nonlypophilic complexes resulting from ester hydrolysis. Unretained complexes were not metabolized in primate brai n tissue. More extensive studies were performed with Tc-99m-bicisate, which demonstrated poor brain retention in several nonprimate species (i.e., dogs, ferrets, pigs, and rodents). In rodent and nonhuman prima te tissue, Tc-99m-bicisate was rapidly metabolized to a monoacid ester (Tc-99m-N,N'-1,2-ethylenediylbis-L-cysteine monoethyl ester). Therefo re, brain metabolism of Tc-99m-bicisate results in the formation of an acid product(s) that is selectively trapped in primate brain.