Studies of the retention mechanism of the brain perfusion imaging agent 99mTc-bicisate (99mTc-ECD).

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.

Metabolism of 99mTc-L,L-ethyl cysteinate dimer in healthy volunteers.

99mTc-L,L-Ethyl cysteinate dimer (ECD) is a brain-perfusion imaging agent, which exhibits selective retention in brain and rapid renal excretion. The pharmacokinetics and metabolism of ECD were studied in vivo in healthy humans and its metabolism in vitro was evaluated in tissue from human brain. In vitro studies showed 99mTc-L,L-ECD to be metabolized to a polar 99mTc-complex. It has been shown previously that most of the activity of 99mTc retained in the brain of the monkey in vivo is in the form of a polar 99mTc complex (Walovitch, Hill, Garrity, Cheesman, Burgess, O'Leary, Watson, Ganey, Morgan and Williams, 1989). Whole body images of the distribution of 99mTc-L,L-ECD (10 mCi i.v.) in four adult males showed good uptake in brain, with slow elimination (6.8 +/- 0.3% injected dose [mean +/- SE] at 5 min), with less than 25% decrease in activity during 4 hr of imaging. Background areas in the head and lungs washed out rapidly, providing ideal imaging conditions. Elimination of 99mTc from venous blood was biphasic, with a plateau of activity between 2-15 min (7-8% injected dose) before a terminal phase, with a t1/2 of a few hours. Organic extraction of whole venous blood showed greater than 50% of the 99mTc-L,L-ECD to be in the form of polar metabolite(s) at 5 min. They were identified in the urine as the 99mTc ethylenediylbis-L-cysteine, monoethyl ester complex (ECM) and the 99mTc-ethylenediylbis-L-cysteine complex (EC). These metabolites were excreted rapidly (75% injected dose in urine within 6 hr). The results of this study support the hypothesis that the selective retention in brain, rapid blood elimination and renal excretion of 99mTc-L,L-ECD is due to its metabolic transformation to polar end products.

Characterization of technetium-99m-L,L-ECD for brain perfusion imaging, Part 1: Pharmacology of technetium-99m ECD in nonhuman primates.

Technetium-99m ethyl cysteinate dimer ([99mTc]ECD) is a neutral, lipophilic complex which rapidly crosses the blood-brain barrier. Brain retention and tissue metabolism of [99mTc]ECD is dependent upon the stereochemical configuration of the complex. While both L,L and D,D enantiomers are extracted by the brain, only the L,L but not the D,D form, is metabolized and retained in the monkey brain (4.7% injected dose initially, T 1/2 greater than 24 hr). Dynamic single photon emission computed tomography imaging studies in one monkey indicates 99mTc-L,L-ECD to be distributed in a pattern consistent with regional cerebral blood flow for up to 16 hr postinjection. Dual-labeled 99mTc-L,L-ECD and [14C]iodoantipyrine autoradiography studies performed 1 hr after administration show cortical gray to white matter ratios of both isotopes to be equivalent (approximately 4-5:1). These data suggest that 99mTc-L,L-ECD will be useful for the scintigraphic assessment of cerebral perfusion in humans.