A strategy for increasing the brain uptake of a radioligand in animals: Use of a drug that inhibits plasma protein binding

A positron-emitter labeled radioligand for the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor, [C-11]L-703,717, was examined for its ability to penetrate the brain in animals by simultaneous use with drugs h aving high-affinity separate binding sites on human serum albumin. [C-11]L- 703,717 has poor blood-brain barrier (BBB) permeability because it binds ti ghtly to plasma proteins. Co-injection of warfarin (50-200 mg/kg), a drug t hat binds to albumin and resembles L-703,717 in structure, dose-dependently enhanced the penetration by [C-11]L-703,717 in mice, resulting in a five-f old increase in the brain radioactivity at 1 min after the injection. Drugs structurally unrelated to L-703,717, salicylate, phenol red, and L-tryptop han, were less effective or ineffective in increasing the uptake of [C-11]L -703,717. These results suggest that the simultaneous use of a drug that in hibits the binding of a radioligand to plasma proteins is a useful way to o vercome the poor BBB permeability of the radioligand triggered by its right binding to plasma proteins. In brain distribution studies in rodents, it w as found that, after the increase in brain uptake with warfarin, much of th e glycine site antagonist accumulates in the cerebellum but its pharmacolog ical specificity did not match the glycine site of NMDA receptors. NUCL MED BIOL 27;4:357-360, 2000. (C) 2000 Elsevier Science Inc. All rights reserve d.