The N-methyl-D-aspartate receptor coagonist D-serine is a substrate for the neutral amino acid transporters ASCT1 and ASCT2, which may regulate its extracellular levels in the central nervous system (CNS).

Phenylglycine (PG) analogs that are inhibitors of ASCT1 and ASCT2. L-4-fluorophenylglycine (L-4FPG), L-4-hydroxyPG (L-4OHPG), and L-4-chloroPG (L-4ClPG) all showed high plasma bioavailability when administered systemically to rats and mice. L-4FPG showed good brain penetration with brain/plasma ratios of 0.7-1.4; however, values for L-4OHPG and L-4ClPG were lower. The ability of L-4FPG to penetrate the brain makes this compound a useful tool to further evaluate the function of ASCT1 and ASCT2 transporters in the CNS.

Pharmacokinetic studies in rats and mice indicated high bioavailability by intraperitoneal or subcutaneous routes, with t_1/2 values that allowed the evaluation of compound effects by a single acute administration in the animal models. Surprisingly, L-4FPG showed good blood-brain barrier penetration, with brain-to-plasma ratios ranging from 0.7 to 1.4 in the rat and from 0.7 to 0.9 in the mouse. L-4OHPG and L-4ClPG had lower values.

Pharmacokinetic studies in mice for L-4FPG, L-4OHPG, and L-4ClPG were performed by Medicilon.

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