Distribution, survival and biological effects in mice of a behaviorally active, enzymatically stable peptide: pharmacokinetics of cyclo(Leu-Gly) and puromycin-induced amnesia.

Cyclo(Leu-Gly), the enzymatically resistant diketopiperazine formally derived from the C-terminal dipeptide sequence of oxytocin, exhibits activity in several behavioral systems. The distribution of cyclo(Leu-14C(U)Gly) in brain, and the time course of the disappearance of this labeled peptide from brain and plasma after subcutaneous injection into mice have been studied. The intact peptide was distributed equally in the five cerebral areas studied, for up to 96 hours after injection. Two exponential components were determined for peptide disappearance rates in plasma and brain; peptide half-lives in plasma up to 10 hr and from 24--96 hr after injection were, respectively, 0.8 and 33 hr; in brain, 1.0 and 42 hr. The peptide was found to accumulate in brain intracellular space to some degree. The time course of distribution of labeled cyclo(Leu-Gly) in subcellular fractions of mouse brain was also examined, and the concentration of peptide in the synaptosomal fraction was significantly correlated with the degree of protection against puromycin-induced amnesia of a maze-learning test. The results obtained not only confirm that cyclo(Leu-Gly) penetrates brain tissue intact and remains intact after peripheral administration in order to exert its behavioral effects, but, moreover, suggest an intriguing dynamic relationship between peptide concentration in the synaptosomal fraction and behavioral activity.