In our work with the new opioid receptor ligand, N-(3-[18F]fluoropropyl)-N-nordiprenorphine, ([18F]FPND), we have noted significant sex-dependent differences in metabolism and distribution. In female rats, metabolism of this ligand proceeds without significant P-450-mediated oxidation of the N-fluoroalkyl side chain, while in male rats, this is the dominant metabolic pathway. In biodistribution experiments, striatal uptake of this ligand is higher in female than in male rats, but no difference in cerebellar uptake is observed. In male rats, no metabolites of [18F]FPND are produced that cross the blood-brain barrier. In contrast, female rats produce a metabolite that both crosses the blood-brain barrier and exhibits opioid receptor-specific binding superior to that of the parent compound. These studies demonstrate that the possibility of sex-dependent metabolism must be considered when the rat is employed to screen new radiopharmaceuticals.