In preclinical studies, [R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4- piperidinemethanol] [formula: see text] (MDL 100,907), a putative atypical antipsychotic, was characterized in vitro as a potent and selective ligand for the serotonin2A (5-HT2A) receptor and was evaluated in vitro and in vivo as a potent 5-HT2A receptor antagonist. Furthermore, MDL 100,907's potential CNS safety profile and selectivity as a potential antipsychotic agent were evaluated and compared with benchmark compounds. MDL 100,907 demonstrated low nanomolar or subnanomolar binding in vitro at the 5-HT2A receptor and showed a > 100-fold separation from all other receptors measured. MDL 100,907 had subnanomolar potency as a 5-HT2A antagonist in vitro in reversing 5-HT-stimulated inositol phosphate accumulation in NIH 3T3 cells transfected with the rat 5-HT2A receptor. In vivo, MDL 100,907 potently inhibited 5-methoxy-N, N-dimethyltryptamine-induced head twitches in mice or 5-hydroxytryptophan-induced head twitches in rats. In vivo functional tests in mice revealed a > 500-fold separation between doses that produced 5-HT2A antagonism and doses that produced alpha 1-adrenergic or striatal D2 antagonism. Using inhibition of D-amphetamine-stimulated locomotion in mice as a measure of potential antipsychotic efficacy, MDL 100,907 showed a superior CNS safety index relative to the reference compounds, haloperidol, clozapine, risperidone, ritanserin, and amperozide, in each of five tests for side effect potential, including measures of ataxia, general depressant effects, alpha 1-adrenergic antagonism, striatal D2 receptor antagonism, and muscle relaxation. MDL 100,907 did not antagonize apomorphine-induced stereotypes in rats, suggesting that it potentially lacks extrapyramidal side effect liability. MDL 100,907 showed selectivity as a potential antipsychotic in that it lacked consistent activity in selected rodent models of anticonvulsant, antidepressant, analgesic, or anxiolytic activity. In summary, these preclinical data indicate that MDL 100,907 is a potent and selective ligand at the 5-HT2A receptor. MDL 100,907's potent 5-HT2A antagonist activity might account for its activity in preclinical models of antipsychotic potential. Ongoing clinical evaluation with MDL 100,907 will test the hypothesis that 5-HT2A receptor antagonism is sufficient for antipsychotic activity in humans.