Journal of Neurochemisiry Raven Press, Ltd., New York 0 1990 International Society for Neurochemistry A Method for the In Vivo Investigation of the Serotonergic 5-HT2 Receptors in the Human Cerebral Cortex Using Positron Emission Tomography and "F-Labeled Setoperone *Jer6me Blin, "Giuliano Sette, *Marc0 Fiorelli, TOlivier Bletry, $Jean Luc Elghozi, "Christian Crouzel, and *$Jean Claude Baron *Service Hospitulier Frkdkric Joliot, CEA, Hipital d'Orsay, Orsay; ?Service de M&decine Interne, Hipital de la Piti;, SLahoratoire de Pharmacologie, INSERM U. 7, Hipital Necker, Paris; and EjINSERW U. 320, Cum, France Abstract: Following previous validation in baboons, we have studied the characteristics of [ '8F]setoperone as a radioligand for investigating serotonergic 5-hydroxytryptamine2 (5-HTz) receptors in the normal, unmedicated human brain with positron emission tomography (PET); subjccts orally pre- treated with therapeutic amounts of ketanserin, sulpiride, or prazosin were also studied to evaluate the specificity and sen- sitivity of [ 'XF]setoperone brain specific binding. In controls (n = lo), the tracer showed a clear-cut retention in both fron- tal cortex and striatum (known to contain a high density of 5-HT2 receptors) relative to cerebellum (known to be devoid of 5-HT2 receptors). In the seven young controls (20-39 years old), the frontal cortex/cerebellum and striatum/cerebellum ratios increased during the first hour to reach similar values of 2.53 k 0.12 and 2.38 5 0.1 1 (mcan -t SEM), respectively, and were essentially stable during the second hour. Pretreat- ment with ketanserin (a 5-HT2 blocker) significantly reduced the frontal cortex/cerebellum ratio to 0.7-1.0 at 65 min, whereas the striatum/cerebellum ratio was significantly, but only partially, reduced. During sulpiride treatment (a D2 blocker), the frontal cortex/cerebellum ratio was not altered, whereas the striatum/cerebellum ratio was significantly, but only partially, reduced. With prazosin pretreatment (an 01'- adrenergic blocker). neither the frontal cortex/cerebellum nor the striatum/cerebellum ratio was modified. These data in humans with PET demonstrate that ['8F]setoperone labels with high sensitivity and selectivity 5-HTz receptors in the frontal cortex; in striata, however, binding is to both 5-HT2 and D2 receptors. The deproteinated-to-whole plasma radio- activity concentration ratio increased with time following in- jection. The mean percentage of intact ['*F]setoperone, in deproteinated plasma, was 82, 74, 53, 45, 30, and 22% at 5, 10, 20, 30, 60, and 1 10 min following injection, respectively. These data indicate that [ ''Flsetoperone (a) is significantly bound to plasma proteins and (b) is significantly metabolized into several labeled metabolites that are much more hydro- philic than setoperone and, hence, presumably do not cross the blood-brain barrier. These results suggest the suitability of [''Flsetoperone data for modeling of 5-HT2receptor bind- ing in brain. Key Words: 5-Hydroxytryptamine2 receptors- Human brain-[ 18F]Setoperone-Positron emission to- mography-Metabolites-Frontal cortex. Blin J. et al. A method for the in vivo investigation of the serotonergic 5- HTz receptors in the human cerebral cortex using positron emission tomography and "F-labeled setoperone. J. Neuro- chem. 54, 1744-1 754 ( 1990). Following the recent development of [3H]ketanse- rin and other high-affinity serotonergic 5-hydroxy- tryptaminez (5-HT2) receptor antagonists (Leysen et al., I982), interest has been considerable in the inves- tigation of this subclass of serotonergic receptors in the cerebral cortex obtained postmortem from demented (Cross et al., 1984a.b. 1986; Crow et al., 1984: Perry et al., 1984; Reynolds et al., 1984a),depressed (Stanley, 1983; Mann et al., 1986; Owen et al., 1986; McKeith et al., 1987), or schizophrenic (MacKay et al., 1978; Whitaker et al., 198 1; Reynolds et al., 19843; Mita et al., 1986) subjects. Alterations in serotonergic trans- mission involving these postsynaptic receptors could well play a role in the disorders of higher cortical func- Received July 4, 1989; revised manuscript received September 30, 1989: accepted October 12, 1989. Address correspondence and reprint requests to Dr. J. Blin at his present address: National Institute of Neurological Disorders and Stroke, Building 10, Room 5C106, National Institutes of Health, Bethesda, MD 20892, U.S.A. Drs. G. Sette and M. Fiorelli were on leave from 111 Clinica Neu- rologica, Universid Degli Studi, "La Sapienza" di Roma, Viale dell'universiti, 30, 001 85 Rome, Italy. Abbreviations used: CM, canthomeatal; FDG, fluoro-2-deoxy-D- glucose; 5-HT, 5-hydroxytryptamine; ID, injected dose; N-MBL, N- methylbromolysergic acid diethylamide; OM, orbitomeatal; PET, positron emission tomography: ROI, region of interest. I744