In Vivo Characterization of p-[ 18 F]MPPF, a FluoroAnalog of WAY-100635 for Visualization of 5-HT 1A Receptors NATHALIE GINOVART, 1,2 * WADAD HASSOUN, 1,2 DIDIER LE BARS, 1 DINAH WEISSMANN, 2 AND VINCENT LEVIEL 1,2 1 CERMEP Cyclotron Unit, Lyon, France 2 Laboratoire de Neuropharmacologie mole ´culaire, CNRS, Faculte ´ RTH Lae ¨nnec, Lyon, France KEY WORDS 5-HT 1A receptors; autoradiography; positron emission tomography; cat ABSTRACT The in vivo and ex vivo distributions and the pharmacological profile of the fluorinated phenylpiperazine derivative p-[ 18 F]MPPF (4-(2'-methoxyphenyl)-1-[2'-(N- 2-pyridinyl)-p-fluorobenzamido]-ethylpiperazine) were evaluated in the cat brain as a potential selective antagonist for 5-HT 1A receptors using PET. After intravenous injection of p-[ 18 F]MPPF in cats, there was a rapid accumulation of radioactivity in the brain, with 4% of the total radioactivity injected present in the brain at 4 minutes postinjection. The highest uptakes of radioactivity were observed in the hippocampus and cingulate cortex, regions known to be rich in 5-HT 1A receptors, whereas lower levels of radioactivity were observed in the cerebellum. The mean ratio of radioactivity in the hippocampus to the cerebellum was 4.29 (SD = 0.21; n = 5) from 40 to 90 minutes postinjection of p-[ 18 F]MPPF. The corresponding ratio for the cingulate cortex was 3.01 (SD = 0.16; n = 5). Specific binding in the hippocampus and the cingulate cortex was markedly reduced following injection of unlabeled WAY-100635 and pindolol but was unaffected by treatment with 1, 5-HT 2 , or reuptake inhibitor agents indicating reversibility and selectivity of p-[ 18 F]MPPF binding to 5-HT 1A receptors. Ex vivo autoradiographic study with p-[ 18 F]MPPF in cat brain sections showed labeling of areas rich in 5-HT 1A receptors with a regional brain distribution that closely matched that observed using PET. These results indicate that p-[ 18 F]MPPF may be a useful candidate for noninvasive PET imaging of 5-HT 1A receptors in the living human brain. Synapse 35:192–200, 2000.  2000 Wiley-Liss, Inc. INTRODUCTION The serotonin (5-hydroxytryptamine, 5-HT) system has been implicated in several psychiatric and neurologi- cal disorders (Cross, 1988, 1990), and is often a target for new approaches to the treatment of these disorders. The diverse actions of 5-HT are mediated by a number of specific receptors. Pharmacological and mo- lecular cloning techniques have identified at least 14 different subtypes of 5-HT receptors, which have been classified in seven families (5-HT 1–7 ) on the basis of their structural homology, pharmacological profile, and predominant transduction system (Hoyer et al., 1994). Among these receptors, 5-HT 1A receptors are of particu- lar interest because of their potential role in anxiety and depression (Gozlan et al., 1983; Andrade and Nicoll, 1987). In various species, including man, 5-HT 1A receptors are located predominantly in brain regions concerned with mood and anxiety (the limbic system, i.e., hippocampus, septum, amygdala) and in areas governing temperature, feeding, and locomotion (dorsal and median raphe nuclei). Whereas 5-HT 1A receptors on raphe neurons are predominantly somatodendritic (Verge ´ et al., 1985; Weissmann-Nanopoulos et al., 1985), those in the hippocampus and cerebral cortex are essentially postsynaptic (Verge ´ et al., 1986; Palacios et al., 1990). Studies to investigate the function of 5-HT 1A recep- tors in vivo have been hampered by the lack of selective antagonists for this receptor and have relied on the effects of selective agonists, such as 8-OH-DPAT (Go- zlan et al., 1983). However, WAY-100635 [(N-(2-(4-[2- methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)-cy- clohexanecarboxamide] was recently described as an antagonist with high affinity (K D approximately Contract grant sponsors: INSERM/CFB, the Fondation de France. *Correspondence to: Nathalie Ginovart, CERMEP Cyclotron Unit, 59 Boule- vard Pinel, 69003 Lyon, France. E-mail: nathalie@cermep.fr Received 15 February 1999; Accepted 18 May 1999. SYNAPSE 35:192–200 (2000)  2000 WILEY-LISS, INC.