Nuclear Medicine h Biology, Vol. 23, pp. 47-52, 1996. Copyright 0 1996 Elsevier Science Inc. ELSEVIER ISSN 0969-8051/96/$15.00 + 0.00 SSDI 0969-8051(95)02014-2 [“F]Haloperidol Binding in Baboon Brain in Viwo Khalil A. Yousef, Joanna S. Fowler,” Nora D. Volkow, Stephen L. Dewey, CoMeen Shea, David J. Schlyer, S. John Gatley, Jean Logan and Alfred P. Wolf CHEMISTRY AND MEDICAL DEPARTMENTS, BROOKHAVEN NATIONAL LABORATORY, UPTON, NY 11973 USA ABSTRACT. The binding of [ “Flhaloperidol to dopamine D2 and to sigma recognition sites in baboon brain was examined using positron emission tomography (PET). Studies were performed at baseline and after treatment with either haloperidol (to evaluate saturability), (+)-butaclamol (which has specificity for dopa- mine D2 receptors) or (-)-butaclamol (which has specificity for sigma sites). Binding was widespread. Treatment with (-)-butaclamol had no effect, whereas (+)-butaclamol selectively reduced the uptake in striatum. Haloperidol increased the clearance rate from all brain regions. These results indicate that the binding profile of [‘*F]haloperidol does not permit the selective examination of either dopamine D2 or sigma sites using PET. NUCL MED BIOL 23;1:47-52, 1996. KEY WORDS. [‘8F]haloperidol, PET, Sigma binding sites, Dopamine D2 receptors Haloperidol is one of the oldest and most widely used antipsychotic drugs (Wysowski and Baum, 1989). It binds to a number of neurotrans- mitter receptors, including the dopamine D2 receptor (Seeman and Lee, 1975), the alpha 1 adrenergic receptor (Black, 1987) and the 5HT2 receptor (Leysen et al., 1982). Although its therapeutic charac- teristics are most commonly attributed to dopamine D2 receptor ac- tivity, its regional brain distribution is not like that of dopaminer- gic ligands. Although autoradiographic studies with [3H]haloperidol showed high retention in dopaminergic areas, they also showed high retention in nondopaminergic regions (Laduron et al., 1978). The distribution of nondopaminergic binding sites labeled by [3H]haloperi- do1 was different from that labeled by dopaminergic ligands but similar to the sigma-opioid binding sites (Tam and Cook, 1984; Contreras et al., 1987). In mice, the binding of [3H]haloperidol to sigma sites in viva has been found to account for 56% of the total brain activity (Weiss- man et al., 1990). Postmortem studies in human brain with [3H]halo- peridol (in the presence of 50 nM spiroperidol) showed highest binding in cerebellum and cortical regions (Weissman et al., 1988). In the cerebellum, [3H]haloperidol bound to a single saturable class of recep- tors with Kd = 0.95 nM. Binding was sensitive to inhibition by drugs which have affinity for sigma sites [d-pentazocine, di-tolyl guanidine, 3-PPP and (-)-butaclamol]. We recently examined the regional distribution and clearance of haloperidol in the human brain using PET and [‘sF]haloperidol to determine its pharmacokinetics and to characterize its binding (Schlyer et al., 1992). We observed a widespread distribution with highest up- take in cerebellum, basal ganglia and thalamus and minimal clearance over a 10-h period in normal volunteers. The widespread binding of haloperidol in the human brain contrasted markedly with the high striatal localization of [‘sF]N-methylspiroperidol, a dopamine D2 ra- diotracer. In particular, the high concentration in the cerebellum sug- gested that binding may be occurring to sigma recognition sites. How- ever, for ethical reasons, we could neither evaluate the effects of halo- ‘All correspondence should be addressed to: Joanna S. Fowler, Chemistry De- partment, Brookhaven National Laboratory, Upton, NY 11973. Accepted 6 May 1995. peridol administration nor examine haloperidol’s binding to other sites in the normal human brain. Haloperidol’s high affinity for the sigma recognition site and our observation of uptake in the human cerebellum demonstrated the need for a more detailed examination of its binding. We report here an investigation of the binding of [“Flhaloperidol in the baboon brain to assess saturability and the extent to which it represented binding to sigma sites and to dopamine (DA) D2 receptors. Studies were carried out over a 2-h experimental period, and baseline scans were run on each baboon to assess regional distribution and clearance. The reproducibil- ity of repeated PET scans was also measured to serve as a control for administration of the following drugs: haloperidol to evaluate satura- bility, (+)-butaclamol to assess binding to dopamine D2 receptors and (-)-butaclamol to assess binding to sigma sites. MATERIALS AND METHODS Baboons All baboon studies were carried out under approval by the Institutional Animal Care and Use Committee at Brookhaven National Laboratory. Seventeen PET studies were carried out in four different baboons. Studies and drug treatments are summarized in Table 1. There was a recovery time period of at least 3 weeks between injections. All base- line studies preceded drug treatment studies. PET Studies Studies were carried out on the CT1 931 whole-body tomograph (res- olution: 6.5 x 6.5 x 6.5 mm FWHM at center of field of view). No- carrier-added [‘RF]haloperidol was prepared as described previously (Schlyer et al., 1992). Baboons were initially anesthetized with an intramuscular injection of ketamine hydrochloride (10 mg/kg; admin- istered 2 h prior to [“F]haloperidol), intubated and maintained on gas anesthesia (oxygen, nitrous oxide and isoflurane) throughout the study. Baboons were prepared for radiotracer injection and for arterial plasma sampling, as described previously (Dewey et al., 1990), and received 2-8 mCi of [‘Xflhaloperidol (1 Ci/pmol; ~95% radiochemical purity).