SYNAPSE 13:295-309 (1993) SPECT Imaging of Dopamine and Serotonin Transporters With zyx [ 123 I]P-CIT: Pharmacological Characterization of Brain Uptake in Nonhuman Primates MARC LARUELLE, RONALD M. BALDWIN, ROBERT T. MALISON, YOLANDA ZEA-PONCE, SAM1 zyxwvutsrqpo S. ZOGHBI, MOHAMMED S. AL-TIKRITI, ELZBIETA H. SYBIRSKA, RALPH C. ZIMMERMANN, GARY WISNIEWSKI, JOHN L. NEUMEYER, RICHARD A. MILIUS, SHAOYIN WANG, EILEEN 0. SMITH, ROBERT H. ROTH, DENNIS S. CHARNEY, PAUL B. HOFFER, AND ROBERT B. INNIS Departments zyxwvutsrqp of Psychiatry, Pharmacology, and Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut and West Haven VA Medical Center, West Haven, Connecticut 06511 (M.L., R.M.B., R.T.M., Y.Z.P., S.S.Z., zyxwvutsrqp M.S.A.-T., E.H.S., R.C.Z., G.W., E.O.S., R.H.R., D.S.C., P.B.H., R.B.I.) and Research Biochemicals Znc., Natick, Massachusetts 01760 (J.L.N., R.A.M., S. W.) KEY WORDS zyxwvutsr SPECT, Brain, Pharmacology ABSTRACT Single photon emission computed tomography (SPECT) studies of re- gional kinetic uptake and pharmacological specificity of [1231]methyl 3P-(4-iodophenyl) tropane-2P-carboxylate ([1231]p-CIT) were performed in nonhuman primates (n = 41). In control experiments, activity was concentrated in striatum and in hypothalamic1 midbrain regions. Striatal uptake increased for 140-180 min and displayed stable levels thereafter. Striatal to cerebellar activity ratios were 7.3 2 0.9 (mean kSEM) at 300 min. About 75% of striatal uptake was displaceable by injection of nonradioactive P-CIT. Hypothalamic/midbrain activity reached maximal levels at approximately 45 min. A slow washout phase followed this peak activity. Activities in frontal, occipital, and cerebellar regions were characterized by an early peak (20-30 rnin), followed by rapid washout. Displacement studies demonstrated that striatal uptake was associated with dopamine (DA) transporters, as it was displaced by GBR 12909, a selective DA uptake inhibitor, but not by citalopram, a selective serotonin (5-HT) uptake inhibitor. The inverse was true in the hypothalamic/midbrain area, suggesting that the uptake in this area was associated primarily with 5-HT transporters. Maprotiline, a selective norepinephrine uptake inhib- itor, did not affect [1231]p-CIT uptake. In vivo site occupancy ED,, values of cocaine, zy 2~-carbomethoxy-3~-(4-fluorophenyl)tropane (CFT), and 6-CIT were measured in the striatum with a stepwise displacement paradigm. In vivo ED50 values correlated strongly with in vitro IC,o values for binding to DA transporters. Infusion of high dose of L-DOPA (250 pmolkg) failed to displace striatal [1231]P-CIT binding, suggesting that the binding would not be affected by L-DOPA administration in Parkinsonian patients. However, studies performed with injection of d-amphetamine indirectly suggested that high synap- tic levels of DA may compete with [1231]p-CIT binding. These studies suggest that [1231]p- CIT will be a useful SPECT tracer of DA and 5-HT transporters in living human brain. Published 1993 Wiley-Liss, Inc. INTRODUCTION be decreased in the putamen and prefrontal cortex of Parkinsonian subjects (Cash et al., 1985; Raisman et al., 1986). Decreased 5-HT transporter density has been reported in cortical and subcortical regions of sui- Alterations of dopamine (DA) and serotonin (5-HT) transporters have been described in several neuropsy- chiatric conditions. Postmortem studies reported de- creased DA transporter density in caudate and puta- men in Parkinson’s disease (Hirai et al., 1988; et lgg7; Kaufman and Madras 1991; Ma’- Received June 11,1992, accepted in revised form October 6,1992 et 1988; Niznik et ””) and Address reprint requests to Dr Marc Laruelle,VAMedical Centerill6 A2,950 disease (Allard, 1990). 5-HT transporters also appear to PUBLISHED 1993 WILEY-LISS, INC Campbell Avenue, West Haven, CT 06516