?-CIT SPECT demonstrates blockade of 5HT-uptake sites by citalopram in the human brain in vivo

Abstract

The cocaine analogue 2-beta-carbomethoxy-3-beta-(4-iodophenyl)-tropane (beta-CIT) is a potent ligand for both dopamine- and serotonin uptake sites which in its 123I labeled form can be used for single photon emission computerized tomography (SPECT). It was demonstrated previously by SPECT-studies in non-human primates that 123I-beta-CIT binds to dopamine transporters in the striatum and to serotonin transporters in hypothalamus and midbrain. The aim of the present study was to compare 123I-beta-CIT binding in the brain stem of normal controls and a group of subjects under treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram. 123I-beta-CIT-SPECT was performed in 12 depressed patients under 20 mg (n = 5), 40 mg (n = 6) and 60 mg (n = 1) citalopram daily, in one untreated depressed patient and in 11 controls at regular time intervals up till 24 hours p.inj. A highly significant reduction of beta-CIT binding was found in an area including mesial thalamus, hypothalamus, midbrain and pons in patients under citalopram compared to controls (44.1 +/- 14.4 vs. 82.3 +/- 18.6cpm's/mCi x kg body weight; specific binding 4 hrs p.inj.; p = 0.0001). No differences were seen between the high and low dose group and no changes were found in the striatum. 123I-beta-CIT binding in the brain stem and striatum in one untreated depressed patient fell within the range of control values. To our knowledge this is the first report directly demonstrating the effect of a selective serotonin uptake inhibitor in the brain in humans in vivo. SPECT measurements of serotonin uptake sites in patients with depression and other psychiatric disorders might provide better insights into the pathophysiology of these disorders and into mechanisms of drug action.

Validation of [123I]β-CIT SPECT to Assess Serotonin Transporters In Vivo in Humans: a Double-Blind, Placebo-Controlled, Crossover Study with the Selective Serotonin Reuptake Inhibitor Citalopram

“…As the differences were small and because several studies reported stable uptake in the (hypo)thalamus, midbrain, cerebral cortex, and cerebellum at 4 h p.i. (Brücke et al, 1993;Pirker et al, 1995), it was suggested that both time points are reliably for measurements of SERTs with [ 123 I]b-CIT (Pirker (Pirker et al, 1995;Kugaya et al, 2003). Human PET studies using the SERT-selective radiotracer [ 11 C]DASB also showed high occupancy of SERTs in the midbrain and thalamus after (sub)therapeutic doses of various SSRIs (Meyer et al, 2004).…”

“…These findings suggest that [ 123 I]b-CIT binding in the cerebral cortex is predominantly caused by binding to SERTs. However, other studies were not able to show that [ 123 I]b-CIT binds to cortical SERTs (Laruelle et al, 1993) or did not study this issue (Pirker et al, 1995;Kugaya et al, 2003). In addition, a SSRI displacement study with the SERT-selective PET radioligand [ 11 C]McN 5652 in nonhuman primates also failed to show specific binding in the cerebral cortex (Parsey et al, 2000).…”

“…It is not likely that binding ratios have been affected by the increased cerebellar uptake, because the binding ratios are considered to be stable 4 h p.i. (Brücke et al, 1993;Pirker et al, 1995Pirker et al, , 2000. Therefore, increased tracer availability would increase both specific and nonspecific (cerebellar) binding in the same proportion.…”

“…In humans, in vivo [ 123 I]b-CIT SPECT imaging of the SERT has been used, among others, to study SERT availability in depression and alcoholism and to study the neurotoxic effects of ecstasy (Malison et al, 1998;Heinz et al, 1998;Reneman et al, 2001a, b (Pirker et al, 1995(Pirker et al, , 2000 or to study the effects of [ 123 I]b-CIT binding to SERTs and DATs in vivo in humans after blocking of SERTs with a SSRI (Pirker et al, 1995;Tauscher et al, 1999;Kugaya et al, 2003). One study validated the use of in vivo [ 123 I]b-CIT SPECT in detecting MDMA-induced serotonergic neurotoxicity in SERT-rich brain areas in a monkey (Reneman et al, 2002).…”

“…Some of these studies were performed in depressed patients, whereas depression may be an important confounder. For example, lower [ 123 I]b-CIT binding ratios were reported in SERT-rich areas in depressed patients treated with SSRIs compared to healthy volunteers (Pirker et al, 1995;Tauscher et al, 1999), whereas also in untreated depressive patients decreased SERT binding has been described (Malison et al, 1998). Only Kugaya and co-workers (2003) studied the in vivo alterations of [ 123 I]b-CIT binding during SSRI treatment in both depressive patients and in healthy volunteers.…”