Regional distribution of specific high affinity binding sites for 3H-imipramine and 3H-paroxetine in human brain

Abstract

The binding of 3H-paroxetine and 3H-imipramine has been compared in 17 different regions of 12 human control brains. Our findings reveal that the regional distribution is similar for both radioligands and their bindings tend to be parallel in the brain. The highest binding site density was found in basal ganglia (hypothalamus Bmax 780 +/- 102 fmol/mg protein for 3H-imipramine binding and Bmax 515 approximately 83 for 3H-paroxetine binding). The lowest values were found in cortical areas (cingulate cortex 191 +/- 18.5 fmol/mg for 3H-imipramine binding and 88 +/- 7.5 fmol/mg for 3H-paroxetine binding). The Kd values for 3H-paroxetine binding to neuronal membranes were similar in all brain regions (mean +/- s.d. Kd 0.07 +/- 0.007 nM) and also for 3H-imipramine binding (mean +/- s.d. Kd 1.05 +/- 0.12 nM). As these values are the same as in platelet membrane, the results obtained indicate that both binding sites are identical in neuronal and in platelet membranes. These findings suggest that both ligands are good markers of the 5HT transporter. However, the higher affinity of 3H-paroxetine confirms that this compound is a better radioligand for the 5HT uptake site.

Comparative Evaluation in Nonhuman Primates of Five PET Radiotracers for Imaging the Serotonin Transporters: [11C]McN 5652, [11C]ADAM, [11C]DASB, [11C]DAPA, and [11C]AFM

“…Several postmortem studies have documented the distribution of SERT cells in the human brain (Cortes et al, 1988;Laruelle et al, 1988;Backstrom et al, 1989;Plenge et al, 1990;Rosel et al, 1997). High SERT density is observed at the level of the midbrain nuclei, reflecting the presence of SERT on both the 5-HT cell body (raphe nuclei) and on terminals of the dense 5-HT innervation of the adjacent structures (substantia nigra, nucleus interpeduncularis, locus ceruleus, nucleus nervi Br]5-bromo-6-nitroquipazine have been evaluated as potential PET or SPECT radiotracers and found to be unsuitable due to high lipophilicity and/or high nonspecific binding (Hashimoto et al, 1987;Lasne et al, 1989;Dannals et al, 1990;Hume et al, 1991;Nelson et al, 1991;Livni et al, 1994;Scheffel et al, 1994;Jagust et al, 1996;Bergstrom et al, 1997;Smith et al, 1997;Zea-Ponce et al, 1997;Lundkvist et al, 1999).…”

High affinity [3H]imipramine and [3H]paroxetine binding sites in suicide brains

“…The density of [3H]paroxetine and [3H]imipramine binding sites defined with 5-HT as displacing agent was similarly distributed among brain regions studied, with a higher Bmax in hypothalamus (Cumming and Gjedde, 1993 Rosel et al, 1997a) and lower values in frontal cortex (B~ickstrom et al, 1989;Plenge et al, 1990). These results are similar in depressed suicides and in controls.…”

Tracer Kinetic Modeling of [11C]AFM, a New PET Imaging Agent for the Serotonin Transporter

“…25 Three versions of the binding potential were then computed from the V T values: 25 Here the cerebellum gray matter was used as the reference region. Previous studies reported extremely low 2,3 or low 4,5,26 SERT density in the cerebellum.…”

“…An automated blood counting system (PBS-101; Veenstra Instruments, Joure, The Netherlands) was used to measure the radioactivity in whole blood during the first 7 minutes, with blood withdrawn continuously at 4 mL/min. Thereafter, 15 samples (1 to 6 mL) were collected manually at 3,5,7,10,15,20,25,30,40,50,60,75,90,105, and 120 minutes after tracer administration. For each sample, plasma was obtained by refrigerated centrifugation (2930 g at 41C for 5 minutes).…”

“…Intermediate levels are in the limbic system (hippocampus and cingulate cortex), and lower levels in the neocortex regions, with cerebellum displaying lowest to negligible SERT density. [2][3][4][5] Over the years, a number of high-affinity ligands have been developed for SERT imaging with PET. 6 was the first successful and widely used tracer.…”