mcn-5652 and vanoxerine

The [(18)F]fluoromethyl analog of (+)-McN5652 ([(18)F]FMe-McN) for imaging serotonin transporter (SERT) with positron emission tomography (PET) has recently been synthesized. We describe here the biological evaluation of [(18)F]FMe-McN in rats. Biodistribution studies of [(18)F]FMe-McN in rat brain ex vivo after an intravenous injection showed a high accumulation of radioactivity in the regions rich in SERT, such as raphe nuclei, hypothalamus, thalamus, substantia nigra, locus coeruleus, and amygdala. Region-to-cerebellum ratios reached a maximum value of 9 in raphe nuclei within 3.5 h after administration. The specificity and selectivity of [(18)F]FMe-McN binding to SERT was studied by preinjecting blocking doses of serotonin, norepinephrine, and dopamine transporter inhibitors. Fluoxetine, a specific inhibitor for SERT, decreased the specific binding of [(18)F]FMe-McN in raphe nuclei by 91 +/- 4%; in other regions rich in SERT, similar results were obtained. GBR12909 and nisoxetine, selective inhibitors for dopamine transporter (DAT) and norepinephrine transporter (NET), respectively, showed no significant effects on the uptake of [(18)F]FMe-McN. Our studies show that [(18)F]FMe-McN has a clear potential as a tracer for studies with PET of SERT function in humans.

Topics: Animals; Autoradiography; Brain; Carrier Proteins; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Female; Fluorine Radioisotopes; Fluoxetine; Isoquinolines; Male; Membrane Glycoproteins; Membrane Transport Modulators; Membrane Transport Proteins; Nerve Tissue Proteins; Norepinephrine Plasma Membrane Transport Proteins; Piperazines; Radioactive Tracers; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Symporters; Tomography, Emission-Computed

A radioligand for imaging central serotonin (5-hydroxytryptamine; 5-HT) uptake sites by positron emission tomography (PET) has yet to be developed. Such a tracer would be useful for the study of normal and altered serotonergic neurotransmission as well as for the detection of serotonergic neurotoxicity. This paper describes the labeling of the highly potent serotonin (5-HT) uptake blocker, McN-5652-Z (trans-1,2,3,5,6,10 beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoquinoline; racemic mixture), with 11C and the evaluation of this radiotracer in rodents with respect to its in vivo binding characteristics. In mouse brain, 11C-McN-5652-Z accumulated rapidly in regions with high densities of 5-HT uptake sites. The ratio between hypothalamus and cerebellum was 1.5:1 at 15 min and increased with time to 4.6:1 at 90 min after injection. The distribution of 11C-McN-5652 in rat brain at 60 min correlated well with regional concentrations of 5-HT uptake sites (r = 0.86). The specificity and selectivity of 11C-McN-5652 binding to the 5-HT transporter were tested by preinjecting blocking doses of known 5-HT, dopamine and norepinephrine uptake inhibitors, and a 5-HT2 receptor blocker before injection of the radiotracer. Preinjection of increasing doses of unlabeled McN-5652-Z inhibited 11C-McN-5652-Z binding in a dose-dependent fashion. These results suggest that the in vivo binding of the radiotracer was specific, selective for 5-HT uptake sites, saturable and that 11C-McN-5652-Z holds promise as a radiotracer for PET imaging of 5-HT uptake sites in the mammalian brain.

Topics: Animals; Binding Sites; Brain; Carbon Radioisotopes; Desipramine; Isoquinolines; Mice; Neurotransmitter Uptake Inhibitors; Paroxetine; Piperazines; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Antagonists; Tomography, Emission-Computed