[125I]5-iodo-6-nitroquipazine: a potent and selective ligand for the 5-hydroxytryptamine uptake complex. II. In vivo studies in rats.
The in vivo regional distribution and pharmacological profile of [125I]5-iodo-6-nitroquipazine in the rat brain were studied to evaluate this compound as a potential in vivo imaging agent of the 5-hydroxytryptamine (serotonin or 5-HT) uptake complex. This radioligand penetrated the blood-brain barrier quickly and efficiently, with 1.9% of injected dose found in the whole brain at 5 min post i.v. injection. The regional brain distribution of radioactivity at time points later than 2 h was highly correlated with the known distribution of serotonin uptake sites and terminals. Coadministration of 2 mg/kg paroxetine inhibited > 90% of the total in vivo binding of [125I]5-iodo-6-nitroquipazine. Other serotonin uptake inhibitors, such as fluoxetine and sertraline, were also effective inhibitors of [125I]5-iodo-6-nitroquipazine brain binding in vivo. Non-serotonergic uptake blockers (desipramine, nomifensine, and GBR-12909) and the postsynaptic serotonin receptor agent LSD had no effect on [125I]5-iodo-6-nitroquipazine binding in vivo even at high doses. Lesioning of the serotonergic system by p-chloramphetamine produced approximately 90% decrease in specific in vivo binding. Extraction and analysis of brain radioactivity indicated that approximately 95% of the extractable radioactivity was unmetabolized [125I]5-iodo-6-nitroquipazine. These results indicate that [125I]5-iodo-6-nitroquipazine is a specific, useful radioligand for studying serotonergic uptake sites and terminals in animals, and an 123I-radiolabeled form of the drug would be an excellent candidate for non-invasive single photon emission computed tomography (SPECT) imaging of these sites in the living human brain.
Center for Functional Imaging, Lawrence Berkeley Laboratory, University of California, Berkeley 94720.
A
A
Biegon
C A
CA
Mathis
S M
SM
Hanrahan
W J
WJ
Jagust
D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D007457:Iodine Radioisotopes; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011814:Quipazine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution
D002352:Carrier Proteins; D007457:Iodine Radioisotopes; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011814:Quipazine; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493232:Slc6a4 protein, rat; C075014:5-iodo-6-nitro-2-piperazinylquinoline