[I-125] 5-IODO-6-NITROQUIPAZINE - A POTENT AND SELECTIVE LIGAND FOR THE 5-HYDROXYTRYPTAMINE UPTAKE COMPLEX .2. IN-VIVO STUDIES IN RATS

The in vivo regional distribution and pharmacological profile of [I-125]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 [I-125]5-iodo-6-nitroquipazine. Other serotonin uptake inhibitors, such as fluoxetine and sertraline, were also effective inhibitors of [I-125]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 [I-125]5-iodo-6-nitroquipazine binding in vivo even at high doses. Lesioning of the serotonergic system by p-chloroamphetamine 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 [I-125]5-iodo-6-nitroquipazine. These results indicate that [I-125]5-iodo-6-nitroquipazine is a specific, useful radioligand for studying serotonergic uptake sites and terminals in animals, and an I-123-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.