Preclinical evaluation of [18F]2FNQ1P as the first fluorinated serotonin 5-HT6 radioligand for PET imaging.

PURPOSE: Brain serotonin 6 receptor (5-HT6) is one of the most recently identified serotonin receptors. It is a potent therapeutic target for psychiatric and neurological diseases, e.g. schizophrenia and Alzheimer's disease. Since no specific fluorinated radioligand has yet been successfully used to study this receptor by positron emission tomography (PET) neuroimaging, the objective of the present study was to study the first 5-HT6 (18)F-labelled radiotracer. METHODS: 2FNQ1P, inspired by the quinolone core of a previous radiotracer candidate, GSK215083, was selected according its 5-HT6 affinity and selectivity and was radiolabelled by (18)F nucleophilic substitution. The cerebral distribution of [(18)F]2FNQ1P was studied in vivo in rats, cats and macaque monkeys. RESULTS: The chemical and radiochemical purities of [(18)F]2FNQ1P were >98 %. In rats, in vitro competition with the 5-HT6 antagonist, SB258585, revealed that the radioligand was displaced dose dependently. Rat microPET studies showed low brain uptake of [(18)F]2FNQ1P, reversed by the P-glycoprotein inhibitor, cyclosporin. On the contrary, PET scans in cats showed good brain penetration and specific striatal binding blocked after pretreatment with unlabelled 2FNQ1P. PET scans in macaque monkeys confirmed high specific binding in both cortical and subcortical regions, specifically decreased by pretreatment with the 5-HT6 receptor antagonist, SB258585. CONCLUSION: 2FNQ1P was initially selected because of its suitable characteristics for 5-HT6 receptor probing in vitro in terms of affinity and specificity. Although in vivo imaging in rats cannot be considered as predictive of the clinical characteristics of the radiotracer, [(18)F]2FNQ1P appeared to be a suitable 5-HT6 PET tracer in feline and primate models. These preclinical results encourage us to pursue the clinical development of this first fluorinated 5-HT6 PET radiotracer.

Forelimb dyskinesia mediated by high-frequency stimulation of the subthalamic nucleus is linked to rapid activation of the NR2B subunit of N-methyl-D-aspartate receptors.

Dyskinesia is a major side-effect of chronic l-DOPA administration, the reference treatment for Parkinson's disease. High-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates parkinsonian motor symptoms and indirectly improves dyskinesia by decreasing the L-DOPA requirement. However, inappropriate stimulation can also trigger dyskinetic movements, in both human and rodents. We investigated whether STN-HFS-evoked forelimb dyskinesia involved changes in glutamatergic neurotransmission as previously reported for L-DOPA-induced dyskinesias, focusing on the role of NR2B-containing N-methyl-D-aspartate receptors (NR2B/NMDARs). We applied STN-HFS in normal rats at intensities above and below the threshold for triggering forelimb dyskinesia. Dyskinesiogenic STN-HFS induced the activation of NR2B (as assessed by immunodetection of the phosphorylated residue Tyr(1472)) in neurons of the subthalamic nucleus, entopeduncular nucleus, motor thalamus and forelimb motor cortex. The severity of STN-HFS-induced forelimb dyskinesia was decreased in a dose-dependent manner by systemic injections of CP-101,606, a selective blocker of NR2B/NMDARs, but was either unaffected or increased by the non-selective N-methyl-D-aspartate receptor antagonist, MK-801.