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Preclinical evaluation of [18F]2FNQ1P as the first fluorinated serotonin 5-HT6 radioligand for PET imaging.
- Source :
-
European journal of nuclear medicine and molecular imaging [Eur J Nucl Med Mol Imaging] 2015 Mar; Vol. 42 (3), pp. 495-502. Date of Electronic Publication: 2014 Oct 21. - Publication Year :
- 2015
-
Abstract
- 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.<br />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.<br />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.<br />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.
- Subjects :
- Animals
Cats
Drug Evaluation, Preclinical
Fluorine Radioisotopes pharmacokinetics
Furans chemical synthesis
Macaca fascicularis
Male
Naphthoquinones chemical synthesis
Piperazines pharmacokinetics
Protein Binding
Radiopharmaceuticals chemical synthesis
Rats
Rats, Sprague-Dawley
Serotonin Antagonists pharmacokinetics
Sulfonamides pharmacokinetics
Tissue Distribution
Brain diagnostic imaging
Furans pharmacokinetics
Naphthoquinones pharmacokinetics
Positron-Emission Tomography
Radiopharmaceuticals pharmacokinetics
Receptors, Serotonin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1619-7089
- Volume :
- 42
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- European journal of nuclear medicine and molecular imaging
- Publication Type :
- Academic Journal
- Accession number :
- 25331460
- Full Text :
- https://doi.org/10.1007/s00259-014-2936-y