title: Evaluation of serotonin 5-HT(1A) receptors in rodent models using [¹⁸F]mefway PET.
abstract: BACKGROUND
  Serotonin 5-HT(1A) receptors have been investigated in various CNS disorders, including epilepsy, mood disorders, and neurodegeneration. [¹⁸F]Mefway (N-{2-[4-(2'-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(cis/trans-4'-[¹⁸F]fluoromethylcyclohexane)-carboxamide) has been developed as a suitable positron emission tomography (PET) imaging agent for these receptors. We have now evaluated the suitability of [¹⁸F]trans-mefway in rat and mouse models using PET and computerized tomography (CT) imaging and corroborated with ex vivo and in vitro autoradiographic studies.
  
  
  METHODS
  Normal Sprague-Dawley rats and Balb/C mice were used for PET/CT imaging using intravenously injected [¹⁸F]trans-mefway. Brain PET data were coregistered with rat and mouse magnetic resonance imaging template and regional distribution of radioactivity was quantitated. Selected animals were used for ex vivo autoradiographic studies to confirm regional brain distribution and quantitative measures of binding, using brain region to cerebellum ratios. Binding affinity of trans-mefway and WAY-100635 was measured in rat brain homogenates. Distribution of [¹⁸F]trans-4-fluoromethylcyclohexane carboxylate ([¹⁸F]FMCHA), a major metabolite of [¹⁸F] trans-mefway, was assessed in the rat by PET/CT.
  
  
  RESULTS
  The inhibition constant, K(i) for trans-mefway was 0.84 nM and that for WAY-100635 was 1.07 nM. Rapid brain uptake of [¹⁸F]trans-mefway was observed in all rat brain regions and clearance from cerebellum was fast and was used as a reference region in all studies. Distribution of [¹⁸F]trans-mefway in various brain regions was consistent in PET and in vitro studies. The dorsal raphe was visualized and quantified in the rat PET but identification in the mouse was difficult. The rank order of binding to the various brain regions was hippocampus > frontal cortex > anterior cingulate cortex > lateral septal nuclei > dorsal raphe nuclei.
  
  
  CONCLUSIONS
  [¹⁸F]trans-Mefway appears to be an effective 5-HT(1A) receptor imaging agent in rodents for studies of various disease models.
authors.affiliation: Preclinical Imaging, Department of Radiological Sciences, University of California, Irvine, California, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Saigal
authors.forename: Alisha K
authors.initials: AK
authors.lastname: Bajwa
authors.forename: Sara S
authors.initials: SS
authors.lastname: Faheem
authors.forename: Robert A
authors.initials: RA
authors.lastname: Coleman
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Pandey
authors.forename: Cristian C
authors.initials: CC
authors.lastname: Constantinescu
authors.forename: Vanessa
authors.initials: V
authors.lastname: Fong
authors.forename: Jogeshwar
authors.initials: J
authors.lastname: Mukherjee
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D005462:Fluorine Radioisotopes / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010879:Piperazines / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology
chemical_list: D005462:Fluorine Radioisotopes; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; D058829:Serotonin 5-HT1 Receptor Antagonists; C515664:mefway; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
keywords: 5-HT1A receptors; WAY-100635; mefway; microPET; serotonin