Comparative assessment of (18) F-Mefway as a serotonin 5-HT1A receptor PET imaging agent across species: Rodents, nonhuman primates, and humans.
We have developed (18) F-trans-Mefway ((18) F-Mefway) for positron emission tomography (PET) imaging studies of serotonin 5-HT1A receptors which are implicated in various brain functions. Translation of imaging the 5-HT1A receptor in animal models to humans will facilitate an understanding of the role of the receptor in human brain disorders. We report comparative brain distribution of (18) F-Mefway in normal mice, rats, monkeys, and healthy human volunteers. Mefway was found to be very selective, with subnanomolar affinity for the 5-HT1A receptor. Affinities of >55 nM were found for all other human-cloned receptor subtypes tested. Mefway was found to be a poor substrate (>30 μM) for the multidrug resistance 1 protein, suggesting low likelihood of brain uptake being affected by P-glycoprotein. Cerebellum was used as a reference region in all imaging studies across all species due to the low levels of (18) F-Mefway binding. Consistent binding of (18) F-Mefway in cortical regions, hippocampus, and raphe was observed across all species. (18) F-Mefway in the human brain regions correlated with the known postmortem distribution of 5-HT1A receptors. Quantitation of raphe was affected by the resolution of the PET scanners in rodents, whereas monkeys and humans showed a raphe to cerebellum ratio of approximately 3. (18) F-Mefway appears to be an effective 5-HT1A receptor imaging agent in all models, including humans. (18) F-Mefway therefore may be used to quantify 5-HT1A receptor distribution in brain regions for the study of various CNS disorders. J. Comp. Neurol. 524:1457-1471, 2016. © 2015 Wiley Periodicals, Inc.
Preclinical Imaging, Department of Radiological Sciences, University of California, Irvine, California, 92697-5000.
Jogeshwar
J
Mukherjee
Preclinical Imaging, Department of Radiological Sciences, University of California, Irvine, California, 92697-5000.
Alisha K
AK
Bajwa
Department of Medical Physics and Waisman Center, University of Wisconsin, Madison, Wisconsin, 53705.
Dustin W
DW
Wooten
Department of Medical Physics and Waisman Center, University of Wisconsin, Madison, Wisconsin, 53705.
Ansel T
AT
Hillmer
Preclinical Imaging, Department of Radiological Sciences, University of California, Irvine, California, 92697-5000.
Min-Liang
ML
Pan
Preclinical Imaging, Department of Radiological Sciences, University of California, Irvine, California, 92697-5000.
Suresh K
SK
Pandey
Preclinical Imaging, Department of Radiological Sciences, University of California, Irvine, California, 92697-5000.
Neil
N
Saigal
Department of Medical Physics and Waisman Center, University of Wisconsin, Madison, Wisconsin, 53705.
Bradley T
BT
Christian
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D001931:Brain Mapping; D004305:Dose-Response Relationship, Drug; D005260:Female; D005583:Fourier Analysis; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010879:Piperazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011224:Prazosin / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D058668:Adrenergic alpha-1 Receptor Antagonists; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; D017366:Serotonin Receptor Agonists; C515664:mefway; D044282:Receptor, Serotonin, 5-HT1A; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D011224:Prazosin
P-glycoprotein; hippocampus; raphe nucleus; receptor selectivity; translational research