Serotonin 5HT1A receptors have been investigated in a number of CNS disorders, including depression, anxiety, sleep disorders, epilepsy, Parkinson's disease (PD) and Alzheimer's disease (AD). Our particular interest is to apply 5HT1A receptor imaging for the study of mood disorders and AD. Efforts are underway to improve in vivo properties of 5-HT1A agents, 11 C-WAY-100635, 18 F-MPPF and 18 F-FCWAY currently in human use. We have identified and synthesized F-Mefway, which contains a fluorine-18 on a primary carbon 18 to make the compound more stable to defluorination. Mefway has high affinity for 5HT1A receptors and in vitro rodent brain slices exhibited selective binding of F-mefway in hippocampus, cortex and other brain regions, 18 with limited binding in the cerebellum. Preliminary in vitro studies showed serotonin displaced 18 F-mefway from various brain regions with IC50 in the range of 169-243 nM. PET studies in a rhesus monkey showed F- 18 mefway binding to temporal cortex, hippocampus, raphe and other brain regions with ratios of hippocampus to cerebellum = 10. Plasma analysis indicated the presence of approx. 30% of 18 F-mefway and no observed defluorination. The high ratios in specific brain regions such as the hippocampus suggest that F-mefway has 18 potential as a PET imaging agent for 5HT1A receptors in humans. Therefore, our overall goals in this application are to synthesize and characterize pure cis- and trans-isomers of Mefway, study pharmacological characteristics of the isomers and investigate PET imaging characteristics of the 18 F-fluorine radiolabeled analogs in order to identify which of the isomers will be more suitable for human PET studies. In order to extend our findings to human studies, dosimetry of 18F-mefway will be measured in rats and monkeys. Drug- induced serotonin competition studies will be carried out using PET imaging studies in rodents to study serotonin effects. In order to assess the value of F-mefway in AD, two important areas of expertise at UCI 18 have come together in this application to address specific hypotheses using multidisciplinary approaches that include expertise in brain imaging techniques and a research group focusing on animal models of brain aging at the PET Brain Imaging Center and the Institute for Brain Aging and Dementia, respectively. In vitro studies will be carried out on two mice transgenic models of AD, the Tg2576 and 3xTg mice in order to correlate senile plaque and neurofibrillary tangle formation with the loss of serotonin 5HT1A receptors using F-mefway. Due 18 to the high hippocampus to cerebellum ratio (approx 10) and advantages of the fluorine-18 radiolabel, 18 F- mefway may have potential use in the study of AD. ? Development of imaging methods for understanding serotonin effects in the brain will help understand mood disorders and methods to study alterations of the serotonin receptor abnormailites in transgenic mice models will have implications in diagnosis, treatment planning and therapeutics development of Alzheimer's disease and other disorders of the central nervous system. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG030524-02
Application #
7434384
Study Section
Special Emphasis Panel (ZRG1-BDCN-A (11))
Program Officer
Hsiao, John
Project Start
2007-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$183,824
Indirect Cost
Name
University of California Irvine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Mukherjee, Jogeshwar; Bajwa, Alisha K; Wooten, Dustin W et al. (2016) Comparative assessment of (18) F-Mefway as a serotonin 5-HT1A receptor PET imaging agent across species: Rodents, nonhuman primates, and humans. J Comp Neurol 524:1457-71
Thio, Joanne P; Liang, Christopher; Bajwa, Alisha K et al. (2015) Synthesis and Evaluation of Mefway Analogs as Ligands for Serotonin 5HT1A Receptors. Med Chem Res 24:1480-1486
Hillmer, Ansel T; Wooten, Dustin W; Bajwa, Alisha K et al. (2014) First-in-human evaluation of 18F-mefway, a PET radioligand specific to serotonin-1A receptors. J Nucl Med 55:1973-9
Wooten, Dustin W; Hillmer, Ansel T; Moirano, Jeffrey M et al. (2013) 5-HT1A sex based differences in Bmax, in vivo KD, and BPND in the nonhuman primate. Neuroimage 77:125-32
Constantinescu, Cristian C; Sevrioukov, Evgueni; Garcia, Adriana et al. (2013) Evaluation of [18F]Mefway biodistribution and dosimetry based on whole-body PET imaging of mice. Mol Imaging Biol 15:222-9
Saigal, Neil; Bajwa, Alisha K; Faheem, Sara S et al. (2013) Evaluation of serotonin 5-HT(1A) receptors in rodent models using [ยน?F]mefway PET. Synapse 67:596-608
Wooten, Dustin W; Hillmer, Ansel T; Moirano, Jeffrey M et al. (2012) Measurement of 5-HT(1A) receptor density and in-vivo binding parameters of [(18)F]mefway in the nonhuman primate. J Cereb Blood Flow Metab 32:1546-58
Wooten, D W; Moraino, J D; Hillmer, A T et al. (2011) In vivo kinetics of [F-18]MEFWAY: a comparison with [C-11]WAY100635 and [F-18]MPPF in the nonhuman primate. Synapse 65:592-600
Wooten, Dustin; Hillmer, Ansel; Murali, Dhanabalan et al. (2011) An in vivo comparison of cis- and trans-[18F]mefway in the nonhuman primate. Nucl Med Biol 38:925-32