Mefway (18F)
{{Short description|Chemical compound}}
{{DISPLAYTITLE:Mefway (18F)}}
{{drugbox
| drug_name = Mefway (18F)
| image = Mefway 18F skeletal.svg
| IUPAC_name = 4-[(18F)fluoromethyl]-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexane-1-carboxamide
| synonyms =
| CAS_number = 943962-60-5
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 0NM517978A
| PubChem= 11963740
| ChemSpiderID = 10137857
| ATC_prefix = none
| smiles = COC1=CC=CC=C1N2CCN(CC2)CCN(C3=CC=CC=N3)C(=O)C4CCC(CC4)C[18F]
| C=26 | H=35 | F=1 | N=4 | O=2
| StdInChI=1S/C26H35FN4O2/c1-33-24-7-3-2-6-23(24)30-17-14-29(15-18-30)16-19-31(25-8-4-5-13-28-25)26(32)22-11-9-21(20-27)10-12-22/h2-8,13,21-22H,9-12,14-20H2,1H3/i27-1
| StdInChIKey = BQGLPDFQLBNUGU-FMLNDMEQSA-N
| pregnancy_category = N/A
| legal_status = Research compound
}}
Mefway is a serotonin 5-HT1A receptor antagonist used in medical research, usually in the form of mefway (18F) as a positron emission tomography (PET) radiotracer.{{cite journal | vauthors = Saigal N, Pichika R, Easwaramoorthy B, Collins D, Christian BT, Shi B, Narayanan TK, Potkin SG, Mukherjee J | display-authors = 6 | title = Synthesis and biologic evaluation of a novel serotonin 5-HT1A receptor radioligand, 18F-labeled mefway, in rodents and imaging by PET in a nonhuman primate | journal = Journal of Nuclear Medicine | volume = 47 | issue = 10 | pages = 1697–706 | date = October 2006 | pmid = 17015907 }}
Chemistry
Mefway is closely related to the research compound WAY-100,635. The compound adds a fluoromethyl group to the cyclohexyl ring of WAY-100,635 and it is effectively prepared with automation module.{{cite journal | vauthors = Choi JY, Kim CH, Ryu YH, Seo YB, Truong P, Kim EJ, Choi TH, Kang J, Lee M, Kim DG, Lee JD, Jeon TJ | display-authors = 6 | title = Optimization of the radiosynthesis of [(18) F]MEFWAY for imaging brain serotonin 1A receptors by using the GE TracerLab FXFN-Pro module | journal = Journal of Labelled Compounds & Radiopharmaceuticals | volume = 56 | issue = 12 | pages = 589–94 | date = October 2013 | pmid = 24285234 | doi = 10.1002/jlcr.3067 }}
There are two isomers with regard to the cyclohexane ring, of which the trans conformation has the higher 5-HT1A specificity.{{cite journal | vauthors = Wooten D, Hillmer A, Murali D, Barnhart T, Schneider ML, Mukherjee J, Christian BT | title = An in vivo comparison of cis- and trans-[18F]mefway in the nonhuman primate | journal = Nuclear Medicine and Biology | volume = 38 | issue = 7 | pages = 925–32 | date = October 2011 | pmid = 21741252 | pmc = 3190069 | doi = 10.1016/j.nucmedbio.2011.04.001 }}
Animal PET studies
In one study the uptake and retention of mefway (18F) was found to be similar to that found for 11C-WAY-100,635. Head-to-head comparison of mefway (18F) and 11C-WAY-100,635 have been evaluated. Since 11C-WAY-100,635 is the current 'gold standard' and difficult to synthesize, a suitable fluorine-18 replacement as in mefway is highly desired.{{cite journal | vauthors = Wooten DW, Moraino JD, Hillmer AT, Engle JW, Dejesus OJ, Murali D, Barnhart TE, Nickles RJ, Davidson RJ, Schneider ML, Mukherjee J, Christian BT | display-authors = 6 | title = In vivo kinetics of [F-18]MEFWAY: a comparison with [C-11]WAY100635 and [F-18]MPPF in the nonhuman primate | journal = Synapse | volume = 65 | issue = 7 | pages = 592–600 | date = July 2011 | pmid = 21484878 | pmc = 3080024 | doi = 10.1002/syn.20878 }} In addition, mefway (18F) showed comparable brain uptake and the target-to-reference ratios compared to fcway(18F){{cite journal | vauthors = Choi JY, Kim BS, Kim CH, Kim DG, Han SJ, Lee K, Kim KM, An G, Choi TH, Yoo SD, Ryu YH | display-authors = 6 | title = 18 F]FCWAY in rodents | journal = Synapse | volume = 68 | issue = 12 | pages = 595–603 | date = December 2014 | pmid = 25056144 | doi = 10.1002/syn.21771 | s2cid = 23706884 }}
The ability to separately measure dissociation constant, KD and receptor density Bmax has been shown to be of potential value rather than simply comparing binding potential, BPND. Multiple injection mefway PET experiments can be used for the in-vivo measurement of 5-HT1A receptor density.{{cite journal | vauthors = Wooten DW, Hillmer AT, Moirano JM, Ahlers EO, Slesarev M, Barnhart TE, Mukherjee J, Schneider ML, Christian BT | display-authors = 6 | title = Measurement of 5-HT(1A) receptor density and in-vivo binding parameters of [(18)F]mefway in the nonhuman primate | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 32 | issue = 8 | pages = 1546–58 | date = August 2012 | pmid = 22472611 | pmc = 3421091 | doi = 10.1038/jcbfm.2012.43 }}
Imaging studies of mefway on in vivo and ex vivo rat brains indicate that the substance binds to the known 5-HT1A receptor regions including the dorsal raphe. These findings support that the dorsal raphe is measurable in rat PET studies.{{cite journal | vauthors = Saigal N, Bajwa AK, Faheem SS, Coleman RA, Pandey SK, Constantinescu CC, Fong V, Mukherjee J | display-authors = 6 | title = Evaluation of serotonin 5-HT(1A) receptors in rodent models using [18F]mefway PET | journal = Synapse | volume = 67 | issue = 9 | pages = 596–608 | date = September 2013 | pmid = 23504990 | pmc = 3744326 | doi = 10.1002/syn.21665 }} Mefway (18F) undergoes in vivo defluorination in rodent brain and this phenomenon was effectively suppressed by cytochrome P450 inhibitor (i.e. fluconazole).{{cite journal | vauthors = Choi JY, Kim CH, Jeon TJ, Kim BS, Yi CH, Woo KS, Seo YB, Han SJ, Kim KM, Yi DI, Lee M, Kim DG, Kim JY, Lee KC, Choi TH, An G, Ryu YH | display-authors = 6 | title = Effective microPET imaging of brain 5-HT(1A) receptors in rats with [(18) F]MeFWAY by suppression of radioligand defluorination | journal = Synapse | volume = 66 | issue = 12 | pages = 1015–23 | date = December 2012 | pmid = 22927318 | doi = 10.1002/syn.21607 | s2cid = 5266871 }} Animal models of Parkinson's disease and the acute physical stress model exhibited significant decrement of binding potential in the hippocampus {{cite journal | vauthors = Lee M, Ryu YH, Cho WG, Jeon TJ, Lyoo CH, Kang YW, Lee SJ, Kim CH, Kim DG, Kang JH, Seo YB, Yi CH, Lee K, Choi TH, Choi JY | display-authors = 6 | title = Dopaminergic neuron destruction reduces hippocampal serotonin 1A receptor uptake of trans-[(18)F]Mefway | journal = Applied Radiation and Isotopes | volume = 94 | pages = 30–34 | date = December 2014 | pmid = 25064461 | doi = 10.1016/j.apradiso.2014.06.016 }}{{cite journal | vauthors = Choi JY, Shin S, Lee M, Jeon TJ, Seo Y, Kim CH, Kim DG, Yi CH, Lee K, Choi TH, Kang JH, Ryu YH | display-authors = 6 | title = Acute physical stress induces the alteration of the serotonin 1A receptor density in the hippocampus | journal = Synapse | volume = 68 | issue = 8 | pages = 363–8 | date = August 2014 | pmid = 24771590 | doi = 10.1002/syn.21748 }}
Human PET studies
First-in-human studies have shown in vivo stability of mefway (18F) and its localization to 5-HT1A receptor-rich regions in the human brain, including the raphe nucleus.{{cite journal | vauthors = Hillmer AT, Wooten DW, Bajwa AK, Higgins AT, Lao PJ, Betthauser TJ, Barnhart TE, Rowley HA, Stone CK, Johnson SC, Mukherjee J, Christian BT | display-authors = 6 | title = First-in-human evaluation of 18F-mefway, a PET radioligand specific to serotonin-1A receptors | journal = Journal of Nuclear Medicine | volume = 55 | issue = 12 | pages = 1973–9 | date = December 2014 | pmid = 25453045 | pmc = 4316674 | doi = 10.2967/jnumed.114.145151 }} Mefway (18F) is highly selective for the human serotonin 5-HT1A receptor and may therefore may be used to quantify serotonin 5-HT1A receptor distribution in brain regions for the study of various central nervous system disorders.{{cite journal | vauthors = Mukherjee J, Bajwa AK, Wooten DW, Hillmer AT, Pan ML, Pandey SK, Saigal N, Christian BT | display-authors = 6 | title = Comparative assessment of (18) F-Mefway as a serotonin 5-HT1A receptor PET imaging agent across species: Rodents, nonhuman primates, and humans | journal = The Journal of Comparative Neurology | volume = 524 | issue = 7 | pages = 1457–71 | date = May 2016 | pmid = 26509362 | pmc = 4783179 | doi = 10.1002/cne.23919 }}