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Mefway (18F)

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Mefway (18F)
Clinical data
Pregnancy
category
  • N/A
ATC code
  • none
Legal status
Legal status
  • Research compound
Identifiers
  • 4-[(18F)fluoromethyl]-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexane-1-carboxamide
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC26H35FN4O2
Molar mass454.590 g·mol−1
3D model (JSmol)
  • COC1=CC=CC=C1N2CCN(CC2)CCN(C3=CC=CC=N3)C(=O)C4CCC(CC4)C[18F]
  • InChI=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
  • Key:BQGLPDFQLBNUGU-FMLNDMEQSA-N

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.[1]

Chemistry

[edit]

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.[2] There are two isomers with regard to the cyclohexane ring, of which the trans conformation has the higher 5-HT1A specificity.[3]

Animal PET studies

[edit]

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.[4] In addition, mefway (18F) showed comparable brain uptake and the target-to-reference ratios compared to fcway(18F)[5]

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.[6]

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.[7] Mefway (18F) undergoes in vivo defluorination in rodent brain and this phenomenon was effectively suppressed by cytochrome P450 inhibitor (i.e. fluconazole).[8] Animal models of Parkinson's disease and the acute physical stress model exhibited significant decrement of binding potential in the hippocampus [9][10]

Human PET studies

[edit]

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.[11] 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.[12]

References

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  1. ^ Saigal N, Pichika R, Easwaramoorthy B, Collins D, Christian BT, Shi B, et al. (October 2006). "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 of Nuclear Medicine. 47 (10): 1697–706. PMID 17015907.
  2. ^ Choi JY, Kim CH, Ryu YH, Seo YB, Truong P, Kim EJ, et al. (October 2013). "Optimization of the radiosynthesis of [(18) F]MEFWAY for imaging brain serotonin 1A receptors by using the GE TracerLab FXFN-Pro module". Journal of Labelled Compounds & Radiopharmaceuticals. 56 (12): 589–94. doi:10.1002/jlcr.3067. PMID 24285234.
  3. ^ Wooten D, Hillmer A, Murali D, Barnhart T, Schneider ML, Mukherjee J, Christian BT (October 2011). "An in vivo comparison of cis- and trans-[18F]mefway in the nonhuman primate". Nuclear Medicine and Biology. 38 (7): 925–32. doi:10.1016/j.nucmedbio.2011.04.001. PMC 3190069. PMID 21741252.
  4. ^ Wooten DW, Moraino JD, Hillmer AT, Engle JW, Dejesus OJ, Murali D, et al. (July 2011). "In vivo kinetics of [F-18]MEFWAY: a comparison with [C-11]WAY100635 and [F-18]MPPF in the nonhuman primate". Synapse. 65 (7): 592–600. doi:10.1002/syn.20878. PMC 3080024. PMID 21484878.
  5. ^ Choi JY, Kim BS, Kim CH, Kim DG, Han SJ, Lee K, et al. (December 2014). "18 F]FCWAY in rodents". Synapse. 68 (12): 595–603. doi:10.1002/syn.21771. PMID 25056144. S2CID 23706884.
  6. ^ Wooten DW, Hillmer AT, Moirano JM, Ahlers EO, Slesarev M, Barnhart TE, et al. (August 2012). "Measurement of 5-HT(1A) receptor density and in-vivo binding parameters of [(18)F]mefway in the nonhuman primate". Journal of Cerebral Blood Flow and Metabolism. 32 (8): 1546–58. doi:10.1038/jcbfm.2012.43. PMC 3421091. PMID 22472611.
  7. ^ Saigal N, Bajwa AK, Faheem SS, Coleman RA, Pandey SK, Constantinescu CC, et al. (September 2013). "Evaluation of serotonin 5-HT(1A) receptors in rodent models using [18F]mefway PET". Synapse. 67 (9): 596–608. doi:10.1002/syn.21665. PMC 3744326. PMID 23504990.
  8. ^ Choi JY, Kim CH, Jeon TJ, Kim BS, Yi CH, Woo KS, et al. (December 2012). "Effective microPET imaging of brain 5-HT(1A) receptors in rats with [(18) F]MeFWAY by suppression of radioligand defluorination". Synapse. 66 (12): 1015–23. doi:10.1002/syn.21607. PMID 22927318. S2CID 5266871.
  9. ^ Lee M, Ryu YH, Cho WG, Jeon TJ, Lyoo CH, Kang YW, et al. (December 2014). "Dopaminergic neuron destruction reduces hippocampal serotonin 1A receptor uptake of trans-[(18)F]Mefway". Applied Radiation and Isotopes. 94: 30–34. doi:10.1016/j.apradiso.2014.06.016. PMID 25064461.
  10. ^ Choi JY, Shin S, Lee M, Jeon TJ, Seo Y, Kim CH, et al. (August 2014). "Acute physical stress induces the alteration of the serotonin 1A receptor density in the hippocampus". Synapse. 68 (8): 363–8. doi:10.1002/syn.21748. PMID 24771590.
  11. ^ Hillmer AT, Wooten DW, Bajwa AK, Higgins AT, Lao PJ, Betthauser TJ, et al. (December 2014). "First-in-human evaluation of 18F-mefway, a PET radioligand specific to serotonin-1A receptors". Journal of Nuclear Medicine. 55 (12): 1973–9. doi:10.2967/jnumed.114.145151. PMC 4316674. PMID 25453045.
  12. ^ Mukherjee J, Bajwa AK, Wooten DW, Hillmer AT, Pan ML, Pandey SK, et al. (May 2016). "Comparative assessment of (18) F-Mefway as a serotonin 5-HT1A receptor PET imaging agent across species: Rodents, nonhuman primates, and humans". The Journal of Comparative Neurology. 524 (7): 1457–71. doi:10.1002/cne.23919. PMC 4783179. PMID 26509362.
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