title: (R)-[¹¹C]Emopamil as a novel tracer for imaging enhanced P-glycoprotein function.
abstract: BACKGROUND
  2-Isopropyl-5-[methyl-(2-phenylethyl)amino]-2-phenylpentanenitrile (emopamil; EMP) is a calcium channel blocker of the phenylalkylamine class, with weak substrate properties for P-glycoprotein (P-gp). A weak substrate for P-gp would be suitable for measuring enhanced P-gp function. This study was performed to synthesise (R)- and (S)-[(11)C]EMP and characterise their properties as P-gp tracers.
  
  
  METHODS
  We synthesised (R)- and (S)-[(11)C]EMP and compared their biodistribution, peripheral metabolism, and effects of the P-gp inhibitor cyclosporine A (CsA, 50 mg/kg). We compared the brain pharmacokinetics of (R)-[(11)C]EMP and (R)-[(11)C]verapamil [(R)-[(11)C]VER] at baseline and CsA pretreatment with small animal positron emission tomography (PET).
  
  
  RESULTS
  (R)- and (S)-[(11)C]EMP were synthesised from (R)- and (S)-noremopamil, respectively, by methylation with [(11)C]methyl triflate in the presence of NaOH at room temperature. (R)- and (S)-[(11)C]EMP yields were ~30%, with specific activity>74 GBq/μmol and radiochemical purity>99%. (R)-[(11)C]EMP showed significantly greater uptake in the mouse brain than (S)-[(11)C]EMP. Both showed homogeneous non-stereoselective regional brain distributions. (R)- and (S)-[(11)C]EMP were rapidly metabolised to hydrophilic metabolites. Unchanged plasma (S)-[(11)C]EMP level was significantly lower than that of (R)-[(11)C]EMP 15 minutes post-injection, whilst>88% of radioactivity in the brain was intact at 15 minutes post-injection and was non-stereoselective. CsA pretreatment increased brain activity ~3-fold in mice, but was non-stereoselective. The baseline area-under-the-curve (AUC) of brain radioactivity (0-60 minutes) of (R)-[(11)C]EMP was 2-fold higher than that of (R)-[(11)C]VER, but their AUCs after CsA pretreatment were comparable.
  
  
  CONCLUSIONS
  (R)-[(11)C]EMP is a novel tracer for imaging P-gp function with higher baseline uptake than (R)-[(11)C]VER.
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. Electronic address: toyohara@pet.tmig.or.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Toyohara
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; Research Institute for Science and Engineering, Waseda University, Tokyo, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Aramaki
authors.affiliation: School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Zaitsu
authors.affiliation: School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Shimizu
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D002250:Carbon Radioisotopes; D016572:Cyclosporine / Q000494:pharmacology; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D013237:Stereoisomerism; D014018:Tissue Distribution / Q000187:drug effects; D014700:Verapamil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D002250:Carbon Radioisotopes; D016572:Cyclosporine; D014700:Verapamil; C052752:emopamil
keywords: Brain; Emopamil; Enantiomer; P-Glycoprotein; Positron emission tomography