title: Synthesis and 18F-labeling of the analogues of Omecamtiv Mecarbil as a potential cardiac myosin imaging agent with PET.
abstract: BACKGROUND
  Cardiac myosin is a potential molecular target for heart failure imaging since its changes can be used to assess the function of heart. In this study, two analogues of Omecamtiv Mecarbil, which is the first selective activator of cardiac myosin, were synthesized and radio-labeled with (18)F. Then the radio-compounds were evaluated as potential cardiac myosin imaging agent.
  
  
  METHODS
  The labeling precursor and the nonradioactive compounds were synthesized and characterized by IR, (1)H NMR, (13)C NMR and MS analysis. By substituting bromo of precursors with (18)F, the radiolabeled compounds [(18)F]8 and [(18)F]10 were prepared and further evaluated for their in vitro physicochemical properties, stabilities, protein binding assay and ex vivo biodistribution.
  
  
  RESULTS
  Starting with [(18)F]F(-) Kryptofix 2.2.2./K2CO3 solution, the total reaction time for [(18)F]8 and [(18)F]10 was about 40 min respectively, with final high-performance liquid chromatography purification included. Typical decay-corrected radiochemical yield stayed at 12.47% ± 3.30% (n=8), the radiochemical purity, 98% or more. Their specific activity was estimated as 50 GBq/μmol. Both [(18)F]8 and [(18)F]10 could be stable after incubation in water at room temperature and in serum or binding buffer at 37 °C for 3h. Biodistribution in normal mice showed that both [(18)F]8 and [(18)F]10 have good heart uptake at 2 min post-injection time. Compound [(18)F]10 has better heart retention and higher heart to background ratios than those of [(18)F]8. In vitro protein binding assay demonstrates that [(18)F]10 may have high affinity with myosin from bovine heart.
  
  
  CONCLUSIONS
  [(18)F]8 and [(18)F]10 were synthesized with good radiochemical yield and high radiochemical purity (>98%). One of the compounds ([(18)F]10) has higher bovine heart myosin binding affinity and better heart/liver ratio. It will be further evaluated as a potent cardiac myosin imaging agent in normal and systolic heart failure model with positron emission tomography in the future.
authors.affiliation: Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Mingru
authors.initials: M
authors.lastname: Zhang
authors.forename: Tiantian
authors.initials: T
authors.lastname: Mou
authors.forename: Zuoquan
authors.initials: Z
authors.lastname: Zhao
authors.forename: Cheng
authors.initials: C
authors.lastname: Peng
authors.forename: Yunchuan
authors.initials: Y
authors.lastname: Ma
authors.forename: Wei
authors.initials: W
authors.lastname: Fang
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002417:Cattle; D055598:Chemical Phenomena; D060326:Chemistry Techniques, Synthetic; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D007553:Isotope Labeling; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D009218:Myosins / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D013379:Substrate Specificity; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D005462:Fluorine Radioisotopes; C547293:omecamtiv mecarbil; D014508:Urea; D009218:Myosins