title: Molecular imaging of neurovascular cell death in experimental cerebral stroke by PET.
abstract: Clinical molecular imaging of apoptosis is a highly desirable yet unmet challenge. Here we provide the first report on (18)F-labeled 5-fluoropentyl-2-methyl-malonic acid ((18)F-ML-10), a small-molecule, (18)F-labeled PET tracer for the imaging of apoptosis in vivo; this report includes descriptions of the synthesis, radiolabeling, and biodistribution of this novel apoptosis marker. We also describe the use of (18)F-ML-10 for small-animal PET of neurovascular cell death in experimental cerebral stroke in mice.
  
  
  METHODS
  (18)F-ML-10 was synthesized by nucleophilic substitution from the respective mesylate precursor, and its biodistribution was assessed in healthy rats. Permanent occlusion of the middle cerebral artery (MCA) was induced in mice, and small-animal PET was performed 24 h later.
  
  
  RESULTS
  Efficient radiolabeling of ML-10 with (18)F was achieved. Biodistribution studies with (18)F-ML-10 revealed rapid clearance from blood (half-life of 23 min), a lack of binding to healthy tissues, and rapid elimination through the kidneys. No significant tracer metabolism in vivo was observed. Clear images of distinct regions of increased uptake, selectively in the ischemic MCA territory, were obtained in the in vivo small-animal PET studies. Uptake measurements ex vivo revealed 2-fold-higher uptake in the affected hemisphere and 6- to 10-fold-higher uptake in the region of interest of the infarct. The cerebral uptake of (18)F-ML-10 was well correlated with histologic evidence of cell death. The tracer was retained in the stroke area but was cleared from blood and from intact brain areas.
  
  
  CONCLUSIONS
  (18)F-ML-10 is useful for noninvasive PET of neurovascular histopathology in ischemic cerebral stroke in vivo. Such an assessment may assist in characterization of the extent of stroke-related cerebral damage and in the monitoring of disease course and effect of treatment.
authors.affiliation: NST NeuroSurvival Technologies Ltd., Petach Tikva, Israel. ayelet@nst.co.il
authors.forename: Ayelet
authors.initials: A
authors.lastname: Reshef
authors.forename: Anat
authors.initials: A
authors.lastname: Shirvan
authors.forename: Rikki N
authors.initials: RN
authors.lastname: Waterhouse
authors.forename: Hagit
authors.initials: H
authors.lastname: Grimberg
authors.forename: Galit
authors.initials: G
authors.lastname: Levin
authors.forename: Avi
authors.initials: A
authors.lastname: Cohen
authors.forename: Luckner G
authors.initials: LG
authors.lastname: Ulysse
authors.forename: Gad
authors.initials: G
authors.lastname: Friedman
authors.forename: Gunnar
authors.initials: G
authors.lastname: Antoni
authors.forename: Ilan
authors.initials: I
authors.lastname: Ziv
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D008297:Male; D008764:Methylmalonic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D015336:Molecular Probe Techniques; D009474:Neurons / Q000000981:diagnostic imaging* / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D020521:Stroke / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology
chemical_list: C532430:5-fluoropentyl-2-methylmalonic acid; D019275:Radiopharmaceuticals; D008764:Methylmalonic Acid