title: 18F-FPEB, a PET radiopharmaceutical for quantifying metabotropic glutamate 5 receptors: a first-in-human study of radiochemical safety, biokinetics, and radiation dosimetry.
abstract: Identification of safe and valid PET radioligands for metabotropic glutamate receptor, type 5 (mGluR5), is essential to measure changes in brain mGluR5 in neuropsychiatric disorders, to confirm central mGluR5 occupancy of drug candidates, and to guide dose selection for obtaining an optimum therapeutic window. Here we present the results of a first-in-human study assessing the safety and effectiveness of a novel PET radiopharmaceutical, (18)F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ((18)F-FPEB), for quantifying regional brain concentrations of mGluR5.
  
  
  METHODS
  Quantification of whole-body biokinetics was conducted in 6 healthy adults (3 men and 3 women). The radiation safety profile was estimated with OLINDA/EXM software. Subsequently, pairs of dynamic brain scans were obtained for 11 healthy men to identify optimal methods for derivation of regional distribution volume and binding potential and to determine the repeatability of measurement.
  
  
  RESULTS
  The whole-body effective radiation dose was approximately 17 μSv/MBq (62 mrem/mCi), with the gallbladder receiving the highest dose of 190 μSv/MBq. In brain studies, time-activity curves showed high accumulation in the insula/caudate nucleus, moderate uptake in the thalamus, and the lowest concentration in the cerebellum/pons. The plasma reference graphical analysis method appeared optimal for (18)F-FPEB; it showed acceptable test-retest variability of nondisplaceable binding potential (<10%) and identified the highest nondisplaceable binding potential values (from ∼0.5 in the globus pallidus to ∼3.5 in the insula) for target regions. Safety assessments revealed no clinically meaningful changes in vital signs, electrocardiogram, or laboratory values.
  
  
  CONCLUSIONS
  (18)F-FPEB is safe and well tolerated, and its regional cerebral distribution is consistent with previous reports in the literature for metabotropic glutamate receptors. The repeatability of measurement suggests that (18)F-FPEB is suitable for quantifying mGluR5 in humans.
authors: Russell H Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. dfwong@jhmi.edu
authors: Dean F
authors: DF
authors: Wong
authors: Rikki
authors: R
authors: Waterhouse
authors: Hiroto
authors: H
authors: Kuwabara
authors: Jongho
authors: J
authors: Kim
authors: James R
authors: JR
authors: Brašić
authors: Wichana
authors: W
authors: Chamroonrat
authors: Michael
authors: M
authors: Stabins
authors: Daniel P
authors: DP
authors: Holt
authors: Robert F
authors: RF
authors: Dannals
authors: Terence G
authors: TG
authors: Hamill
authors: P David
authors: PD
authors: Mozley
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008297:Male; D008954:Models, Biological; D009570:Nitriles / Q000493:pharmacokinetics; D010865:Pilot Projects; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000493:pharmacokinetics; D011829:Radiation Dosage; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014018:Tissue Distribution; D051598:Whole Body Imaging
chemical_list: C527000:3-fluoro-5-((pyridin-3-yl)ethynyl)benzonitrile; D005462:Fluorine Radioisotopes; C578935:GRM5 protein, human; D009570:Nitriles; D011725:Pyridines; D019275:Radiopharmaceuticals; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate
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