18F-FPEB, a PET radiopharmaceutical for quantifying metabotropic glutamate 5 receptors: A first-in-human study of radiochemical safety, biokinetics, and radiation dosimetry

Dean F. Wong, Rikki Waterhouse, Hiroto Kuwabara, Jongho Kim, James R. Brašíc, Wichana Chamroonrat, Michael Stabins, Daniel P. Holt, Robert F. Dannals, Terence G. Hamill, P. David Mozley

Research output: Contribution to journalArticlepeer-review

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-inhuman study assessing the safety and effectiveness of a novel PET radiopharmaceutical, 18F-3-fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ( 18F-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 mSv/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 18F-FPEB; it showed acceptable test-retest variability of nondisplaceable binding potential (<10%) and identified the highest nondisplaceable binding potential values (from ∼.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. Conclusion: 18F-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 18F-FPEB is suitable for quantifying mGluR5 in humans. COPYRIGHT

Original languageEnglish (US)
Pages (from-to)388-396
Number of pages9
JournalJournal of Nuclear Medicine
Volume54
Issue number3
DOIs
StatePublished - Mar 1 2013

Keywords

  • 3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile (FPEB)
  • F-FPEB
  • Human radiation dosimetry
  • Metabotropic glutamate receptor subtype 5 (mGluR5)
  • Neuroreceptors
  • Positron emission tomography (PET)
  • Radioligand

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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