Efficient radiosynthesis and preclinical evaluation of [ 18 F]FOMPyD as a positron emission tomography tracer candidate for TrkB/C receptor imaging

J Labelled Comp Radiopharm. 2020 Mar;63(3):144-150. doi: 10.1002/jlcr.3827. Epub 2020 Jan 29.

Abstract

Herein we report an efficient radiolabeling of a 18 F-fluorinated derivative of dual inhibitor GW2580, with its subsequent evaluation as a positron emission tomography (PET) tracer candidate for imaging of two neuroreceptor targets implicated in the pathophysiology of neurodegeneration: tropomyosin receptor kinases (TrkB/C) and colony stimulating factor receptor (CSF-1R). [18 F]FOMPyD was synthesized from a boronic acid pinacolate precursor via copper-mediated 18 F-fluorination concerted with thermal deprotection of the four Boc groups on a diaminopyrimidine moiety in an 8.7±2.8% radiochemical yield, a radiochemical purity >99%, and an effective molar activity of 187±93 GBq/μmol. [18 F]FOMPyD showed moderate brain permeability in wild-type rats (SUVmax = 0.75) and a slow washout rate. The brain uptake was partially reduced (ΔAUC40-90 = 11.6%) by administration of the nonradioactive FOMPyD (up to 30 μg/kg). In autoradiography, [18 F]FOMPyD exhibits ubiquitous distribution in rat and human brain tissues with relatively high nonspecific binding revealed by self-blocking experiment. The binding was blocked by TrkB/C inhibitors, but not with a CSF-1R inhibitor, suggesting selective binding to the former receptor. Although an unfavorable pharmacokinetic profile will likely preclude application of [18 F]FOMPyD as a PET tracer for brain imaging, the concomitant one-pot copper-mediated 18 F-fluorination/Boc-deprotection is a practical technique for the automated radiosynthesis of acid-sensitive PET tracers.

Keywords: GW2580; PET; [18F]FOMPyD; brain imaging; colony stimulating factor receptor (CSF-1R); copper-mediated 18F-fluorination; fluorine-18; positron emission tomography; tropomyosin receptor kinase (Trk).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Cell Line, Tumor
  • Humans
  • Male
  • Membrane Glycoproteins / metabolism*
  • Positron-Emission Tomography / methods*
  • Radiochemistry
  • Rats
  • Receptor, trkB / metabolism*
  • Receptor, trkC / metabolism*

Substances

  • Membrane Glycoproteins
  • Receptor, trkB
  • Receptor, trkC
  • tropomyosin-related kinase-B, human