Syntheses and evaluation of carbon-11- and fluorine-18-radiolabeled pan-tropomyosin receptor kinase (Trk) inhibitors: exploration of the 4-aza-2-oxindole scaffold as Trk PET imaging agents

ACS Chem Neurosci. 2015 Feb 18;6(2):260-76. doi: 10.1021/cn500193f. Epub 2014 Nov 10.


Tropomyosin receptor kinases (TrkA/B/C) are critically involved in the development of the nervous system, in neurological disorders as well as in multiple neoplasms of both neural and non-neural origins. The development of Trk radiopharmaceuticals would offer unique opportunities toward a more complete understanding of this emerging therapeutic target. To that end, we first developed [(11)C]GW441756 ([(11)C]9), a high affinity photoisomerizable pan-Trk inhibitor, as a lead radiotracer for our positron emission tomography (PET) program. Efficient carbon-11 radiolabeling afforded [(11)C]9 in high radiochemical yields (isolated RCY, 25.9% ± 5.7%). In vitro autoradiographic studies in rat brain and TrkB-expressing human neuroblastoma cryosections confirmed that [(11)C]9 specifically binds to Trk receptors in vitro. MicroPET studies revealed that binding of [(11)C]9 in the rodent brain was mostly nonspecific despite initial high brain uptake (SUVmax = 2.0). Modeling studies of the 4-aza-2-oxindole scaffold led to the successful identification of a small series of high affinity fluorinated and methoxy derivatized pan-Trk inhibitors based on our lead compound 9. Out of this series, the fluorinated compound 10 was selected for initial evaluation and radiolabeled with fluorine-18 (isolated RCY, 2.5% ± 0.6%). Compound [(18)F]10 demonstrated excellent Trk selectivity in a panel of cancer relevant kinase targets and a promising in vitro profile in tumors and brain sections but high oxidative metabolic susceptibility leading to nonspecific brain distribution in vivo. The information gained in this study will guide further exploration of the 4-aza-2-oxindole scaffold as a lead for Trk PET ligand development.

Keywords: Tropomyosin receptor kinases; aza-oxindole; brain imaging; carbon-11; fluorine-18; imaging; neuroblastoma; positron emission tomography; radiochemistry; tyrosine kinase inhibitor.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoradiography
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Carbon Radioisotopes
  • Drug Design
  • Drug Evaluation
  • Fluorine Radioisotopes
  • Humans
  • Indoles / chemical synthesis
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / metabolism
  • Molecular Docking Simulation
  • Molecular Structure
  • Neuroblastoma / diagnostic imaging
  • Neuroblastoma / metabolism
  • Photochemical Processes
  • Positron-Emission Tomography / methods*
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Pyrrolidines / chemical synthesis
  • Quinolines / chemical synthesis
  • Radiopharmaceuticals / chemical synthesis*
  • Rats, Sprague-Dawley
  • Receptor, trkB


  • Carbon Radioisotopes
  • Fluorine Radioisotopes
  • GW 468816
  • Indoles
  • Membrane Glycoproteins
  • Protein Kinase Inhibitors
  • Pyrrolidines
  • Quinolines
  • Radiopharmaceuticals
  • Protein-Tyrosine Kinases
  • Receptor, trkB
  • tropomyosin-related kinase-B, human