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

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 [¹¹C]­GW441756 ([¹¹C]<b>9</b>), a high affinity photoisomerizable pan-Trk inhibitor, as a lead radiotracer for our positron emission tomography (PET) program. Efficient carbon-11 radiolabeling afforded [¹¹C]<b>9</b> 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 [¹¹C]<b>9</b> specifically binds to Trk receptors <i>in vitro</i>. MicroPET studies revealed that binding of [¹¹C]<b>9</b> in the rodent brain was mostly nonspecific despite initial high brain uptake (SUV_max = 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 <b>9</b>. Out of this series, the fluorinated compound <b>10</b> was selected for initial evaluation and radiolabeled with fluorine-18 (isolated RCY, 2.5% ± 0.6%). Compound [¹⁸F]<b>10</b> demonstrated excellent Trk selectivity in a panel of cancer relevant kinase targets and a promising <i>in vitro</i> profile in tumors and brain sections but high oxidative metabolic susceptibility leading to nonspecific brain distribution <i>in vivo</i>. 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