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  • Trk receptors critically support the development and mainten


    Trk receptors critically support the development and maintenance of the nervous system, , but their over-expression in various neural and non-neural neoplasms such as breast, pancreatic, lung and neuroendocrine tumors also confers aggressive phenotypes to tumor Obeticholic Acid and correlates with poor prognosis. In the last decade, many studies have focused on the development of Trk ligands, especially ATP-competitive inhibitors for the treatment of cancer ()., , Currently, the inhibition of Trk receptors is investigated in six clinical trials and numerous pre-clinical studies. Comprehensive kinase inhibitor analysis recently demonstrated that the orally bioactive diaminopyrimidine colony-stimulating factor-1 receptor (CSF-1R) inhibitor GW2580 () strongly inhibits Trk receptors—especially TrkB (; CSF-1R=2.2nM, TrkA=630nM, TrkB=36nM, TrkC=120nM). Notably, GW2580 exhibits one of the most specific kinase inhibition profiles among known kinase inhibitors (no supplementary inhibition of other kinases with <3μM) which, when considering PET imaging, represents an advantageous target selectivity. Therefore, we hypothesized that the high selectivity of could constitute a promising basis for the development of PET-TKI probes with potential imaging applications for CSF-1R, since CSF-1R also represents a useful PET imaging target. CSF-1R regulates mononuclear phagocyte differentiation and proliferation and as such plays a central role in multiple macrophage-mediated pathological conditions. In particular, infiltration of tumor-associated macrophages (TAMs) within tumor microenvironments relying upon CSF-1R for survival and differentiation, is associated with poor prognosis in numerous cancers. Thus, translation of into a dual Trk/CSF-1R PET probe could be highly useful in many cases where cancer cells overexpress Trk receptors while abundant CSF-1R is found within the stromal cells due to high TAMs infiltration. The structure of GW2580 possesses two aromatic methoxy moieties potentially amenable for carbon-11 (=20min) labeling (). However, fluorine-18 displays better nuclear properties (=109min; 97% β; (β+)=0.64MeV) which allow for a more flexible radiosynthesis and lead to high quality PET images. It is also documented that the introduction of fluorine into bioactive molecules may positively influence physicochemical properties and oxidative/hydrolytic metabolic stabilities. This study thus describes the design, synthesis and biological evaluation of a small series of fluorinated analogs of GW2580. The derivatives where selected in order to be accessible as F-isotopologues. A new potent fluorinated Trk(B/C)/CSF-1R inhibitor was identified, which was consequently labeled with fluorine-18. In addition, exhaustive selectivity profiling over a panel of 342 kinases established that maintains the remarkable selectivity of the non-fluorinated lead compound . Three fluorinated derivatives of inhibitor where rationally designed based on the available co-crystal structure of TrkB with GW2580 (PDB code: ) and developed with the objectives of maintaining the potency/selectivity profile of the lead while being amenable towards F-labeling. Our rationale consisted of introducing structural modifications on the -methoxybenzyl (PMB) ring occupying the selectivity hydrophobic pocket formed by residues Ile616, Leu611, Leu608 and Leu688. The diaminopyrimidine fragment in contact with the hinge region and the 1-(benzyloxy)-2-methoxybenzene central ring interacting withAsp710 from the DFG motif () were left untouched. Inspection of the hydrophobic back pocket revealed that the - and -position of the tail fragment can probably only accommodate small structural modifications. The orientation from one side of the PMB ring left the -position solvent exposed thus suggesting that this position might be compatible with bulkier alterations. Therefore, fluoroaryl-derivatives and ( and -activated position for labeling—vide supra) and the 2-fluoroethoxy-derivative (B) were synthesized and evaluated.