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  • Trk receptors critically support the development

    2019-10-16

    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 Cyanine 5-dUTP 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.