Neuroinflammation is associated with many neuropsychiatric disorders. In neuroinflammation, there is a generally greater expression of colony-stimulating factor 1 receptor (CSF1R) on microglia than in healthy brain. This suggests that CSF1R can be a target for studying neuroinflammation with positron emission tomography (PET). BLZ945 (4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide) is a potent (IC50 = 1 nM) and selective inhibitor of CSF1R. We envisaged that BLZ945 could be labeled with carbon-11 (t1/2 = 20 min) and thereby provide a candidate PET radioligand for CSF1R. Racemic [11C]BLZ945 was produced in two-steps (Figure). Thus, the prepared racemic picolinamide, Psa97 (~1.8 µmol), was treated with [11C]MeI in DMSO (0.4 mL) in the presence of TBAOH (1 M, 2 eq.) at 100 °C for 5 min, and then with excess TBAF (12 eq.) at 100 °C for 5 min. Racemic [11C]BLZ945 was purified with HPLC and formulated for intravenous injection. The whole radiosynthesis required 49 min and gave formulated radioligand in 6.5% yield. Evaluation of racemic [11C]BLZ945 in non-human primates and rodents with PET showed low brain uptake (SUV = 0.7). Further investigation showed that this radioligand was a substrate for two efflux pumps, P-glycoprotein 1 (Pg-P) and breast cancer resistance protein (BCRP) at the blood-brain barrier. The unexpected efflux transporter liability of racemic [11C]BLZ945 renders this radioligand (and by inference the single homochiral (R,R)-eutomer) as ineffective.

Synthesis and evaluation of racemic [11C]BLZ945: Candidate radioligand for PET imaging of brain macrophage colony-stimulating factor 1 receptor

2019 Fall National Meeting

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