ER176, when labeled with carbon-11 (t1/2 = 20 min), is a high-performing radioligand for imaging and quantifying TSPO, a biomarker of neuroinflammation, in human brain with positron emission tomography (PET). [11C]ER176 ([11C]1) analogs that might be labeled with longer-lived fluorine-18 (t1/2 = 110 min) and provide comparable imaging performance would be more widely useful. We synthesized three new fluoro analogs (2a−2c) of ER176 and found them to be high-affinity TSPO ligands. We labeled them by 11C-methylation so that we could compare them with [11C]1 and guide our selection of ligand for evaluation with an 18F label. Labeling precursors (4a−4c) were synthesized in good yields (55 to 80%) by amidation of 3 followed by Pd-catalyzed coupling with an appropriate fluorophenylboronic acid. [11C]2a−[11C]2c were obtained by 11C-methylation of 4a−4c, respectively. PET was performed in rhesus monkey over 120 min after intravenous injection of radioligand, and in the same monkey after pre-treatment with the selective TSPO ligand, PK11195 (5 mg/kg, i.v.). Arterial input functions were determined in parallel. Brain radioactivity uptakes were comparable with those of [11C]1 and were strongly blocked with PK11195. VTs, the indices of total binding in brain, were similar to that of [11C]1. They were decreased 69−84% by PK11195 (c.f., 85% for [11C]1), indicating high proportions of TSPO-specific binding. These new radiotracers merit evaluation after labeling with fluorine-18.

Synthesis of three fluoro-containing [11C]ER176 analogs for PET imaging of TSPO in monkey brain

2019 Fall National Meeting

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