Synthesis and Screening in Mice of Fluorine-Containing PET Radioligands for TSPO: Discovery of a Promising ¹⁸F-Labeled Ligand

Abstract

Translocator protein 18 kDa (TSPO) is a biomarker of neuroinflammation. [¹¹C]ER176 robustly quantifies TSPO in the human brain with positron emission tomography (PET), irrespective of subject genotype. We aimed to develop an ER176 analog with potential for labeling with longer-lived fluorine-18 (<i>t</i>_1/2 = 109.8 min). New fluoro and trifluoromethyl analogs of ER176 were prepared through a concise synthetic strategy. These ligands showed high TSPO affinity and low human genotype sensitivity. Each ligand was initially labeled by a generic ¹¹C-methylation procedure, thereby enabling speedy screening in mice. Each radioligand was rapidly taken up and well retained in the mouse brain at baseline after intravenous injection. Preblocking of TSPO showed that high proportions of brain uptake were specifically bound to TSPO at baseline. Overall, the 3-fluoro analog of [¹¹C]ER176 ([¹¹C]<b>3b</b>) displayed the most promising imaging properties. Therefore, a method was developed to label <b>3b</b> with [¹⁸F]fluoride ion. [¹⁸F]<b>3b</b> gave similarly promising PET imaging results and deserves evaluation in higher species.