[Carboxyl-11C]Labelling of Four High-Affinity cPLA2α Inhibitors and Their Evaluation as Radioligands in Mice by Positron Emission Tomography

Article abstract of DOI:10.1002/cmdc.201700697

Cytosolic phospholipase A2α (cPLA2α) may play a critical role in neuropsychiatric and neurodegenerative disorders associated with oxidative stress and neuroinflammation. An effective PET radioligand for imaging cPLA2α in living brain might prove useful for biomedical research, especially on neuroinflammation. We selected four high-affinity (IC₅₀ 2.1–12 nm) indole-5-carboxylic acid-based inhibitors of cPLA2α, namely 3-isobutyryl-1-(2-oxo-3-(4-phenoxyphenoxy)propyl)-1H-indole-5-carboxylic acid (1); 3-acetyl-1-(2-oxo-3-(4-(4-(trifluoromethyl)phenoxy)phenoxy)propyl)-1H-indole-5-carboxylic acid (2); 3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-(2-oxo-3-(4-phenoxyphenoxy)propyl)-1H-indole-5-carboxylic acid (3); and 3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-(3-(4-octylphenoxy)-2-oxopropyl)-1H-indole-5-carboxylic acid (4), for labelling in carboxyl position with carbon-11 (t_1/2=20.4 min) to provide candidate PET radioligands for imaging brain cPLA2α. Compounds [¹¹C]1–4 were obtained for intravenous injection in adequate overall yields (1.1–5.5 %) from cyclotron-produced [¹¹C]carbon dioxide and with moderate molar activities (70–141 GBq μmol^?1) through the use of Pd⁰-mediated [¹¹C]carbon monoxide insertion on iodo precursors. Measured logD_7.4 values were within a narrow moderate range (1.9–2.4). After intravenous injection of [¹¹C]1–4 in mice, radioactivity uptakes in brain peaked at low values (≤0.8 SUV) and decreased by about 90 % over 15 min. Pretreatments of the mice with high doses of the corresponding non-radioactive ligands did not alter brain time–activity curves. Brain uptakes of radioactivity after administration of [¹¹C]1 to wild-type and P-gp/BCRP dual knock-out mice were similar (peak 0.4 vs. 0.5 SUV), indicating that [¹¹C]1 and others in this structural class, are not substrates for efflux transporters.