[Carboxyl‐11c]labelling of Four High‐Affinity Cpla2α Inhibitors and Their Evaluation As Radioligands in Mice by Positron Emission Tomography

Cytosolic phospholipase A2 alpha (cPLA2 alpha) may play a critical role in neuropsychiatric and neurodegenerative disorders associated with oxidative stress and neuroinflammation. An effective PET radioligand for imaging cPLA2 alpha in living brain might prove useful for biomedical research, especially on neuroinflammation. We selected four high-affinity (IC50 2.1-12nm) indole-5-carboxylic acid-based inhibitors of cPLA2 alpha, 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)=20.4min) to provide candidate PET radioligands for imaging brain cPLA2. Compounds [C-11]1-4 were obtained for intravenous injection in adequate overall yields (1.1-5.5%) from cyclotron-produced [C-11]carbon dioxide and with moderate molar activities (70-141GBqmol(-1)) through the use of Pd-0-mediated [C-11]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 [C-11]1-4 in mice, radioactivity uptakes in brain peaked at low values (<= 0.8 SUV) and decreased by about 90% over 15min. 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 [C-11]1 to wild-type and P-gp/BCRP dual knock-out mice were similar (peak 0.4 vs. 0.5 SUV), indicating that [C-11]1 and others in this structural class, are not substrates for efflux transporters.