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

Abstract

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 to 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 (t1/2 = 20.4 min) to provide candidate PET radioligands for imaging brain cPLA2α. [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) through the use of Pd(0)-mediated [11C]carbon monoxide insertion on iodo precursors. Measured logD7.4 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. Pre-treatments 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 efflux transporters substrates.

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

“…Since GIVA cPLA 2 plays a critical role in neurodegenerative disorders associated with neuroinflammation, an effective positron emission tomography (PET) radioligand for imaging GIVA cPLA 2 in living brain might prove a useful tool for biomedical research. Thus, four high-affinity indole-5-carboxylic acid-based inhibitors of GIVA cPLA 2 (IC 50 2.1 to 12 nM) were selected for labelling in carboxyl position with carbon-11 (t 1/2 = 20.4 min) to provide candidate PET radioligands for imaging brain enzyme [40]. However, all the synthesized and tested [ 11 C]arylcarboxylic acids showed low brain penetration and lack of retention in mouse brain in vivo showing that these compounds are ineffective brain PET radioligands for GIVA cPLA 2 .…”

Copper(I)-Mediated 11C-Carboxylation of (Hetero)arylstannanes

“…Metal-catalyzed direct carboxylation of aryl halides and pseudo-halides employing CO 2 in drug discovery has recently been reviewed in the context of identifying opportunities for the radiolabeling of [ 11 C]­carboxylic acid based drugs via [ 11 C]­CO 2 fixation . Only a handful of aromatic 11 C-carboxylic acids have been radiolabeled and translated for preclinical PET imaging, − and new 11 C-carboxylation approaches are avidly sought. For example, retinoid X receptor (RXR) agonists and partial agonists are a class of drugs for oncology and neurodegenerative diseases that generally contain an aromatic carboxylic acid moiety .…”

[11C]Carbon monoxide: advances in production and application to PET radiotracer development over the past 15 years

“…, Alzheimer’s, Huntington’s, Parkinson’s diseases)(van der Wildt et al 2016)16 GADNeuropsychiatric disease ( e.g. , schizophrenia)(Taddei et al 2017b)b17 cPLA2αOxidative stress and neuroinflammation(Fisher et al 2018)18 Functionalized [ 11 C]synthon for potential PET radiotracers ( e.g. , barbiturates)(Barletta et al 2006)19 AT 2 RProstate cancer and idiopathic pulmonary fibrosis(Stevens et al 2016)20 Efflux transporter P-gpNeurological disease ( e.g.…”

“…31). The desired 11 C-labeled inhibitors were obtained ready for intravenous injection in 1.1–5.5% overall yields from [ 11 C]carbon dioxide and with an A m in the 70–141 GBq/μmol range (Fisher et al 2018). These candidate radiotracers were evaluated with PET imaging in mice.…”