A robust, click‐chemistry‐inspired procedure for radiolabeling of cyclic ureas was developed. This protocol, suitable for all carbon isotopes (¹¹C, ¹³C, ¹⁴C), is based on the direct functionalization of carbon dioxide: the universal building block for carbon radiolabeling. The strategy is operationally simple and reproducible in different radiochemistry centers, exhibits remarkably wide substrate scope with short reaction times, and demonstrates superior reactivity as compared to previously reported systems. With this procedure, a variety of pharmaceuticals and an unprotected peptide were labeled with high radiochemical efficiency.

A general approach to label urea derivatives with all carbon isotopes (¹¹C, ¹³C and ¹⁴C) is reported.

A general procedure for the late-stage [¹¹C], [¹³C] and [¹⁴C]carbon isotope labeling of cyclic carbamates is reported. This protocol allows the incorporation of carbon dioxide, the primary source of carbon-14 and carbon-11 radioisotopes, in a direct, cost-effective and sustainable manner. A disconnection/reconnection strategy, involving ring opening/isotopic closure, was also implemented.

Upregulation of the cannabinoid type 2 receptors (CB2R) unveils inflammation processes of pathological disorders such as cancer, pain or neurodegenerative diseases. Among others, CB2R agonist A-836339 has been labeled with carbon-11 for PET imaging of the CB2R and displayed promising results in a mouse model of Alzheimer’s disease. The aim of the present work was to develop fluorinated analogs of A-836339 for labeling with fluorine-18 to design a new PET tracer for CB2R imaging. Seven fluorinated analogs of A-836339 were synthesized in two to three steps and their binding affinities and selectivities for both the human and the mouse CB2R were measured as well as their early ADME profiles. Among them, compound 2f (KihCB2R = 0.1 nM, KihCB1R/ KihCB2R = 300) displayed high affinity and selectivity for CB2R but also promising lipophilicity, kinetic solubility and membrane permeation properties and was further selected for in vitro metabolism studies. Incubation of 2f with human or rat liver microsomes followed by LC/MS analysis revealed the presence of six different metabolites mainly resulting from oxidation reactions. A tosylated precursor of 2f was synthesized in two steps and radiolabeled with fluorine-18 to afford [18F]2f in 15 ± 5% radiochemical yield and a molar activity of 110 ± 30 GBq/μmol. Autoradiographies of rat spleen and biodistribution studies in healthy rats including pre-treatments with either CB2R or CB1R-specific compounds suggested that [18F]2f is a specific tracer for the CB2R in vivo. We have therefore demonstrated here that [18F]2f is a promising novel tracer for imaging CB2R in vivo using PET. Further investigation in animal models of inflammation will follow.

Domperidone and metoclopramide are widely prescribed antiemetic drugs with distinct neurological side effects. The impact of P-glycoprotein (P-gp)-mediated efflux at the blood–brain barrier (BBB) on brain exposure and BBB permeation was compared in vitro and in vivo using positron emission tomography (PET) imaging in rats with the radiolabeled analogs [¹¹C]domperidone and [¹¹C]metoclopramide. In P-gp-overexpressing cells, the IC₅₀ of tariquidar, a potent P-gp inhibitor, was drastically different using [¹¹C]domperidone (221 nM [198–248 nM]) or [¹¹C]metoclopramide (4 nM [2–8 nM]) as the substrate. Complete P-gp inhibition led to a 1.8-fold higher increase in the cellular uptake of [¹¹C]domperidone compared with [¹¹C]metoclopramide (p < 0.0001). Brain PET imaging revealed that the baseline brain exposure (AUC_brain) of [¹¹C]metoclopramide was 2.4-fold higher compared with [¹¹C]domperidone (p < 0.001), consistent with a 1.8-fold higher BBB penetration (AUC_brain/AUC_plasma). The maximal increase in the brain exposure (2.9-fold, p < 0.0001) and BBB penetration (2.9-fold, p < 0.0001) of [¹¹C]metoclopramide was achieved using 8 mg/kg of tariquidar. In comparison, neither 8 nor 15 mg/kg of tariquidar increased the brain exposure of [¹¹C]domperidone (p > 0.05). Domperidone is an avid P-gp substrate that was in vitro compared with metoclopramide. Domperidone benefits from a lower brain exposure and a limited risk for P-gp-mediated drug–drug interaction involving P-gp inhibition at the BBB.