Imaging agents for myeloperoxidase

Abstract

The myeloperoxidase (MPO) inhibitors 1 and 2 were prepared as their isotopologues with carbon-14, carbon-13, and nitrogen-15 or tritium with high specific activity and purity. Starting from potassium [ 14 C]cyanide or [ 14 C]formate provided metabolically stable 14 C-labels on [ 14 C]-1 and [ 14 C]-2. Catalytic hydrogenation was used for the preparation of [ 3 H]-2, giving multiple enriched positions as shown by 3 H NMR. 1 and 2 are promising in vitro and in vivo imaging radioligands and have the potential to provide key information with regard to MPO expression, function, stoichiometry, and pharmacology.

Imaging agent of a TRPA1 inhibitor

“…Treatment of 3 with tritium gas and palladium on carbon afforded 4 and subsequent hydrolysis with sodium hydroxide in methanol afforded the deprotected benzaldehyde 5 . Finally, a tetrachlorosilane catalyzed multicomponent one‐step fusion of 5 with the indene 6 and thiourea gave 1 with a specific activity of 0.90 TBq/mmol and a 99% radiochemical purity after purification. Four months later, a resynthesis was needed as the substance had decomposed completely upon storage at −20°C.…”

Development of rapid multistep carbon-11 radiosynthesis of the myeloperoxidase inhibitor AZD3241 to assess brain exposure by PET microdosing

“…It has been demonstrated that a 3 H-radioligand from this pyrrolo-pyrimidone series could specifically label inflammatory lesions in the spinal cord known to express MPO in a murine model of autoimmune encephalomyelitis [9]. In addition, it has been demonstrated that increase in brain MPO expression in animal models can be imaged using MRI and bis-5HT-DTPA(Gd) [19,20].…”

“…AZD3241 and related pyrrolo-pyrimidone compounds have previously been labeled with carbon-14 in the thio-carbonyl position in a 4-step reaction starting from [ 14 C]potassium cyanide [9,15]. The previously demonstrated rapid transformation of [ 14 C]potassium cyanide to benzoyl [ 14 C]isothiocyanate via [ 14 C]potassium thiocyanate and the scope for optimizing reaction times in subsequent steps (Malmquist, personal communication) suggested that a similar route could have a potential also for 11 C-radiolabeling.…”

“…This approach was not possible for AZD3241, a molecule that, like most drug molecules, was synthesized with no intention to allow for rapid radiolabeling. However the series of compounds has previously been labeled with carbon-14 in the thio-carbonyl position starting from [ 14 C]KCN [9] suggesting that the same approach potentially could be utilized for the more challenging 11 C-labeling of AZD3241.…”

Late-Stage Carbon-14 Labeling and Isotope Exchange: Emerging Opportunities and Future Challenges

“…Lithium 14 C-formate was prepared in situ after a reduction of [ 14 C]­CO 2 with superhydride LiEt 3 BH. After the solution was concentrated, the precursor 3 was added in the presence of EDCI to form the corresponding formylated intermediate, which was further converted into the desired product 4 under basic conditions . The overall radiochemical yield from CO 2 was low (8%), but sufficient compound was delivered to be administered to rats for quantitative whole body autoradiography (QWBA) experiments.…”