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

Nuclear Medicine and Biology
P JohnströmL Farde

Abstract

The myeloperoxidase inhibitor AZD3241 has been selected as a candidate drug currently being developed to delay progression in patients with neurodegenerative brain disorders. Part of the decision tree for translation of AZD3241 into clinical studies included the need for assessment of brain exposure in non-human primates by PET microdosing. For that purpose a rapid multistep method for (11)C-labeling of AZD3241 was developed. AZD3241 was labeled in the thio-carbonyl position starting from [(11)C]potassium cyanide in a 4-step procedure using microwave assisted heating. In the first step [(11)C]potassium cyanide was converted to [(11)C]potassium thiocyanate followed by reaction with benzoyl chloride to yield benzoyl [(11)C]isothiocyanate. The benzoyl [(11)C]isothiocyanate was subsequently reacted with the precursor ethyl 3-(2-isopropoxyethylamino)-1H-pyrrole-2-carboxylate and the formed intermediate underwent a base catalyzed cyclization to obtain [(11)C]AZD3241 in the final step. To assess [(11)C]AZD3241 brain exposure PET measurements were performed in three cynomolgus monkeys. [(11)C]AZD3241 was produced in good and reproducible radiochemical yield 710 ± 294 MBq (mean ± SD, n = 7). Total time of synthesis was 60 min from end o...Continue Reading

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Citations

Aug 5, 2018·The Journal of Pharmacology and Experimental Therapeutics·Martin L MarroJean B Regard
Sep 10, 2020·Nature Reviews. Drug Discovery·Tal BurtYuichi Sugiyama
May 28, 2019·Proceedings of the National Academy of Sciences of the United States of America·Cuihua WangJohn W Chen
Aug 12, 2016·Australian Journal of Chemistry·Steven H Liang, Neil Vasdev
Jul 21, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Peter BallardDarren Cross
Dec 21, 2017·Analytical Biochemistry·Louisa V Forbes, Anthony J Kettle

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