title: Synthesis and initial preclinical evaluation of the P2X7 receptor antagonist [¹¹C]A-740003 as a novel tracer of neuroinflammation.
abstract: Neuroinflammation, in particular activation of microglia, is thought to play an important role in the progression of neurodegenerative diseases. In activated microglia, the purinergic P2X7 receptor is upregulated. A-740003, a highly affine and selective P2X7 receptor antagonist, is a promising candidate for the development of a radiotracer for imaging of neuroinflammation by positron emission tomography. For this purpose, [(11)C]A-740003 was synthesised and evaluated in vivo with respect to both tracer metabolism and biodistribution. In plasma, a moderate metabolic rate was seen. In healthy rat brain, only marginal uptake of [(11)C]A-740003 was observed and, therefore, metabolites in brain could not be determined. Whether the minimal brain uptake is due to the low expression levels of the P2X7 receptor in healthy brain or to limited transport across the blood-brain barrier has yet to be elucidated.
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Bieneke
authors.initials: B
authors.lastname: Janssen
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Vugts
authors.forename: Uta
authors.initials: U
authors.lastname: Funke
authors.forename: Arnold
authors.initials: A
authors.lastname: Spaans
authors.forename: Robert C
authors.initials: RC
authors.lastname: Schuit
authors.forename: Esther
authors.initials: E
authors.lastname: Kooijman
authors.forename: Marissa
authors.initials: M
authors.lastname: Rongen
authors.forename: Lars R
authors.initials: LR
authors.lastname: Perk
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Lammertsma
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002247:Carbon Isotopes / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D008297:Male; D058920:Purinergic P2X Receptor Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: C515928:(N-(1-(((cyanoimino)(5-quinolinylamino) methyl) amino)-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide); D000081:Acetamides; D002247:Carbon Isotopes; D058920:Purinergic P2X Receptor Antagonists; D011804:Quinolines; D019275:Radiopharmaceuticals
keywords: A-740003; P2X7 receptor; carbon-11; neuroinflammation; positron emission tomography; radiolabelling