title: Synthesis and in vivo Evaluation of Fluorine-18 and Iodine-123 Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine Derivatives as PET and SPECT Radiotracers for Mapping A2A Receptors.
abstract: Imaging agents that target adenosine type 2A (A2A ) receptors play an important role in evaluating new pharmaceuticals targeting these receptors, such as those currently being developed for the treatment of movement disorders like Parkinson's disease. They are also useful for monitoring progression and treatment efficacy by providing a noninvasive tool to map changes in A2A receptor density and function in neurodegenerative diseases. We previously described the successful evaluation of two A2A -specific radiotracers in both nonhuman primates and in subsequent human clinical trials: [(123) I]MNI-420 and [(18) F]MNI-444. Herein we describe the development of both of these radiotracers by selection from a series of A2A ligands, based on the pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine core of preladenant. Each of this series of 16 ligands was found to bind to recombinant human A2A receptor in the low nanomolar range, and of these 16, six were radiolabeled with either fluorine-18 or iodine-123 and evaluated in nonhuman primates. These initial in vivo results resulted in the identification of 7-(2-(4-(4-(2-[(18) F]fluoroethoxy)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine ([(18) F]MNI-444) and 7-(2-(4-(2-fluoro-4-[(123) I]iodophenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-amine ([(123) I]MNI-420) as PET and SPECT radiopharmaceuticals for mapping A2A receptors in brain.
authors.affiliation: Molecular NeuroImaging, a division of inviCRO, 60 Temple Street, Suite 8B, New Haven, CT, 06510, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Vala
authors.affiliation: Molecular NeuroImaging, a division of inviCRO, 60 Temple Street, Suite 8B, New Haven, CT, 06510, USA. tmorley@mnimaging.com.
authors.forename: Thomas J
authors.identifier: 0000-0002-0222-3844
authors.initials: TJ
authors.lastname: Morley
authors.affiliation: Molecular NeuroImaging, a division of inviCRO, 60 Temple Street, Suite 8B, New Haven, CT, 06510, USA.
authors.forename: Xuechun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Molecular NeuroImaging, a division of inviCRO, 60 Temple Street, Suite 8B, New Haven, CT, 06510, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Papin
authors.affiliation: Molecular NeuroImaging, a division of inviCRO, 60 Temple Street, Suite 8B, New Haven, CT, 06510, USA.
authors.forename: Adriana Alexandre S
authors.initials: AA
authors.lastname: Tavares
authors.affiliation: Molecular NeuroImaging, a division of inviCRO, 60 Temple Street, Suite 8B, New Haven, CT, 06510, USA.
authors.forename: H Sharon
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Molecular NeuroImaging, a division of inviCRO, 60 Temple Street, Suite 8B, New Haven, CT, 06510, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Constantinescu
authors.affiliation: Molecular NeuroImaging, a division of inviCRO, 60 Temple Street, Suite 8B, New Haven, CT, 06510, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Barret
authors.affiliation: Molecular NeuroImaging, a division of inviCRO, 60 Temple Street, Suite 8B, New Haven, CT, 06510, USA.
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Carroll
authors.affiliation: Molecular NeuroImaging, a division of inviCRO, 60 Temple Street, Suite 8B, New Haven, CT, 06510, USA.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Baldwin
authors.affiliation: Molecular NeuroImaging, a division of inviCRO, 60 Temple Street, Suite 8B, New Haven, CT, 06510, USA.
authors.forename: Gilles D
authors.initials: GD
authors.lastname: Tamagnan
authors.affiliation: Molecular NeuroImaging, a division of inviCRO, 60 Temple Street, Suite 8B, New Haven, CT, 06510, USA.
authors.forename: David
authors.initials: D
authors.lastname: Alagille
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005462:Fluorine Radioisotopes; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007456:Iodine Isotopes; D008253:Macaca mulatta; D008968:Molecular Conformation; D010215:Papio; D049268:Positron-Emission Tomography; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: C583370:7-(2-(4-(2-fluoro-4-iodophenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; D005462:Fluorine Radioisotopes; D006575:Heterocyclic Compounds, 3-Ring; D007456:Iodine Isotopes; D011743:Pyrimidines; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals; D043705:Receptor, Adenosine A2A; D011994:Recombinant Proteins; D014230:Triazoles; C539997:2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidine-5-amine
keywords: PET; Parkinson′s disease; SPECT; adenosine 2A receptor; movement disorders