Bioorganic & Medicinal Chemistry Letters 26 (2016) 4857–4860

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry Letters

journal homepage: www.elsevier.com/locate/bmcl

Radiosynthesis and preliminary PET evaluation of 18F-labeled 2-(1- (3-fluorophenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitrile for imaging AMPA receptors ⇑ ⇑ Gengyang Yuan a,b, Graham B. Jones a, Neil Vasdev b, , Steven H. Liang b, a Department of Chemistry & Chemical Biology, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA b Gordon Center for Medical Imaging & Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, 55 Fruit St., Boston, MA 02114, USA article info abstract

Article history: To prompt the development of 18F-labeled positron emission tomography (PET) tracers for the a-amino- Received 25 July 2016 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, we have prepared 18F-labeled 2-(1-(3- Accepted 29 July 2016 fluorophenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl)benzonitrile ([18F]8). The radiosynthe- Available online 9 August 2016 sis was achieved by a one-pot two-step method that utilized a spirocyclic hypervalent iodine(III) medi- ated radiofluorination to prepare the 18F-labeled 1-bromo-3-fluorobenzene ([18F]15) intermediate with Keywords: K18F. A subsequent copper(I) iodide mediated coupling reaction was carried out with 2-(2-oxo-5-(pyrim- AMPA receptor idin-2-yl)-1,2-dihydropyridin-3-yl)benzonitrile (10)to[18F]8 in 10 ± 2% uncorrected radiochemical yield Positron emission tomography relative to starting 18F-fluoride with >99% radiochemical purity and 29.6 ± 7.4 Gbq/lmol specific activity Fluorine-18 Radiotracer at the time of injection. PET imaging studies with the title radiotracer in normal mice demonstrated good Perampanel brain uptake (peak standardized uptake value (SUV) = 2.3 ± 0.1) and warrants further in vivo validation. Ó 2016 Elsevier Ltd. All rights reserved.

Glutamate has been recognized as a principle excitatory neuro- and neurodegenerative diseases, including epilepsy, ischemia, transmitter in the brain since late 1970s.1 It exerts postsynaptical stroke, Parkinson’s disease and Alzheimer’s disease.7,8 In particular, effects primarily through the metabotropic and ionotropic competitive AMPA receptor antagonists have been the focus of glutamate receptors (mGluRs and iGluRs, respectively).2 iGluRs drug discovery, with the first reported compound, 2,3-dihydroxy- structurally incorporate ligand-gated tetrametric ion channels 6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX), in and allow fast synaptic responses to the glutamate. The iGluRs 1991,9,10 which led to the two clinically translated drugs, namely, 11,12 are composed of three families, namely, N-methyl-D-aspartate becampanel (AMP397) and selurampanel (BGG492). To date, (NMDA), kainite, and a-amino-3-hydroxy-5-methyl-4-isoxa- there has not been an AMPA receptor antagonist to reach the mar- zolepropionic acid (AMPA) receptors.3–6 Modulation of these ket. Meanwhile, non-competitive AMPA receptor antagonists, receptors can be used in the treatment of psychiatric disorders which occupy the less polar allosteric binding site, are not expected to be significantly influenced by endogenous glutamate 13,14 Abbreviations: mGluRs, metabotropic glutamate receptors; iGluRs, ionotropic levels, as compared to the competitive antagonists. In this glutamate receptors; NMDA, N-methyl-D-aspartate; AMPA, a-amino-3-hydroxy-5- category, talampanel (GYKI-537773) was studied in a Phase II clin- methyl-4-isoxazolepropionic acid; PET, positron emission tomography; CNS, cen- ical trial as an antiepileptic agent.15,16 Irampanel (BIIR561) reached 18 18 tral nervous system; TEA[ F], [ F]tetraethylammonium fluoride; SPIAD, 17 0 0 0 Phase I/IIa clinical trials for the treatment of stroke. Perampanel (1r,3r,5r,7r)-spiro[adamantane-2,2 -[1,3]dioxane]-4 ,6 -dione; RCC, radiochemical Ò Ò (Fycompa ) was approved by the United States Food and Drug conversion; K222, Kryptofix or 4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8] hexacosanein; DMF, N,N-dimethylmethanamide; TMEDA, N,N,N0,N0-tetram- Administration for treating refractory partial onset seizures in ethylethylenediamine; DMEDA, N,N0-dimethylethylenediamine; TEAB, tetraethy- 2012, and as an adjunctive treatment for primary generalized lammonium bicarbonate; SUV, standardized uptake value; RCY, radiochemical tonic–clonic seizures in 2015.18–21 yield; DMSO, dimethyl sulfoxide; BBB, crossed the blood–brain barrier; TAC, time– As a non-invasive imaging technology, positron emission activity curve; ROI, region of interest. ⇑ Corresponding authors. Tel.: +1 617 643 4736 (N.V.); tel.: +1 617 726 6107; fax: tomography (PET) is capable of in vivo quantification of +1 617 726 6165 (S.H.L.). biochemical and pharmacological progress via radiolabeled tar- E-mail addresses: [email protected] (N. Vasdev), liang.steven@mgh. geted molecular probes. Quantification of AMPA in the living brain harvard.edu (S.H. Liang). http://dx.doi.org/10.1016/j.bmcl.2016.07.078 0960-894X/Ó 2016 Elsevier Ltd. All rights reserved. 4858 G. Yuan et al. / Bioorg. Med. Chem. Lett. 26 (2016) 4857–4860

by PET would enable investigations of the AMPA system under nor- half-life (t1/2 = 109.7 min) compared with carbon-11 mal and disease conditions, assessment of AMPA distribution in (t1/2 = 20.4 min), the goal of the present work is to develop a prac- the brain and periphery, and target engagement for validation of tical method for the radiosynthesis of the 18F-labeled isotopologue promising drug candidates in clinical trials. To date, only a handful of 8 for imaging AMPA receptors with PET. Herein, we describe a of AMPA PET radiotracers, most of which are 11C-labeled mole- novel one-pot two-step radiosynthesis of [18F]8, enabled by a cules, have been reported (Fig. 1). The radiosyntheses of isoquino- spirocyclic hypervalent iodine(III) activated radiofluorination of line derivatives [11C]1,[18F]2 and 11C-labeled Perampanel ([11C]4) the non-activated arene, and subsequent CuI mediated cross cou- have been reported, but their potential as PET tracers needs to be pling with 2-(2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) further evaluated in vivo.22,23 The isoquinoline derivative [11C]3, benzonitrile 10. We further report preliminary PET imaging studies showed rapid clearance from the central nervous system (CNS) with [18F]8 in mice. and low specific binding in rats.24 Among the recently disclosed Radiofluorination of non-activated arenes still represents a PET tracers [11C]5–8 and [18F]9,[11C]5 and [11C]7 showed very challenging problem, despite extensive efforts devoted to this low brain penetration in rhesus monkey (i.e., standardized uptake field.27–31 Unsurprisingly, attempts to achieve conventional nucle- 18 value (SUV)max = 0.5), and [ F]9 exhibited inconsistent distribu- ophilic aromatic substitution of the electron-deficient 2-(1-(3- tion with the localization of AMPA receptors in rat brain. Whereas, nitrophenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) [11C]6 demonstrated good radioactivity uptake in both rat and benzonitrile 11 with K[18F] or [18F]tetraethylammonium fluoride 18 monkey brains (i.e., SUVmax = 1.6), consistent binding patterns with (TEA[ F]) led to no reaction (For the synthesis of 11, see the AMPA localization and target specific binding features, hence, Scheme S1, Supporting Information, SI).32,26 These results led us this radiotracer shows potential as PET tracer for AMPA receptors. to utilize our recent developed radiofluorination method, which A fluorinated isoquinoline derivative [11C]8 was radiolabeled via takes advantage of spirocyclic hypervalent iodine(III) species as [11C]HCN, displayed even higher radioactivity uptake in rhesus the 18F-radiolabeling precursors.33–37 To prepare the precursor monkey brain (i.e., SUVmax = 2.7), and maintained the promising for radiofluorination, aryl iodide 12 was first converted to the properties demonstrated with [11C]6.25,26 In combination with hypervalent spirocyclic iodine(III) compound, 13, under oxidative the advantages of fluorine-18 that are attributed to its longer conditions, and subsequently reacted with (1r,3r,5r,7r)-spiro

O 11 11 N O [ C]1, R1=OCH3, R2=[ C]OCH3 N N R1 O [18F]2, R =OCH , R =[18F]F 1 3 2 11CN

11 11 [ C]3, R1=[ C]OCH3, R2=Cl R2 [11C]4 (Perampanel )

11 11 [ C]5, R3=H, R4=NH2, R5=[ C]CN R3 N N 11 11 [ C]6, R3=H, R4=[ C]NHCH3, R5=CN 18 N N R4 N N F [11C]7, R =F, R =NH , R =[11C]CN O 3 4 2 5 O R 5 11 11 CN [ C]8, R3=H, R4=F, R5=[ C]CN

18 18 [ F]9, R3=H, R4=[ F]CH2F, R5=F [18F]8

Figure 1. Chemical structures of the reported PET tracers for AMPA receptors.

O a O b Br I Br 18F Br I O N 12 O [18F]15 N N 18F 13 e O N CN

N N N NH d c [18F]8 N NH N NBoc O CN O O 16I 17 I 10

18 0 Scheme 1. De novo radiosynthesis of [ F]8. Reagents and conditions: (a) (i) NaBO34H2O, glacial acetic acid, 50 °C, Overnight; (ii) (1r,3r,5r,7r)-spiro[adamantane-2,2 - 0 0 18 18 [1,3]dioxane]-4 ,6 -dione (SPIAD) 14, 10% Na2CO3 (aq) (w/v), ethanol/dichloromethane; (b) K[ F] or TEA[ F], DMF, 120 °C, 10 min; (c) di-tert-butyl dicarbonate,

4-dimethylaminopyridine, THF, 0 °C to room temperature, Overnight; (d) 2-cyanophenylboronic acid 1,3-propanediol ester 18, Cesium carbonate, Pd(PPh3)4, DMF, 110 °C, 0 overnight; (e) CuI, K3PO4, trans-N,N -dimethylcyclohexane-1,2-diamine, DMF, 110 °C, 20 min. Download English Version: https://daneshyari.com/en/article/5156143

Download Persian Version:

https://daneshyari.com/article/5156143

Daneshyari.com