Synthesis and preclinical evaluation of carbon-11 labelled N-((5-(4-fluoro-2-[(11)C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine as a PET tracer for NR2B subunit-containing NMDA receptors (original) (raw)
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Journal of Nuclear Medicine, 2020
S-methyl-11 C](±)-7-methoxy-3-(4-(4-(methylthio)phenyl)butyl)-2,3,4,5tetrahydro-1H-benzo[d]azepin-1-ol (11 C-NR2B-SMe) and its enantiomers were synthesized as candidates for imaging the NR2B subunit within the N-methyl-D-aspartate receptor with PET. Methods: Brains were scanned with PET for 90 min after intravenous injection of one of the candidate radioligands into rats. To detect any NR2Bspecific binding of radioligand in brain, various preblocking or displacing agents were evaluated for their impact on the PET brain imaging data. Radiometabolites from brain and other tissues were measured ex vivo and in vitro. Results: Each radioligand gave high early whole-brain uptake of radioactivity, followed by a brief fast decline and then a slow final decline. 11 C-(S)-NR2B-SMe was studied extensively. Ex vivo measurements showed that radioactivity in rat brain at 30 min after radioligand injection was virtually unchanged radioligand. Only less lipophilic radiometabolites appeared in plasma. Highaffinity NR2B ligands, Ro-25-6981, ifenprodil, and CO101244, showed increasing preblocking of whole-brain radioactivity retention with increasing dose (0.01-3.00 mg/kg, intravenously). Five σ 1 antagonists (FTC146, BD1407, F3, F4, and NE100) and 4 σ 1 agonists ((1)-pentazocine, (±)-PPCC, PRE-084, and (1)-SKF10047) were ineffective preblocking agents, except FTC146 and F4 at a high dose. Two potent σ 1 receptor agonists, TC1 and SA4503, showed dose-dependent preblocking effects in the presence or absence of pharmacologic σ 1 receptor blockade with FTC146. Conclusion: 11 C-(S)-NR2B-SMe has adequate NR2B-specific PET signal in rat brain to warrant further evaluation in higher species. TC1 and SA4503 likely have offtarget binding to NR2B in vivo.
European Journal of Medicinal Chemistry, 2019
Purine nucleotides such as ATP and ADP are important extracellular signaling molecules in almost all tissues activating various subtypes of purinoreceptors. In the brain, the P2Y 1 receptor (P2Y 1 R) subtype mediates trophic functions like differentiation and proliferation, and modulates fast synaptic transmission, both suggested to be affected in diseases of the central nervous system. Research on P2Y 1 R is limited because suitable brain-penetrating P2Y 1 Rselective tracers are not yet available. Here, we describe the first efforts to develop an 18 F-labeled PET tracer based on the structure of the highly affine and selective, non-nucleotidic P2Y 1 R allosteric modulator 1-(2-[2-(tert-butyl)phenoxy]pyridin-3-yl)-3-[4-(trifluoromethoxy)phenyl]urea (7). A small series of fluorinated compounds was developed by systematic modification of the p-(trifluoromethoxy)phenyl, the urea and the 2-pyridyl subunits of the lead compound 7. Additionally, the p-(trifluoromethoxy)phenyl subunit was substituted by carborane, a boron-rich cluster with potential applicability in boron neutron capture therapy (BNCT). By functional assays, the new fluorinated derivative 1-{2-[2-(tertbutyl)phenoxy]pyridin-3-yl}-3-[4-(2-fluoroethyl)phenyl]urea (18) was identified with a high P2Y 1 R antagonistic potency (IC 50 = 10 nM). Compound [ 18 F]18 was radiosynthesized by using tetra-n-butyl ammonium [ 18 F]fluoride with high radiochemical purity, radiochemical yield and molar activities. Investigation of brain homogenates using hydrophilic interaction chromatography (HILIC) revealed [ 18 F]fluoride as major radiometabolite. Although [ 18 F]18 showed fast in vivo metabolization, the high potency and unique allosteric binding mode makes this class of compounds interesting for further optimizations and investigation of the theranostic potential as PET tracer and BNCT agent.
Nuclear Medicine and Biology, 2019
Introduction: The serotonin 1B receptor subtype is of interest in the pathophysiology and treatment of depression, anxiety, and migraine. Over recent years 5-HT 1B receptor binding in human brain has been examined with PET using radio ligands that are partial but not full agonists. To explore how the intrinsic activity of a PET radio ligand may affect imaging performance, two high-affinity full 5-HT 1B receptor agonists (AZ11136118, 4; and AZ11895987, 5) were selected from a large compound library and radiolabeled for PET examination in non-human primates. Methods: [ 11 C]4 was obtained through Pd(O)-mediated insertion of [ 11 C]carbon monoxide between prepared iodoarene and homochiral amine precursors. [ 11 C]5 was obtained through N-11 C-methylation of N-desmethyl precursor6 with [ 11 C] methyl triflate. [ 11 C]4 and [ 11 C]5 were studied with PET in rhesus or cynomolgus monkey. [ 11 C]4 was studied with PET in mice and rats to measure brain uptake and specific binding. Ex-vivo experiments in rats were performed to identify whether there were radiometabolites in brain. Physiochemical parameters for [ 11 C]4 (pKa, logD and conformational energetics) were evaluated. Results: Both [ 11 C]4 and [ 11 C]5 were successfully produced in high radiochemical purity and in adequate amounts for PET experiments. After intravenous injection of [ 11 C]4, brain radioactivity *
Bioorganic & Medicinal Chemistry Letters, 2015
An expansive set of N-aryl-N'-(3-(substituted)phenyl)-N'-methylguanidines was prepared in a search for new leads to prospective PET ligands for imaging of the open channel of the N-methyl-D-aspartate (NMDA) receptor in vivo. The N-aryl rings and their substituents were varied, whereas the N-methyl group was maintained as a site for potential labeling with the positronemitter, carbon-11 (t 1/2 = 20.4 min). At micromolar concentration, over half of the prepared compounds strongly inhibited the binding of [ 3 H]TCP to its binding site in the open NMDA receptor in vitro. Four ligands displayed affinities that are similar or superior to those of the promising SPECT radioligand ([ 123 I]CNS1261). The 3'-dimethylamino (19; K i 36.7 nM), 3'trifluoromethyl (20; K i 18.3 nM) and 3'-methylthio (2; K i 39.8 nM) derivatives of N-1-naphthyl-N'-(phenyl)-N'-methylguanidine were identified as especially attractive leads for PET radioligand development.
Journal of Labelled Compounds and Radiopharmaceuticals, 2001
pyridinyl)-1-piperazinyl]ethyl}benzamide was synthesized by nucleophilic aromatic substitution on the nitro precursor in a microwave oven (5 min, 700 W). Overall radiochedcal yield was 20 % (EOB), chemical and radiochemical purity were respectively higher than 95 and 99 %. Specific activity was always higher than 18.5 GBq/pmol (500 mCi/pmol). Biodistribution studies in rabbits were performed leading to 0.77 % ID in the brain at 5 min pi. Radioactivity concentration of brain was significantly higher than that of blood. However, no significant differences in % ID/g tissue of the different isolated brain regions (hippocampus, hypothalamus, striatum, cortex and cerebellum) could be demonstrated.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2017
Clinical and preclinical research with modulators binding to the NMDA receptor GluN2B N-terminal domain (NTD) aim for the treatment of various neurological diseases. However, the interpretation of the results is hampered by the lack of a suitable NMDA PET tracer for assessing the receptor occupancy of candidate drugs. We have developed [11C]Me-NB1 as a PET tracer for imaging GluN1/GluN2B-containing NMDA receptors and used it to investigate in rats the dose-dependent receptor occupancy of eliprodil, a GluN2B NTD modulator. Methods: [11C]Me-NB1 was synthesized and characterized by in vitro displacement binding experiments with rat brain membranes, in vitro autoradiography, blocking and displacement experiments by PET and PET kinetic modeling with an arterial input function. Receptor occupancy by eliprodil was studied in vivo by PET with [11C]Me-NB1. Results: [11C]Me-NB1 was synthesized at 290±90 GBq/µmol specific activity, 7.4±1.9 GBq total activity at the end of synthesis and >99%...