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Benzazepin-l,7-diol-derived radiolabeled ligands with high in vivo NMDA specificity

A radiolabeled, radioactive technology used in the field of benzoazepine-1,7-diol-derived compounds to achieve quality improvement and high selectivity

Pending Publication Date: 2021-07-23
ETH ZZURICH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are currently no NMDA-specific PET ligands with sufficiently high in vivo specificity (i.e., much higher than 30%) to correctly reflect the expression of NMDA receptors in patients with diseases or disorders associated with NMDA receptors. biodistribution

Method used

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  • Benzazepin-l,7-diol-derived radiolabeled ligands with high in vivo NMDA specificity
  • Benzazepin-l,7-diol-derived radiolabeled ligands with high in vivo NMDA specificity
  • Benzazepin-l,7-diol-derived radiolabeled ligands with high in vivo NMDA specificity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-

[0126] Example 1 - Chemistry

[0127] General methods for the synthesis of benzazepin-1-ols are known in the art, eg from Tewes et al., ChemMedChem 2010, 5, 687-695. Figure 4 Representative synthetic routes for the production of labeled compounds used in the present invention are shown. Figure 4 The synthetic route for can be adapted by known methods to deliver derivatives of benzazepin-1-ols as well as substantially all of the compounds used in the present invention. The skilled artisan will routinely adapt synthetic routes to suit the synthesis of any of the PET ligands of the invention.

Embodiment 2-F-18

[0128] Embodiment 2-F-18 Radiolabeling

[0129] produced[ 18F] fluoride, and trap it on an anion exchange column (Waters SepPak Accell QMA carbonate column, no pretreatment), and then it is in Kryptofix 222 (6.3mg / mL), K 2 C 2 o 4 (1mg / mL) and K 2 CO 3 (0.1 mg / mL) in MeCN / H2O (4:1, 0.9 mL) and then dried azeotropically with MeCN (3×1 mL) (Preshlock et al., ChemComm 2016). The reaction was purged with air (20 mL), and the residue was redissolved in 6-8 mg boronate precursors 2a, 2b, 2c ( figure 1 ) and 14mg Cu(OTf) 2 (py) 4 0.3 mL of anhydrous dimethylacetamide (DMA) solution. The resulting solution was stirred at 120 °C for 20 min, then it was diluted with 1.5 mL MeCN / H2O (1:1). After adding 0.4 mL of aqueous NaOH (10 M) solution, the mixture was stirred at 95 °C for 15 min. The product was passed through semi-preparative HPLC (Agilent Eclipse XBD-C18 column, 250 × 9.4mm, 5μm, 0.1%H 3 PO 4 in H 2 O (solvent A), MeCN (solvent B); 0.0-5.0min, 20% B; 5.1-20.0min, 20-...

Embodiment 3

[0130] Example 3 - Autoradiography Technique

[0131] Embedding rodent brain tissue into Tissue- (O.C.T. TM Tissue- European Sakura Instrument Inspection Co., Ltd., Alphen am Rhein, The Netherlands (O.C.T. TM Tissue- Sakura Finetek Europe B.V., Alphen aan den Rijn, Netherlands)). Prepared on a cryostat (Cryo-Star HM560MV; Microm, Thermo Scientific, Wilmington, DE, USA) with a thickness 10 μm horizontal brain sections of rat and mouse. Tissue sections were mounted on SuperFrost Plus slides (Menzel, Braunschweig, Germany) and stored at -20°C until further use. Before the autoradiography experiment, the brain slices were first thawed on ice for 15 minutes and then placed at 0°C in a solution containing 30mM HEPES, 0.56mM MgCl 2 , 110mM NaCl, 3.3mM CaCl 2 , 5 mM KCl and 0.1% fatty acid-free bovine serum albumin (BSA) buffer (pH 7.4) for 10 minutes. After drying, tissue sections were incubated with 1 mL of the corresponding radioligand (3 nM) at 21° C. in a humidified...

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Abstract

The present invention is directed to benzazepin-1,7-diol-derived compounds (I) for use in the diagnosis of NMDA (N-methyl-D-aspartate) receptor-associated diseases or disorders by positron emission tomography (PET), single-photon emission computed tomography (SPECT), liquid based-scintillation- and / or autoradiography-based assays. The invention also relates to a method for the diagnosis of NMDA receptor-associated diseases or disorders by administering to a patient or a sample of a patient in need of such diagnosis a compound of the invention in an amount effective for PET imaging, SPECT imaging, liquid based-scintillation- and / or autoradiography-based assays of NMDA receptors, recording at least one PET or SPECT scan, liquid based-scintillation or autoradiography result, and diagnosing an NMDA receptor-associated disease or disorder from an abnormal NMDA receptor expression pattern on the PET or SPECT scan, in the liquid based-scintillation or autoradiography result. The present invention also provides a method for evaluating a putative NMDA-receptor antagonist in a liquid scintigraphy detection assay or an autoradiography assay using the compounds of the present invention.

Description

technical field [0001] The present invention relates to compounds derived from benzazepin-1,7-diols for use in positron emission tomography (PET), single photon emission computed tomography (SPECT), liquid-based Liquid-based scintillation- and / or autoradiography-based assays are used to diagnose diseases or disorders associated with NMDA (N-methyl-D-aspartate) receptors. The present invention also relates to a method for diagnosing a disease or disorder associated with NMDA receptors by using an effective amount for PET imaging, SPECT imaging, liquid scintillation-based and / or autoradiographic-based analysis of NMDA receptors, administering a compound of the invention to a patient or patient sample in need of such a diagnosis, documenting the results of at least one PET or SPECT scan, liquid scintillation-based or autoradiography-based results, and where the diagnosis is related to NMDA receptor-associated diseases or conditions resulting from abnormal NMDA receptor expressio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16A61P25/00A61K31/55A61K51/04
CPCA61P25/00C07D223/16A61K49/0004A61K51/0468
Inventor S·M·艾梅塔美A·海德H·艾哈迈德
Owner ETH ZZURICH
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