Synthesis of carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as new potential PET AMPA receptor ligands
New carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential positron emission tomography AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid) receptor ligands to image brain diseases. The single...
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| Published in | Bioorganic & medicinal chemistry letters Vol. 16; no. 8; pp. 2229 - 2233 |
|---|---|
| Main Authors | , , , |
| Format | Journal Article |
| Language | English |
| Published |
Oxford
Elsevier Ltd
15.04.2006
Elsevier |
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| Abstract | New carbon-11 and fluorine-18 labeled
N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential positron emission tomography AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid) receptor ligands to image brain diseases. The single crystal structure of the most potent compound
N-acetyl-1-(4′-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (
5a) is first reported. |
|---|---|
| AbstractList | New carbon-11 and fluorine-18 labeled
N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential positron emission tomography AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid) receptor ligands to image brain diseases. The single crystal structure of the most potent compound
N-acetyl-1-(4′-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (
5a) is first reported. New carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential positron emission tomography AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid) receptor ligands to image brain diseases. The single crystal structure of the most potent compound N-acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5a) is first reported. New carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential positron emission tomography AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid) receptor ligands to image brain diseases. The single crystal structure of the most potent compound N-acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5a) is first reported.New carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential positron emission tomography AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid) receptor ligands to image brain diseases. The single crystal structure of the most potent compound N-acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5a) is first reported. New carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential positron emission tomography AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid) receptor ligands to image brain diseases. The single crystal structure of the most potent compound N-acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoqu inoli ne (5a) is first reported. |
| Author | Kong, Deyuan Gao, Mingzhang Zheng, Qi-Huang Clearfield, Abraham |
| Author_xml | – sequence: 1 givenname: Mingzhang surname: Gao fullname: Gao, Mingzhang organization: Department of Radiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA – sequence: 2 givenname: Deyuan surname: Kong fullname: Kong, Deyuan organization: Department of Chemistry, Texas A&M University, College Station, TX 77843, USA – sequence: 3 givenname: Abraham surname: Clearfield fullname: Clearfield, Abraham organization: Department of Chemistry, Texas A&M University, College Station, TX 77843, USA – sequence: 4 givenname: Qi-Huang surname: Zheng fullname: Zheng, Qi-Huang email: qzheng@iupui.edu organization: Department of Radiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA |
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| Cites_doi | 10.1016/j.bmcl.2005.06.038 10.1016/j.bmcl.2005.05.108 10.1016/S0969-8051(98)00087-0 10.1021/jm0210008 10.1021/jo01310a003 10.1002/bmc.494 10.1016/S0969-8051(01)00215-3 |
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| Keywords | Carbon-11 Fluorine-18 Positron emission tomography 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptor N-Acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives Brain diseases Fluorine Isotopes Isoquinoline derivatives Fluorine 18 Radiolabelling Ligand Central nervous system Carbon Isotopes Glutamate receptor AMPA receptor Carbon 11 N-Acetyl-l-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives Chemical synthesis Crystalline structure |
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| References | Zheng, Mock (bib6) 2005; 19 C, which was generated by a Venturi cooling device powered with 100 Mp: 173–175 Plates were visualized by UV light. Normal phase flash chromatography was carried out on EM Science silica gel 60 (230–400 mesh) with a forced flow of the indicated solvent system in the proportions described below. All moisture-sensitive reactions were performed under a positive pressure of nitrogen maintained by a direct line from a nitrogen source. Analytical HPLC was performed using a Prodigy (Phenomenex) 5 F nuclear reaction in a RDS-112 cyclotron on an enriched H and injected onto the semi-preparative HPLC column. The product fraction was collected, the solvent was removed by rotatory evaporation under vacuum, and the final product Wang, Miller, Sledge, Zheng (bib7) 2005; 15 2.13 (s, 3H, NCOCH 6.55 (s, 1H, H-1), 6.60 (s, 1H, H-5), 6.63 (d 5.51, 8.09 Compounds 0.62 (EtOAc). H), 3.15–3.23 (m, 1H, CH 0.66 (1:9 MeOH/CH and compounds min, and RTK 5.02 (s, 1H, H-1), 6.22 (s, 1H, H-5), 6.63 (s, 1H, H-8), 7.12–7.16 (m, 1H, ArH), 7.24–7.25 (m, 3H, ArH). 1-(3′,4′-Dichlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline – Acetyl-6,7-dimethoxy-1-(4′-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline was 15–25%. Chemical purity, radiochemical purity, and specific radioactivity were determined by analytical HPLC method. The chemical purities of precursor H), 3.66-3.75 (m, 1H, CH mmHg) to give a crude product Hz, 1H, OH), 6.49 (s, 1H, H-1), 6.74 (s, 1H, H-5), 6.82 (s, 1H, H-8), 7.11–7.15 (m, 1H, ArH), 7.17–7.25 (m, 3H, ArH). LRMS (EI): 331 (M Vera, Eckelman (bib2) 2001; 28 10 Hz, 1H, OH), 6.47 (s, 1H, H-1), 6.74 (s, 1H, H-5), 6.82 (s, 1H, H-8), 7.16 (d mL) and dichloromethane (10 3.90 (s, 3H, OCH Tracer 6.48 (s, 1H, H-1), 6.66 (s, 1H, H-5), 6.85 (s, 1H, H-8), 6.95 (t OTf was passed into the air-cooled reaction tube at −15 to −20 ) H NMR spectra were recorded on a Bruker QE 300 NMR spectrometer using tetramethylsilane (TMS) as an internal standard. Chemical shift data for the proton resonances were reported in parts per million ClNO H), 2.88–3.07 (m, 2H, CH Hz, 1H, ArH), 7.26–7.35 (m, 2H, ArH). LRMS (EI): 379 (M , 6.47 (s, 1H, H-1), 6.69 (s, 1H, H-5), 6.90 (s, 1H, H-8), 7.41 (d min. The decay corrected radiochemical yield, from . 1 Tracers 6- mmol, 0.8 H), 3.65–3.72 (ddd 4 2–3 K. The structure was solved and refined using the programs SHELXS-97 (Sheldrick, 1997) and SHELXL (Sheldrick 1997). The program X-Seed (Barbour, 1999) was used as an interface to the SHELX programs. X-ray coordinates have been deposited with the Cambridge Crystallographic Data Centre (CCDC) for small molecules and the deposition number is CCDC 294643. 0.59 (EtOAc). column, 4.6 μm C-18 column, 10 in about 90% yield. 1-(4′-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline = 3.62 2.93 C F O(p,n) was formulated in saline, sterile-filtered through a sterile vented Millex-GS 0.22 H 3.19–3.27 (m, 1H, C 3.68 C. min. The radiochemical yield of 250 mm; 3:1:3 CH was formulated with NaH Acetyl-1-(4′-chlorophenyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline mM, pH 6.7 KHPO mM, pH 6.7, KHPO 2.20, 8.09 Mp: 208–210 5.00 (s, 1H, H-1), 6.25 (s, 1H, H-5), 6.62 (s, 1H, H-8), 6.83 (d 365.0580, found 365.0577. mL) under a nitrogen steam efficiently removed water to form anhydrous K was >99%, and the chemical purity of radiotracer 2.60–2.70 (m, 1H, C 0.67 (EtOAc). Gao, Miller, Sledge, Zheng (bib5) 2005; 15 Acetyl-6,7-dimethoxy-1-(4′-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline Mp: 125–127 SO M). This solution was passed onto a C O water (95+%) target was added to a Pyrex vessel which contains K 1.62 (s, 1H, NH), 2.56–2.64 (m, 1H, C H NMR (300 CH min), then the reaction tube was heated at 70–80 cm 8.82 8.83 CO C for 15–20 in tissue biodistribution studies (∼6 3.87 (s, 3H, 7-OCH 3.88 (s, 3H, OCH 3.87 (s, 3H, OCH 3.89 (s, 3H, OCH 3.86 (s, 3H, OCH O) and Kryptofix 2.2.2 (10 F-Kryptofix 2.2.2 complex. The radiolabeling reaction was monitored by analytical radio-HPLC method. Retention times (RTs) in the analytical HPLC system were: RT 6.0 2.14 (s, 3H, NCOCH Mp: 112–114 0.71073 1.78 (s, 1H, NH), 2.72 (dt 0.70 (1:9 MeOH/CH mL) or in micro-PET imaging studies (1–3 H), 3.69–3.75 (m, 1H, CH 5.82 (s, 1H, OH), 6.61 (s, 1H, H-1), 6.66 (s, 1H, H-5), 6.77 (s, 1H, H-8), 7.17–7.21 (m, 4H, ArH). LRMS (EI): 331 (M C with HPLC grade CH 4.57 in about 40% yield and mL CH Mp: 130–132 Hz, 2H, ArH), 8.31 (s, 1H, ArOH). LRMS (EI): 285 (M 3.50, 14.70 H), 3.68–3.74 (m, 1H, CH Cl mM), whose volume was dependent upon the use of the labeled product 6- mL), and the fractions were passed onto a rotatory evaporator. The solvent was removed by evaporation under high vacuum (0.1–1.0 Node, Nishide, Fuji, Fujita (bib3) 1980; 45 1.76 (s, 1H, NH), 2.72 (dt 0.3-0.5 100%). HRMS (EI): calcd for C Hz, 2H, ArH), 7.21 (dd Hz, 2H, ArH), 8.16 (d psi compressed air, until radioactivity reached a maximum (∼3 50 were synthesized using a modification of the literature procedure H), 3.15–3.22 (m, 1H, CH MHz, DMSO- Hz, 2H, ArH), 9.32 (s, 1H, OH). LRMS (EI): 327 (M Mock, Mulholland, Vavrek (bib4) 1999; 26 2.73 (dt Hz, 2H, ArH), 8.11 (d g, 4 equiv of 4.42, 16.18 4.68 Acetyl-6,7-dimethoxy-1-(4′-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline Hz, 1H, ArH), 6.77 (s, 1H, H-8), 6.88 (d H), 2.71–2.84 (m, 2H, CH 6.46 (s, 1H, H-1), 6.67 (s, 1H, H-5), 6.80 (s, 1H, H-8), 7.10 (dd μm cellulose acetate membrane, and collected into a sterile vial. Total radioactivity was assayed and total volume was noted. The overall synthesis time was 15–20 Hz, 2H, ArH). relative to internal standard TMS 3.30–3.40 (m, 1H, C Acetyl-1-(4′-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline filtered, and then evaporated to give a crude product, which was purified by column chromatography (20% EtOAc/hexane) on silica gel to afford nm) and γ-ray (NaI) flow detectors. Semi-preparative HPLC was performed using a Prodigy (Phenomenex) 5 0.68 (1:9 MeOH/CH CN (3× 1 5.0 No-carrier-added (NCA) aqueous H cartridge by gas pressure. The cartridge was washed with H mL) cooled in an ice-water bath was added AlCl H), 3.64–3.71 (ddd min. The contents of the reaction tube were diluted with NaHCO Mp: 89–91 H), 2.84–2.95 (m, 1H, CH H), 3.61–3.65 (m, 1H, CH H), 3.65–3.70 (m, 1H, CH cm was obtained from E. S. Industries, Berlin, NJ, and part number 300121-C18-BD 10 μm filter unit was obtained from Millipore Corporation, Bedford, MA. 0.65 (1:9 MeOH/CH were >96%, the radiochemical purity of target radiotracer 0.48 (1:9 MeOH/CH Mp: 84–86 min. The chemical purities of the target tracers 6- OTf was made according to a literature procedure. C for 3 379.0737, found 379.0725. H), 2.84-2.95 (m, 1H, CH min, RT6- 7- × 285.1359, found 285.1346. 6,7-Dimethoxy-1-(4′-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline Mp: 168–169 6.49 (s, 1H, H-1), 6.66 (s, 1H, H-5), 6.83 (s, 1H, H-8), 7.14–7.16 (m, 1H, ArH), 7.19–7.22 (m, 3H, ArH). LRMS (EI): 345 (M Hz, 1H, C 5.03 (s, 1H, H-1), 6.20 (s, 1H, H-5), 6.63 (s, 1H, H-8), 6.96–7.03 (m, 2H, ArH), 7.20–7.25 (m, 2H, ArH). 4.77 (s, 1H, H-1), 6.16 (s, 1H, H-5), 6.68–6.98 (m, 3H, 2H, ArH and 1H, H-8), 6.98 (d, 2H Mp: 181–183 3.64 (s, 3H,4′-OCH Hz, 2H, ArH), 7.16 (d H), 2.88–2.98 (m, 1H, CH 3.29-3.39 (m, 1H, C Mp: 197–199 mg) was dissolved in CH 3.73 (s, 3H, OCH General procedure for preparation of compounds 0.20 (1:9 MeOH/CH 2.94, 5.14, 13.24 2.94, 5.14, 13.23 3.77 (s, 3H, OCH 3.75 (s, 3H, OCH Hz, 2H, ArH), 7.22 (d 0.27 (EtOAc). 0.71 (1:9 MeOH/CH 345.1126, found 345.1126. H), 3.12–3.20 (m, 1H, CH The reaction mixture was kept to stir for 2 3.38, 16.18 Gitto, Barreca, De Luca, De Sarro, Ferreri, Quartarone, Russo, Constanti, Chimirri (bib1) 2003; 46 Mp: 195–197 2.95–3.02 (m, 1H, CH 3.30, 14.71 H), 3.71–3.76 (m, 1H, CH mg, in 0.2 mg, in 0.5 Sep-Pak type cartridge was obtained from Waters Corporate Headquarters, Milford, MA. Sterile vented Millex-GS 0.22 3.29–3.39 (m, 1H, C silica guard cartridge column 1 H), 2.86–2.99 (m, 1H, CH mL), and the aqueous washing was discarded. The product was eluted from the column with EtOH (2× 3 F (0.5 1.76 (s, 1H, NH), 2.73 (dt and standard sample 0.58 (EtOAc). 2.06 (s, 3H, NCOCH mg, dissolved in 0.5 nm) and γ-ray (NaI) flow detectors. Semi-prep C 2.72 (dt 3.01–3.09 (m, 1H, C Semi-prep SiO H), 3.66–3.73 (ddd Acetyl-1-(4′-chlorophenyl)-7-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline Acetyl-1-(3′-chlorophenyl)-7-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline F. The Sep-Pak column was eluted with 15% MeOH/CH h. Subsequently the mixture was poured into water, extracted with dichloromethane, washed with brine, dried by Na 331.0970, found 331.0966. 2.16 (s, 3H, NCOCH Hz, 1H, ArH), 7.26–7.35 (m, 2H, ArH). LRMS (EI): 365 (M H), 2.84–2.97 (m, 1H, CH typical experimental procedure for the radiosynthesis: The precursor O (2× 3 H), 2.87–2.97 (m, 1H, CH CN) was introduced to the K μm cellulose acetate membrane, and collected into a sterile vial. Total radioactivity was assayed and total volume was noted. The overall synthesis, purification, and formulation time was 60–70 1.74 (s, 1H, NH), 2.73 (dt Hz, 2H, ArH). LRMS (EI): 331 (M min. The reaction mixture was sealed and heated at 120 3.31–3.41 (m, 1H, C Acetyl-1-(3′,4′-dichlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline min from EOB. RTs in the semi-preparative HPLC system were: RT 5.69 (s, 1H, OH), 6.45 (s, 1H, H-1), 6.75 (s, 1H, H-5), 6.78 (s, 1H, H-8), 7.09 (dd 5.80 (s, 1H, OH), 6.58 (s, 1H, H-1), 6.64 (s, 1H, H-5), 6.74 (s, 1H, H-8), 7.13–7.20 (m, 4H, ArH). LRMS (EI): 331 (M H), 2.91–3.02 (m, 1H, CH 5.68 (t 2.15 (s, 3H, NCOCH mL), sterile-filtered through a sterile vented Millex-GS 0.22 327.1465, found 327.1460. CN). Azeotropic distillation at 115 Hz, 2H, ArH). 6,7-Dimethoxy-1-(4′-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline 3.35–4.40 5.02 (s, 1H, H-1), 6.19 (s, 1H, H-5), 6.63 (s, 1H, H-8), 7.18–7.30 (m, 4H, ArH). 1-(3′-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline from mono-demethylation of compounds 1.84, 8.09 Hz, 1H, CH min, RT Experimental details and characterization data. General: All commercial reagents and solvents were used without further purification unless otherwise specified. The 3.61 (s, 3H, OCH 8.09 Mp: 143–145 H), 3.68–3.75 (m, 1H, CH Mp: 143–144 100%]. HRMS (EI): calcd for C 3.63 (s, Zheng (10.1016/j.bmcl.2006.01.042_bib6) 2005; 19 10.1016/j.bmcl.2006.01.042_bib8_1 10.1016/j.bmcl.2006.01.042_bib8_2 10.1016/j.bmcl.2006.01.042_bib8_3 Wang (10.1016/j.bmcl.2006.01.042_bib7) 2005; 15 Gitto (10.1016/j.bmcl.2006.01.042_bib1) 2003; 46 Mock (10.1016/j.bmcl.2006.01.042_bib4) 1999; 26 Node (10.1016/j.bmcl.2006.01.042_bib3) 1980; 45 Vera (10.1016/j.bmcl.2006.01.042_bib2) 2001; 28 10.1016/j.bmcl.2006.01.042_bib8_4 10.1016/j.bmcl.2006.01.042_bib8_5 10.1016/j.bmcl.2006.01.042_bib8_6 10.1016/j.bmcl.2006.01.042_bib8_7 Gao (10.1016/j.bmcl.2006.01.042_bib5) 2005; 15 |
| References_xml | – reference: ), 6.47 (s, 1H, H-1), 6.69 (s, 1H, H-5), 6.90 (s, 1H, H-8), 7.41 (d, – reference: ). Mp: 115–117 – reference: ). Mp: 168–169 – reference: mg, in 0.5 – reference: cm – reference: and standard sample – reference: , 100%). HRMS (EI): calcd for C – reference: μm filter unit was obtained from Millipore Corporation, Bedford, MA. – reference: mL) or in micro-PET imaging studies (1–3 – reference: cartridge by gas pressure. The cartridge was washed with H – reference: H), 2.84–2.89 (m, 1H, CH – reference: min, and RTK – reference: ), 2.71–2.76 (m, 1H, C – reference: μL). To this solution was added 6 N NaOH (2-3 – reference: ), 3.78 (s, 3H, OCH – reference: column, 4.6 – reference: mg) was dissolved in CH – volume: 46 start-page: 197 year: 2003 ident: bib1 publication-title: J. Med. Chem. – reference: ), 5.00 (s, 1H, H-1), 6.25 (s, 1H, H-5), 6.62 (s, 1H, H-8), 6.83 (d, – reference: OTf was made according to a literature procedure. – reference: in tissue biodistribution studies (∼6 – reference: ), 2.95–3.02 (m, 1H, CH – reference: H), 2.89–3.00 (m, 1H, CH – reference: ), 3.00–3.09 (m, 1H, C – reference: H), 2.79–2.90 (m, 1H, CH – reference: Hz, 2H, ArH), 8.31 (s, 1H, ArOH). LRMS (EI): 285 (M – reference: from mono-demethylation of compounds – reference: 0.66 (1:9 MeOH/CH – reference: 331.0970, found 331.0966. – reference: were >96%, the radiochemical purity of target radiotracer [ – reference: 0.66 (EtOAc). – reference: in about 90% yield. – reference: ), 3.61 (s, 3H, OCH – reference: Hz, 1H, CH – reference: , 100%]. HRMS (EI): calcd for C – reference: ), 3.29–3.39 (m, 1H, C – reference: H), 2.88–2.99 (m, 1H, CH – reference: . To a stirred solution of – reference: ), 3.86 (s, 3H, OCH – reference: (1 – reference: , or – reference: 3.50, 14.70 – reference: ), 3.87 (s, 3H, OCH – reference: ), 3.77 (s, 3H, OCH – reference: ), 2.72 (dt, – reference: mL) and dichloromethane (10 – reference: , – reference: min and was subsequently allowed to cool down, at which time the crude product was passed through a Silica Sep-Pak cartridge to remove Kryptofix 2.2.2 and unreacted K – volume: 45 start-page: 4275 year: 1980 ident: bib3 publication-title: J. Org. Chem. – reference: 1 – reference: mg, dissolved in 0.5 – reference: Compounds ( – reference: 1.78 (s, 1H, NH), 2.72 (dt, – reference: -Acetyl-1-(3′-chlorophenyl)-7-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline ( – reference: H), 3.69–3.74 (m, 1H, CH – reference: ), 2.99–3.07 (m, 1H, C – reference: F-Kryptofix 2.2.2 complex. The nitro-precursor – reference: M). This solution was passed onto a C – reference: h. Subsequently the mixture was poured into water, extracted with dichloromethane, washed with brine, dried by Na – reference: = 8.09 – reference: ). Mp: 173–175 – reference: mL/min, and UV (254 – reference: ), 3.47 (s, 3H, OCH – reference: ), 6.49 (s, 1H, H-1), 6.66 (s, 1H, H-5), 6.83 (s, 1H, H-8), 7.14–7.16 (m, 1H, ArH), 7.19–7.22 (m, 3H, ArH). LRMS (EI): 345 (M – reference: K. The structure was solved and refined using the programs SHELXS-97 (Sheldrick, 1997) and SHELXL (Sheldrick 1997). The program X-Seed (Barbour, 1999) was used as an interface to the SHELX programs. X-ray coordinates have been deposited with the Cambridge Crystallographic Data Centre (CCDC) for small molecules and the deposition number is CCDC 294643. – reference: ), 5.69 (s, 1H, OH), 6.45 (s, 1H, H-1), 6.75 (s, 1H, H-5), 6.78 (s, 1H, H-8), 7.09 (dd, – reference: Experimental details and characterization data. General: All commercial reagents and solvents were used without further purification unless otherwise specified. The – reference: H), 2.88–3.07 (m, 2H, CH – reference: ClNO – reference: H), 3.15–3.22 (m, 1H, CH – reference: H), 2.86–2.99 (m, 1H, CH – reference: ) relative to internal standard TMS ( – reference: ), 2.73 (dt, – reference: 6.92 – reference: H), 3.66-3.75 (m, 1H, CH – reference: min. The reaction mixture was sealed and heated at 120 – reference: , or [ – reference: ) were synthesized using a modification of the literature procedure – reference: ). Mp: 125–127 – reference: ). Mp: 130–132 – reference: F-Kryptofix 2.2.2 complex. The radiolabeling reaction was monitored by analytical radio-HPLC method. Retention times (RTs) in the analytical HPLC system were: RT – reference: ) (0.3-0.5 – reference: (1.5 – reference: ). Mp: 195–197 – reference: 2.06 (s, 3H, NCOCH – reference: -Acetyl-1-(3′-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ( – reference: ), 3.31–3.41 (m, 1H, C – reference: mM, pH 6.7 KHPO – reference: 2.94, 12.51 – volume: 15 start-page: 4380 year: 2005 ident: bib7 publication-title: Bioorg. Med. Chem. Lett. – reference: . Semi-prep SiO – reference: mmHg) to give a crude product [ – reference: min), then the reaction tube was heated at 70–80 – reference: and compounds – reference: mL) prepared by – reference: mM, pH 6.7, KHPO – reference: psi compressed air, until radioactivity reached a maximum (∼3 – volume: 26 start-page: 467 year: 1999 ident: bib4 publication-title: Nucl. Med. Biol. – reference: H – reference: 8.82 – reference: 3.38, 16.18 – reference: -Acetyl-6,7-dimethoxy-1-(4′-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline ( – reference: 5.51, 8.09 – reference: 327.1465, found 327.1460. – reference: 3.35–4.40 – reference: H), 2.84-2.95 (m, 1H, CH – reference: mL) cooled in an ice-water bath was added AlCl – reference: Hz, 2H, ArH). 6,7-Dimethoxy-1-(4′-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline ( – reference: ), 3.19–3.27 (m, 1H, C – reference: Hz, 2H, ArH), 9.32 (s, 1H, OH). LRMS (EI): 327 (M – reference: 0.67 (EtOAc). – reference: (5.0 – reference: 0.48 (1:9 MeOH/CH – reference: Hz, 1H, C – reference: in about 40% yield and – reference: H), 3.68–3.74 (m, 1H, CH – reference: mL) under a nitrogen steam efficiently removed water to form anhydrous K – reference: ), 3.64 (s, 3H,4′-OCH – reference: H), 3.12–3.20 (m, 1H, CH – reference: was >99%, and the chemical purity of radiotracer [ – reference: 1.84, 8.82 – reference: ), 3.32–3.42 (m, 1H, C – reference: ), 3.36-3.46 (m, 1H, C – reference: CN/MeOH/20 – reference: 2.14 (s, 3H, NCOCH – reference: H), 3.66–3.73 (ddd, – reference: mL), sterile-filtered through a sterile vented Millex-GS 0.22 – reference: min. The decay corrected radiochemical yield, from – reference: ): – reference: ), 3.70 (s, 3H, OCH – reference: 2.17 (s, 3H, NCOCH – reference: 331.0970, found 331.0963. – reference: ), 5.69 (t, – reference: mg, in 0.2 – reference: silica guard cartridge column 1 – reference: H), 3.69–3.75 (m, 1H, CH – reference: ), 3.29-3.39 (m, 1H, C – reference: 2.94, 5.14, 13.24 – reference: was 15–25%. Chemical purity, radiochemical purity, and specific radioactivity were determined by analytical HPLC method. The chemical purities of precursor – reference: ), 3.01–3.07 (m, 1H, C – reference: mL H – reference: ), 3.89 (s, 3H, OCH – reference: CN) was introduced to the K – reference: ), 5.68 (t, – reference: 331.0970, found 331.0962. – reference: ), 2.69 (dt, – reference: ), 6.46 (s, 1H, H-1), 6.67 (s, 1H, H-5), 6.80 (s, 1H, H-8), 7.10 (dd, – reference: 3.66, 16.15 – reference: Hz, 1H, ArH), 7.26–7.35 (m, 2H, ArH). LRMS (EI): 379 (M – reference: CN:MeOH:20 – reference: 8.83 – reference: -Acetyl-6,7-dimethoxy-1-(4′-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline ( – reference: ). Mp: 194–195 – reference: mM), whose volume was dependent upon the use of the labeled product 6-[ – reference: X-ray crystallography. The crystallographic measurements were carried out on a Siemens P4 diffractometer with graphite-monochromated Mo-Kα radiation ( – reference: ), 3.63 (s, 3H, OCH – reference: min from EOB. RTs in the semi-preparative HPLC system were: RT – reference: F (0.5 – reference: min, RT[ – reference: , 7-[ – reference: 0.57 (EtOAc). – reference: Tracers 6-[ – reference: Å) and 12-kW rotating generator. The data were collected at 110 – reference: 4.82, 15.45 – reference: 3.30, 14.71 – reference: (2–3 – reference: mL), and the fractions were passed onto a rotatory evaporator. The solvent was removed by evaporation under high vacuum (0.1–1.0 – reference: ). – reference: 0.62 (EtOAc). – reference: 365.0580, found 365.0577. – reference: ), 3.76 (s, 3H, OCH – reference: 1.88 – reference: Tracer [ – reference: ), 3.66 (s, 3H, OCH – reference: F – reference: 2.94, 5.14, 13.23 – reference: CN (300 – reference: μm cellulose acetate membrane, and collected into a sterile vial. Total radioactivity was assayed and total volume was noted. The overall synthesis time was 15–20 – reference: Hz, 1H, ArH), 6.77 (s, 1H, H-8), 6.88 (d, – reference: ), 5.82 (s, 1H, OH), 6.61 (s, 1H, H-1), 6.66 (s, 1H, H-5), 6.77 (s, 1H, H-8), 7.17–7.21 (m, 4H, ArH). LRMS (EI): 331 (M – reference: MHz, DMSO- – reference: 3.68 – reference: -Acetyl-1-(3′-chlorophenyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline ( – reference: μm cellulose acetate membrane, and collected into a sterile vial. Total radioactivity was assayed and total volume was noted. The overall synthesis, purification, and formulation time was 60–70 – reference: 5.14, 16.17 – reference: 4.42, 16.18 – reference: (6.0 – reference: ), 3.73 (s, 3H, OCH – reference: H), 2.88–2.97 (m, 1H, CH – reference: , 89%), 284 [(M−H) – reference: H), 3.17–3.24 (m, 1H, CH – reference: ). Mp: 143–144 – reference: 379.0737, found 379.0725. – reference: min. The contents of the reaction tube were diluted with NaHCO – reference: ). Mp: 89–91 – reference: 3.68, 16.18 – reference: mL, 3× 2 – reference: μm C-18 column, 10 – reference: ), 3.87 (s, 3H, 7-OCH – reference: in about 25% yield. – reference: 1.76 (s, 1H, NH), 2.72 (dt, – reference: Hz, 2H, ArH). 6,7-Dimethoxy-1-(4′-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline ( – reference: , typical experimental procedure for the radiosynthesis: The precursor ( – reference: °C with HPLC grade CH – volume: 19 start-page: 671 year: 2005 ident: bib6 publication-title: Biomed. Chromatogr. – reference: 1.62 (s, 1H, NH), 2.56–2.64 (m, 1H, C – reference: Hz, 1H, ArH), 7.26–7.35 (m, 2H, ArH). LRMS (EI): 365 (M – reference: H), 3.61–3.65 (m, 1H, CH – reference: 2.20, 8.09 – reference: Hz, 2H, ArH), 8.11 (d, – reference: O (2× 3 – reference: in about 90% yield. 1-(4′-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ( – reference: °C for 15–20 – reference: 2.16 (s, 3H, NCOCH – reference: , [ – reference: mL CH – reference: μm C – reference: -Acetyl-1-(3′,4′-dichlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ( – reference: 0.63 (EtOAc). – reference: Hz, 1H, OH), 6.49 (s, 1H, H-1), 6.74 (s, 1H, H-5), 6.82 (s, 1H, H-8), 7.11–7.15 (m, 1H, ArH), 7.17–7.25 (m, 3H, ArH). LRMS (EI): 331 (M – reference: ), 6.50 (s, 1H, H-1), 6.64 (s, 1H, H-5), 6.78 (s, 1H, H-8), 6.80 (d, – reference: General procedure for preparation of compounds – reference: -Acetyl-1-(3′,4′-dichlorophenyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline ( – reference: 0.27 (EtOAc). – reference: × – reference: (4 – reference: ). Mp: 112–114 – reference: -Acetyl-6,7-dimethoxy-1-(4′-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline( – reference: Hz, 2H, ArH). – reference: 1.84, 8.09 – reference: ), 3.90 (s, 3H, OCH – reference: 0.68 (1:9 MeOH/CH – reference: min. The chemical purities of the target tracers 6-[ – volume: 15 start-page: 3865 year: 2005 ident: bib5 publication-title: Bioorg. Med. Chem. Lett. – reference: MHz, CDCl – reference: ), 5.14 (s, 1H, H-1), 6.14 (s, 1H, H-5), 6.65 (s, 1H, H-8), 7.42 (d, – reference: 0.70 (1:9 MeOH/CH – reference: H), 3.65–3.72 (ddd, – reference: H), 2.71–2.84 (m, 2H, CH – reference: H), 3.15–3.23 (m, 1H, CH – reference: 0.71073 – reference: ), 6.48 (s, 1H, H-1), 6.66 (s, 1H, H-5), 6.83 (s, 1H, H-8), 7.16 (d, – reference: ). The reaction mixture was kept to stir for 2 – reference: 0.58 (EtOAc). – reference: , filtered, and then evaporated to give a crude product, which was purified by column chromatography (20% EtOAc/hexane) on silica gel to afford – reference: Sep-Pak type cartridge was obtained from Waters Corporate Headquarters, Milford, MA. Sterile vented Millex-GS 0.22 – reference: were >93%. – reference: 285.1359, found 285.1346. 6,7-Dimethoxy-1-(4′-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline ( – reference: H), 3.68–3.75 (m, 1H, CH – reference: Hz, 2H, ArH), 7.22 (d, – reference: ), 3.74 (s, 3H, OCH – reference: , was 30–45%, and the radiochemical purity was >95% by analytical HPLC. Retention times in the analytical HPLC system were: RT – reference: ), 5.02 (s, 1H, H-1), 6.22 (s, 1H, H-5), 6.63 (s, 1H, H-8), 7.12–7.16 (m, 1H, ArH), 7.24–7.25 (m, 3H, ArH). 1-(3′,4′-Dichlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ( – reference: cm was obtained from E. S. Industries, Berlin, NJ, and part number 300121-C18-BD 10 – reference: O(p,n) – reference: H NMR spectra were recorded on a Bruker QE 300 NMR spectrometer using tetramethylsilane (TMS) as an internal standard. Chemical shift data for the proton resonances were reported in parts per million ( – reference: ). Mp: 143–145 – reference: min, RT6-[ – reference: H), 2.87–2.97 (m, 1H, CH – reference: -Acetyl-1-(4′-chlorophenyl)-7-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline ( – reference: 8.45 – reference: ), 4.77 (s, 1H, H-1), 6.16 (s, 1H, H-5), 6.68–6.98 (m, 3H, 2H, ArH and 1H, H-8), 6.98 (d, 2H, – reference: 8.09 – reference: mL) and then passed onto a rotatory evaporator. The solvent was removed by evaporation under high vacuum. The labeled product 6-[ – reference: 10 – reference: ), 2.60–2.70 (m, 1H, C – reference: CN). Azeotropic distillation at 115 – reference: ), 3.65 (s, 3H, OCH – reference: was formulated in saline, sterile-filtered through a sterile vented Millex-GS 0.22 – reference: CH – reference: 2.15 (s, 3H, NCOCH – reference: ), 3.80 (s, 3H, 6-OCH – reference: H), 2.88–2.98 (m, 1H, CH – reference: H), 3.71–3.76 (m, 1H, CH – reference: mmol) in ethanethiol (1 – reference: ), 3.30–3.40 (m, 1H, C – reference: : No-carrier-added (NCA) aqueous H – reference: Hz, 1H, OH), 6.47 (s, 1H, H-1), 6.74 (s, 1H, H-5), 6.82 (s, 1H, H-8), 7.16 (d, – reference: 331.0970, found 331.0965. – reference: Hz, 2H, ArH), 7.16 (d, – reference: 3.62 – reference: ). Mp: 208–210 – reference: ), 3.88 (s, 3H, OCH – reference: μL). The mixture was transferred to a small volume, three-necked reaction tube. – reference: SO – reference: ). Mp: 181–183 – reference: was formulated with NaH – reference: H NMR (300 – reference: ), 5.80 (s, 1H, OH), 6.58 (s, 1H, H-1), 6.64 (s, 1H, H-5), 6.74 (s, 1H, H-8), 7.13–7.20 (m, 4H, ArH). LRMS (EI): 331 (M – reference: -Acetyl-6,7-dimethoxy-1-(4′-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline ( – reference: mL), and the aqueous washing was discarded. The product was eluted from the column with EtOH (2× 3 – reference: 1.74 (s, 1H, NH), 2.73 (dt, – reference: CO – reference: Cl – reference: ), 3.00–3.08 (m, 1H, C – reference: 5.14, 16.22 – reference: nm) and γ-ray (NaI) flow detectors. Semi-preparative HPLC was performed using a Prodigy (Phenomenex) 5 – reference: H), 2.84–2.97 (m, 1H, CH – reference: 0.0). Low resolution mass spectra were obtained using a Bruker Biflex III MALDI-Tof mass spectrometer, and high resolution mass measurements were obtained using a Kratos MS80 mass spectrometer, in the Department of Chemistry at Indiana University. Chromatographic solvent proportions are expressed on a volume: volume basis. Thin layer chromatography was run using Analtech silica gel GF uniplates (5 – reference: mobile phase, 5.0 – reference: 250 – reference: NO – reference: -Acetyl-1-(4′-chlorophenyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline ( – reference: °C for 3 – reference: ), 3.18–3.25 (m, 1H, CH – reference: F nuclear reaction in a RDS-112 cyclotron on an enriched H – reference: , and injected onto the semi-preparative HPLC column. The product fraction was collected, the solvent was removed by rotatory evaporation under vacuum, and the final product [ – reference: ), 3.64 (s, 3H, OCH – reference: O) and Kryptofix 2.2.2 (10 – reference: ), 3.75 (s, 3H, OCH – reference: °C. – reference: Hz, 1H, ArH), 7.36–7.40 (m, 2H, ArH). 6,7-Dimethoxy-1-(4′-hydoxyphenyl)-1,2,3,4-tetrahydroisoquinoline ( – reference: Hz, 2H, ArH), 7.21 (dd, – reference: H), 2.91–3.02 (m, 1H, CH – reference: = – reference: ), 6.48 (s, 1H, H-1), 6.66 (s, 1H, H-5), 6.85 (s, 1H, H-8), 6.95 (t, – reference: H), 2.87–2.96 (m, 1H, CH – reference: OTf was passed into the air-cooled reaction tube at −15 to −20 – reference: H), 2.84–2.95 (m, 1H, CH – reference: mmol, 0.8 – reference: 3.68, 15.44 – reference: ), 5.00 (s, 1H, H-1), 6.19 (s, 1H, H-5), 6.63 (s, 1H, H-8), 7.08 (dd, – reference: CN (3× 1 – reference: g, 4 equiv of – reference: 2.93 – reference: ). Mp: 162–164 – reference: (buffer solution) mobile phase, flow rate 1.5 – reference: ), 6.55 (s, 1H, H-1), 6.60 (s, 1H, H-5), 6.63 (d, – reference: ). Mp: 110–112 – reference: -Acetyl-1-(4′-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ( – reference: was ∼92%. – reference: H), 3.65–3.70 (m, 1H, CH – reference: nm) and γ-ray (NaI) flow detectors. Semi-prep C – reference: 1.76 (s, 1H, NH), 2.73 (dt, – reference: . The mixture containing precursor and product was purified with semi-preparative HPLC method. The contents of the mixture residue were diluted with HPLC mobile phase 3:1:3 CH – reference: Hz, 2H, ArH), 8.16 (d, – reference: 0.71 (1:9 MeOH/CH – reference: PO – reference: – – reference: Hz, 2H, ArH). LRMS (EI): 331 (M – reference: ), 5.03 (s, 1H, H-1), 6.20 (s, 1H, H-5), 6.63 (s, 1H, H-8), 6.96–7.03 (m, 2H, ArH), 7.20–7.25 (m, 2H, ArH). – reference: mm; 3:1:3 CH – reference: 345.1126, found 345.1126. – reference: Hz, 2H, ArH), 7.14 (d, – reference: 4.68 – reference: mL/min flow rate, UV (254 – reference: ), 5.02 (s, 1H, H-1), 6.19 (s, 1H, H-5), 6.63 (s, 1H, H-8), 7.18–7.30 (m, 4H, ArH). 1-(3′-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ( – reference: mL, 0.1 – reference: F] – reference: 4.57 – reference: C] – reference: 0.65 (1:9 MeOH/CH – reference: 2.94, 5.15, 13.23 – reference: , and [ – reference: °C, which was generated by a Venturi cooling device powered with 100 – volume: 28 start-page: 475 year: 2001 ident: bib2 publication-title: Nucl. Med. Biol. – reference: ). Mp: 197–199 – reference: 0.20 (1:9 MeOH/CH – reference: 5.14, 16.18 – reference: 2.13 (s, 3H, NCOCH – reference: (50 – reference: ). Plates were visualized by UV light. Normal phase flash chromatography was carried out on EM Science silica gel 60 (230–400 mesh) with a forced flow of the indicated solvent system in the proportions described below. All moisture-sensitive reactions were performed under a positive pressure of nitrogen maintained by a direct line from a nitrogen source. Analytical HPLC was performed using a Prodigy (Phenomenex) 5 – reference: 0.60 (EtOAc). – reference: ), 3.01–3.09 (m, 1H, C – reference: Hz, 2H, ArH). – reference: min. The radiochemical yield of [ – reference: 2.10–2.95 – reference: H), 3.64–3.71 (ddd, – reference: F. The Sep-Pak column was eluted with 15% MeOH/CH – reference: 0.59 (EtOAc). – reference: ). Mp: 84–86 – reference: O water (95+%) target was added to a Pyrex vessel which contains K – reference: 1.87 (s, 1H, NH), 2.73 (dt, – reference: 2.04 (s, 1H, NH), 2.74 (dt, – reference: ), 2.70 (dt, – ident: 10.1016/j.bmcl.2006.01.042_bib8_4 – ident: 10.1016/j.bmcl.2006.01.042_bib8_5 – ident: 10.1016/j.bmcl.2006.01.042_bib8_3 – ident: 10.1016/j.bmcl.2006.01.042_bib8_2 – volume: 15 start-page: 4380 year: 2005 ident: 10.1016/j.bmcl.2006.01.042_bib7 publication-title: Bioorg. Med. Chem. Lett. doi: 10.1016/j.bmcl.2005.06.038 – ident: 10.1016/j.bmcl.2006.01.042_bib8_7 – ident: 10.1016/j.bmcl.2006.01.042_bib8_6 – ident: 10.1016/j.bmcl.2006.01.042_bib8_1 – volume: 15 start-page: 3865 year: 2005 ident: 10.1016/j.bmcl.2006.01.042_bib5 publication-title: Bioorg. Med. Chem. Lett. doi: 10.1016/j.bmcl.2005.05.108 – volume: 26 start-page: 467 year: 1999 ident: 10.1016/j.bmcl.2006.01.042_bib4 publication-title: Nucl. Med. Biol. doi: 10.1016/S0969-8051(98)00087-0 – volume: 46 start-page: 197 year: 2003 ident: 10.1016/j.bmcl.2006.01.042_bib1 publication-title: J. Med. Chem. doi: 10.1021/jm0210008 – volume: 45 start-page: 4275 year: 1980 ident: 10.1016/j.bmcl.2006.01.042_bib3 publication-title: J. Org. Chem. doi: 10.1021/jo01310a003 – volume: 19 start-page: 671 year: 2005 ident: 10.1016/j.bmcl.2006.01.042_bib6 publication-title: Biomed. Chromatogr. doi: 10.1002/bmc.494 – volume: 28 start-page: 475 year: 2001 ident: 10.1016/j.bmcl.2006.01.042_bib2 publication-title: Nucl. Med. Biol. doi: 10.1016/S0969-8051(01)00215-3 |
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| Snippet | New carbon-11 and fluorine-18 labeled
N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential... New carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential... |
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| SubjectTerms | 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptor Amides - chemical synthesis Amides - pharmacology Animals Anticonvulsants - chemical synthesis Anticonvulsants - pharmacology Anticonvulsants - therapeutic use Biological and medical sciences Brain diseases Carbon - chemistry Carbon-11 Contrast media. Radiopharmaceuticals Fluorine - chemistry Fluorine-18 Isoquinolines - chemical synthesis Isoquinolines - pharmacology Isoquinolines - therapeutic use Isotope Labeling Ligands Medical sciences Mice Molecular Structure N-Acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives Pharmacology. Drug treatments Positron emission tomography Receptors, AMPA - antagonists & inhibitors Seizures - drug therapy |
| Title | Synthesis of carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as new potential PET AMPA receptor ligands |
| URI | https://dx.doi.org/10.1016/j.bmcl.2006.01.042 https://www.ncbi.nlm.nih.gov/pubmed/16455250 https://www.proquest.com/docview/17161857 https://www.proquest.com/docview/67732227 |
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