US20140142318A1 - Pyridylacetylenes for use as radiotracers and imaging agents - Google Patents
Pyridylacetylenes for use as radiotracers and imaging agents Download PDFInfo
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- US20140142318A1 US20140142318A1 US14/162,885 US201414162885A US2014142318A1 US 20140142318 A1 US20140142318 A1 US 20140142318A1 US 201414162885 A US201414162885 A US 201414162885A US 2014142318 A1 US2014142318 A1 US 2014142318A1
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- compound
- methyl
- cyclohex
- enone
- ylethynyl
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- 0 *O/N=C1/C=C(C#CC2=NC(C)=CC=C2)CCC1 Chemical compound *O/N=C1/C=C(C#CC2=NC(C)=CC=C2)CCC1 0.000 description 3
- UWOHEEOCHCCCNH-JQIJEIRASA-N CC1=CC=CC(C#CC2=C/C(=N/O)CCC2)=N1 Chemical compound CC1=CC=CC(C#CC2=C/C(=N/O)CCC2)=N1 UWOHEEOCHCCCNH-JQIJEIRASA-N 0.000 description 1
- KDGNSSNMCNPWHV-BACBYAOASA-M CC1=CC=CC(C#CC2=C/C(=N/O[Rb])CCC2)=N1 Chemical compound CC1=CC=CC(C#CC2=C/C(=N/O[Rb])CCC2)=N1 KDGNSSNMCNPWHV-BACBYAOASA-M 0.000 description 1
- VCSWPWKLBYLMDC-FBMGVBCBSA-N CCO/N=C1/C=C(C#CC2=NC(C)=CC=C2)CCC1 Chemical compound CCO/N=C1/C=C(C#CC2=NC(C)=CC=C2)CCC1 VCSWPWKLBYLMDC-FBMGVBCBSA-N 0.000 description 1
- CNNZLFXCUQLKOB-BMRADRMJSA-N CO/N=C1/C=C(C#CC2=NC(C)=CC=C2)CCC1 Chemical compound CO/N=C1/C=C(C#CC2=NC(C)=CC=C2)CCC1 CNNZLFXCUQLKOB-BMRADRMJSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to novel pyridylacetylene derivatives, their preparation, their use as radiotracers/markers and compositions containing them.
- R is CH 3 , (CH 2 ) n I, (CH 2 ) n Br or (CH 2 ) n F, n being 1, 2, 3 or 4 in free base or acid addition salt form.
- R is 11 CH 3 , ( 3 H) 3 C, (CH 2 ) n 123 I, (CH 2 ) n 76 Br or (CH 2 ) n 18 F, n being 1,2, 3 or 4 in free base or acid addition salt form.
- the compounds can exist as pure stereoisomers or mixtures thereof.
- the invention provides a process for the production of the compounds of formula I and their salts, comprising the steps of
- R a is respectively 11 CH 3 or ( 3 H) 3 C, reacting the compound of formula II
- the reactions can be effected according to known methods, for example as described in the Examples.
- Acid addition salts may be produced from the free bases in known manner, and vice-versa.
- agents of the invention exhibit valuable properties as histopathological labeling agents, imaging agents and/or biomarkers, hereinafter “markers”, for the selective labeling of the metabotropic glutamate receptor subtype 5 (mGlu5 receptor).
- agents of the invention are useful as markers for labeling the central and peripheral mGlu5 receptors in vitro or in vivo (see Example 5-7).
- the agents of the invention are therefore useful, for instance, for determining the levels of receptor occupancy of a drug acting at the mGlu5 receptor, or diagnostic purposes for diseases resulting from an imbalance or dysfunction of mGlu5 receptors, and for monitoring the effectiveness of pharmacotherapies of such diseases.
- the present invention provides an agent of the invention for use as a marker for neuroimaging.
- the present invention provides a composition for labeling brain and peripheral nervous system structures involving mGlu5 receptors in vivo and in vitro comprising an agent of the invention.
- the present invention provides a method for labeling brain and peripheral nervous system structures involving mGlu5 receptors in vitro or in vivo, which comprises contacting brain tissue with an agent of the invention.
- the method of the invention may comprise a further step aimed at determining whether the agent of the invention labeled the target structure.
- Said further step may be effected by observing the target structure using positron emission tomography (PET) or single photon emission computed tomography (SPECT), or any device allowing detection of radioactive radiations.
- PET positron emission tomography
- SPECT single photon emission computed tomography
- Product purification is accomplished by reversed phase HPLC using a C-18 ⁇ -Bondapak column (7.8 ⁇ 300 mm) and a mobile phase consisting of CH 3 CN/0.1% H 3 PO 4 (70/30) at a flow rate of 5 ml/min.
- the retention time of the desired product is between 6 and 7 min.
- the starting materials are prepared as described hereafter:
- the title compound can be prepared by reacting 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime with [ 3 H]-Mel (0.5 equivalent) in the presence of K 2 CO 3 in DMF at 100° C. for 180 min, followed by a purification by reversed phase chromatography.
- the reaction mixture is purified through a tC-18 Sep-Pak cartridge, and the fractions containing the desired product are further purified by a semi-preparative reversed phase HPLC using a C18 Bondclone column (300 ⁇ 7.8 mm) and a mobile phase consisting of CH 3 CN/0.01 M H 3 PO 4 (70/30) at a flow rate of 4 ml/min.
- the fraction containing the product (retention time between 12 and 13 min) is passed through a tC-18 Sep-Pak cartridge and eluted with 1 ml of ethanol. This ethanolic solution is buffered with 0.15M phosphate buffer to give after sterile filtration an isotonic and injectable solution.
- Each animal received 250-300 pmol (0.6-40 MBq) of 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone O-[ 11 C-methyl]-oxime via a lateral tail vein.
- the animals are sacrificed 30 min post-injection. Organ or brain regions such as hippocampus, striatum, cortex and cerebellum are removed and measured in a gamma-counter. The tissue distribution is expressed as percentage of injected dose per gram wet tissue (% ID/g organ).
- K1, K2, K3 are individual values for control animals.
- B1, B2, B3 are individual values for animals co-injected with 2-methyl-6-((3-methoxyphenyl)ethynyl)-pyridine.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pyridine Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to novel pyridylacetylene derivatives, their preparation, their use as radiotracers/markers and compositions containing them.
Description
- The present invention relates to novel pyridylacetylene derivatives, their preparation, their use as radiotracers/markers and compositions containing them.
- More particularly the invention provides a compound of formula I
- wherein
- R is CH3, (CH2)nI, (CH2)nBr or (CH2)nF, n being 1, 2, 3 or 4 in free base or acid addition salt form.
- Compounds of the formula I are preferred, wherein
- R is 11CH3, (3H)3C, (CH2)n 123I, (CH2)n 76Br or (CH2)n 18F, n being 1,2, 3 or 4 in free base or acid addition salt form.
- In the case of possible stereoisomerism, e.g. cis/trans-isomerism of double bonds, the compounds can exist as pure stereoisomers or mixtures thereof.
- In a further aspect, the invention provides a process for the production of the compounds of formula I and their salts, comprising the steps of
-
- a) for the production of a compound of formula Ia
- wherein Ra is respectively 11CH3 or (3H)3C, reacting the compound of formula II
-
- with respectively 11CH3I or C(3H)3I, in the presence of a base, or
- b) for the production of a compound of formula Ib
-
- wherein Rb is respectively (CH2)n 18F, (CH2)n 123I or (CH2)n 76Br, reacting a compound of formula III
-
- wherein n is as defined above and X is OTs or OMs, with respectively 18F⊖, 123I⊖ or 76Br⊖, or reacting the compound of formula II with a compound of formula IV
-
X—Rb IV -
- wherein X and Rb are as defined above,
- and recovering the resulting compound of formula I in free base form or in form of an acid addition salt.
- The reactions can be effected according to known methods, for example as described in the Examples.
- Working up the reaction mixtures and purification of the compounds thus obtained may be carried out in accordance to known procedures.
- Acid addition salts may be produced from the free bases in known manner, and vice-versa.
- The starting materials of formulae II, III and IV are known or may be obtained in analogous manner to know procedures, e.g. as described in the Examples.
- Compounds of formula I in free base or acid addition salt form, hereinafter referred to as agents of the invention, exhibit valuable properties as histopathological labeling agents, imaging agents and/or biomarkers, hereinafter “markers”, for the selective labeling of the metabotropic glutamate receptor subtype 5 (mGlu5 receptor).
- More particularly the agents of the invention are useful as markers for labeling the central and peripheral mGlu5 receptors in vitro or in vivo (see Example 5-7).
- The agents of the invention are therefore useful, for instance, for determining the levels of receptor occupancy of a drug acting at the mGlu5 receptor, or diagnostic purposes for diseases resulting from an imbalance or dysfunction of mGlu5 receptors, and for monitoring the effectiveness of pharmacotherapies of such diseases.
- In accordance with the above, the present invention provides an agent of the invention for use as a marker for neuroimaging.
- In a further aspect, the present invention provides a composition for labeling brain and peripheral nervous system structures involving mGlu5 receptors in vivo and in vitro comprising an agent of the invention.
- In still a further aspect, the present invention provides a method for labeling brain and peripheral nervous system structures involving mGlu5 receptors in vitro or in vivo, which comprises contacting brain tissue with an agent of the invention.
- The method of the invention may comprise a further step aimed at determining whether the agent of the invention labeled the target structure. Said further step may be effected by observing the target structure using positron emission tomography (PET) or single photon emission computed tomography (SPECT), or any device allowing detection of radioactive radiations.
- The following examples illustrate the invention.
- 3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone O[11C-methyl]-oxime is synthesized by reacting [11C]-Mel with the sodium salt of 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime (1 mg) in dry DMF (400 μl). [11C]-Mel is introduced via a slow stream of helium and when addition is completed the reaction mixture is heated to 120° C. for 10 min. Product purification is accomplished by reversed phase HPLC using a C-18 μ-Bondapak column (7.8×300 mm) and a mobile phase consisting of CH3CN/0.1% H3PO4 (70/30) at a flow rate of 5 ml/min. The retention time of the desired product is between 6 and 7 min.
- 3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone O[11C-methyl]-oxime is formulated in a solution containing polysorbatum (2%), ethanol (10%) and saline (0.9%).
- LogD=2.5 (determined using the classical shake-flask method).
- The starting materials are prepared as described hereafter:
-
- a) 3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone
- A solution of 2-ethynyl-6-methyl-pyridine (702 mg, 6 mmol), 3-bromo-cyclohex-2-enone (1.26 g, 7.2 mmol), bis-(triphenylphosphine)-palladium-dichloride (168 mg, 0.24 mmol), copper(I) iodide (93 mg, 0.48 mmol), triethylamine (4.8 ml, 34.4 mmol) in 12ml DMF is heated to 55° C. for 1 h. After that time the solution is diluted with ethyl acetate (500 ml) and washed with sat aq. NaHCO3 (1×150 ml). The water phase is extracted with ethyl acetate (1×150 ml) and the combined organic phases are dried over Na2SO4, filtered and concentrated in vacuo. The residue (1.88 g) is purified on column chromatography (silica gel, eluent hexane/ethyl acetate 3:1 v/v) and the fractions containing the desired compound are collected and concentrated in vacuo to yield 1.05 g (yield=82%) of the title compound as a light yellow oil.
-
- b) 3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime
- A solution of 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone (422 mg, 2 mmol) and hydroxylamine hydrochloride (278 mg, 4 mmol) in pyridine (20 ml) is stirred for 17 h at RT. After that time the solvent is evaporated in vacuo. The residue is dissolved in ethyl acetate (300 ml) and washed with sat NaHCO3 (1×50 ml). The water phase is extracted with ethyl acetate (1×50 ml). The combined organic phases are dried over Na2SO4, filtered and concentrated in vacuo. The residue (0.45 g) is purified on column chromatography (Silica gel, eluent hexane/ethyl acetate 2:1 v/v) and the fractions containing the desired compound are collected and concentrated in vacuo to yield 0.192 g (yield=42%) of the title compound as light yellow crystals, m.p. 166-168° C.
- The title compound can be prepared by reacting 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime with [3H]-Mel (0.5 equivalent) in the presence of K2CO3 in DMF at 100° C. for 180 min, followed by a purification by reversed phase chromatography.
- The sodium salt of the 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime (2 mg) is reacted in dry DMF (400 μl) with [18F]-2-fluoro-ethyltosylate (obtained from ethyleneditosylate and [18F]-KF-Kryptofix complex) at 100° C. for 10 min. The reaction mixture is purified through a tC-18 Sep-Pak cartridge, and the fractions containing the desired product are further purified by a semi-preparative reversed phase HPLC using a C18 Bondclone column (300×7.8 mm) and a mobile phase consisting of CH3CN/0.01 M H3PO4 (70/30) at a flow rate of 4 ml/min. The fraction containing the product (retention time between 12 and 13 min) is passed through a tC-18 Sep-Pak cartridge and eluted with 1 ml of ethanol. This ethanolic solution is buffered with 0.15M phosphate buffer to give after sterile filtration an isotonic and injectable solution.
- The sodium salt of the 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime (2 mg) is reacted in dry DMF (400 μl) with [18F]CH2OTf at 100° C. for 30 min. After an initial purification by passing the reaction mixture through a tC-18 Sep-Pak cartridge, 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone O-[18F-fluoro]-methyl-oxime was finally purified by a semi-preparative reversed phase HPLC using a C18 Bondclone column (300×7.8 mm) and a mobile phase consisting of CH3CN/0.01M H3PO4 (70/30) at a flow rate of 4 ml/min. The product is formulated in analogy to 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone O-(2-[18F-fluoro]-ethyl)-oxime (example 3).
- In vitro, the affinity for the mGlu5 receptor is determined using a radioligand displacement technique as described by Gasparini et al, Biorg. Med. Chem. Lett. 2002, 12, 407-409. 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone O-methyl-oxime shows an IC50 of 8 nM (Hill coefficient 1.08; 95% confidence intervals: 6.0-10.0 nM) for the displacement of [3H]-2-methyl-6-((3-methoxyphenyl)ethynyl)-pyridine from membrane of L-tk cells stably expressing the human mGlu5 receptor (Daggett et al, Neuropharm. 1995, 34:871-886). Using the Cheng-Prusoff equation, a Ki of 4 nM is calculated (radioligand concentration used for the assay: 2 nM).
- Two groups of male adult Sprague-Dawley rats weighing 250-300 g are used for the biodistribution studies. The first group (n=3) serves as the control group and the second group (n=3) serves as the blockade group. Each animal received 250-300 pmol (0.6-40 MBq) of 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone O-[11C-methyl]-oxime via a lateral tail vein. The blockade group is co-injected with 2-methyl-6-((3-methoxyphenyl)ethynyl)-pyridine (1 mg/kg) whereas the control group (n=3) receives a corresponding volume of 0.9% NaCl. The animals are sacrificed 30 min post-injection. Organ or brain regions such as hippocampus, striatum, cortex and cerebellum are removed and measured in a gamma-counter. The tissue distribution is expressed as percentage of injected dose per gram wet tissue (% ID/g organ).
- The table below displays the percentage of the injected dose normalized per gram of tissue. K1, K2, K3 are individual values for control animals. B1, B2, B3 are individual values for animals co-injected with 2-methyl-6-((3-methoxyphenyl)ethynyl)-pyridine.
-
Organ K1 K2 K3 B1 B2 B3 Hippocampus 0.16154 0.25440 0.21264 0.05184 0.06195 0.05972 Striatum 0.22564 0.30685 0.28164 0.06495 0.07158 0.06487 Cortex 0.14849 0.18316 0.16909 0.04964 0.05582 0.05431 Cerebellum 0.03322 0.03925 0.03699 0.04052 0.03608 0.03421 Midbrain 0.07703 0.10559 0.09091 0.03876 0.04700 0.04422 Restbrain 0.05519 0.06520 0.06070 0.03832 0.04762 0.04383 Whole brain 0.11123 0.13659 0.12999 0.04580 0.05118 0.04951
Claims (15)
2. The compound of claim 1 , wherein R is 11CH3.
3. The compound of claim 1 , wherein R is (3H)3C.
4. The compound of claim 1 , wherein R is (CH2)123I.
5. The compound of claim 1 , wherein R is (CH2)2123I.
6. The compound of claim 1 , wherein R is (CH2)3123I.
7. The compound of claim 1 , wherein R is (CH2)4123I.
8. The compound of claim 1 , wherein R is (CH2)76Br.
9. The compound of claim 1 , wherein R is (CH2)276Br.
10. The compound of claim 1 , wherein R is (CH2)376Br.
11. The compound of claim 1 , wherein R is (CH2)476Br.
12. The compound of claim 1 , wherein R is (CH2)18F.
13. The compound of claim 1 , wherein R is (CH2)218F.
14. The compound of claim 1 , wherein R is (CH2)318F.
15. The compound of claim 1 , wherein R is (CH2)418F.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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US14/162,885 US20140142318A1 (en) | 2003-09-26 | 2014-01-24 | Pyridylacetylenes for use as radiotracers and imaging agents |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0322612.3A GB0322612D0 (en) | 2003-09-26 | 2003-09-26 | Organic compounds |
GB0322612.3 | 2003-09-26 | ||
PCT/EP2004/010743 WO2005030723A1 (en) | 2003-09-26 | 2004-09-24 | Pyridylacetylenes for use as radiotracers and imaging agents |
US10/573,162 US8674110B2 (en) | 2003-09-26 | 2004-09-24 | Pyridylacetylenes for use as radiotracers and imaging agents |
US14/162,885 US20140142318A1 (en) | 2003-09-26 | 2014-01-24 | Pyridylacetylenes for use as radiotracers and imaging agents |
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US10/573,162 Continuation US8674110B2 (en) | 2003-09-26 | 2004-09-24 | Pyridylacetylenes for use as radiotracers and imaging agents |
PCT/EP2004/010743 Continuation WO2005030723A1 (en) | 2003-09-26 | 2004-09-24 | Pyridylacetylenes for use as radiotracers and imaging agents |
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US14/162,885 Abandoned US20140142318A1 (en) | 2003-09-26 | 2014-01-24 | Pyridylacetylenes for use as radiotracers and imaging agents |
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US (2) | US8674110B2 (en) |
EP (1) | EP1670762B1 (en) |
JP (1) | JP4965255B2 (en) |
CN (1) | CN100430380C (en) |
AU (2) | AU2004275971B2 (en) |
BR (1) | BRPI0414732A (en) |
CA (1) | CA2539469C (en) |
ES (1) | ES2400713T3 (en) |
GB (1) | GB0322612D0 (en) |
MX (1) | MXPA06003424A (en) |
PL (1) | PL1670762T3 (en) |
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US8349852B2 (en) | 2009-01-13 | 2013-01-08 | Novartis Ag | Quinazolinone derivatives useful as vanilloid antagonists |
JP2013518085A (en) | 2010-02-01 | 2013-05-20 | ノバルティス アーゲー | Pyrazolo [5,1b] oxazole derivatives as CRF-1 receptor antagonists |
WO2011092293A2 (en) | 2010-02-01 | 2011-08-04 | Novartis Ag | Cyclohexyl amide derivatives as crf receptor antagonists |
ES2527849T3 (en) | 2010-02-02 | 2015-01-30 | Novartis Ag | Cyclohexylamide derivatives as CRF receptor antagonists |
WO2012004400A1 (en) * | 2010-07-09 | 2012-01-12 | Recordati Ireland Limited | Novel spiroheterocyclic compounds as mglu5 antagonists |
AR086554A1 (en) | 2011-05-27 | 2014-01-08 | Novartis Ag | DERIVATIVES OF PIPERIDINE 3-ESPIROCICLICA AS AGRONISTS OF GHRELINE RECEPTORS |
EP2852591A1 (en) | 2012-05-03 | 2015-04-01 | Novartis AG | L-malate salt of 2, 7 - diaza - spiro [4.5]dec- 7 - yle derivatives and crystalline forms thereof as ghrelin receptor agonists |
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US6843979B2 (en) | 1999-04-26 | 2005-01-18 | Emory University | 4-haloethenylphenyl tropane:serotonin transporter imaging agents |
AU767726B2 (en) | 1999-04-30 | 2003-11-20 | Pfizer Products Inc. | Radiotracers for in vivo study of acetylcholinesterase and Alzheimer's disease |
WO2001001621A2 (en) * | 1999-06-30 | 2001-01-04 | Sun Microsystems, Inc. | Customizing web content based on network conditions |
JP4815083B2 (en) * | 1999-08-31 | 2011-11-16 | メルク・シャープ・エンド・ドーム・コーポレイション | Heterocyclic compounds and methods of use thereof |
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JP4070431B2 (en) | 2001-07-10 | 2008-04-02 | ジーイー・ヘルスケア・リミテッド | Iodine-added neuroprobe for mapping monoamine reuptake sites |
US20070060618A1 (en) * | 2002-10-24 | 2007-03-15 | Merck & Co., Inc. | Alkyne derivatives as tracers for metabotropic glutamate receptor binding |
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CN1856468A (en) | 2006-11-01 |
CA2539469C (en) | 2012-06-19 |
ES2400713T3 (en) | 2013-04-11 |
PL1670762T3 (en) | 2013-05-31 |
PT1670762E (en) | 2013-02-07 |
GB0322612D0 (en) | 2003-10-29 |
EP1670762B1 (en) | 2012-12-05 |
JP4965255B2 (en) | 2012-07-04 |
MXPA06003424A (en) | 2006-06-20 |
AU2008261192A1 (en) | 2009-01-22 |
WO2005030723A1 (en) | 2005-04-07 |
AU2004275971A1 (en) | 2005-04-07 |
US20090010838A1 (en) | 2009-01-08 |
BRPI0414732A (en) | 2006-11-21 |
EP1670762A1 (en) | 2006-06-21 |
AU2008261192B2 (en) | 2011-08-04 |
US8674110B2 (en) | 2014-03-18 |
CN100430380C (en) | 2008-11-05 |
JP2007506698A (en) | 2007-03-22 |
AU2004275971B2 (en) | 2008-10-02 |
CA2539469A1 (en) | 2005-04-07 |
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