Method of detecting cyclooxygenase-2

Abstract

The invention relates to a method of detecting concentrations of cyclooxygenase-2 in a mammal, the method comprising: administering to the mammal a diagnostically effective amount of a cyclooxygenase-2 selective agent, which is capable of being detected in vivo; and b) detecting the agent so the concentration of cyclooxygenase-2 is detected.

What is claimed is:  
     
         1 . A method of detecting a concentration of cyclooxygenase-2 in a mammal, the method comprising: 
 a) administering to the mammal a diagnostically effective amount of a cyclooxygenase-2 selective agent, which is capable of being detected in vivo; and    b) detecting the agent so the concentration of cyclooxygenase-2 is detected.    
     
     
         2 . The method of    claim 1    wherein the agent is prepared by labeling a cyclooxygenase-2 selective compound with an isotope capable of being detected in vivo.  
     
     
         3 . The method of    claim 2    wherein the compound is selected from compounds of Formula I  
       
         
           
           
               
               
           
         
         wherein A is a ring substituent selected from partially unsaturated heterocyclyl, heteroaryl, cycloalkenyl and aryl;  
         wherein R 1  is at least one substituent selected from heteroaryl, cycloalkyl, cycloalkenyl and aryl, wherein R 1  is substituted with one or more radicals convertible to a detectable isotope;  
         wherein R 2  is methyl or amino; and  
         wherein R 3  is one or more radicals selected from hydrido, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclooxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclo, cycloalkenyl, aralkyl, heterocycloalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl; or a pharmaceutically-acceptable salt or prodrug thereof.  
       
     
     
         4 . The method of    claim 3    wherein A is a radical selected from thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl, benzindazolyl, benzopyranopyrazolyl, phenyl, and pyridyl; wherein R 1  is selected from 5- and 6-membered heteroaryl, and aryl selected from phenyl, biphenyl and naphthyl, wherein R 1  is substituted at a substitutable position with one or more radicals selected from hydroxy, alkoxy, nitro, triflate, halo, and formyl; wherein R 2  is methyl or amino; and wherein R 3  is a radical selected from hydrido, oxo, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, halo, lower alkyl, lower alkyloxy, lower cycloalkyl, phenyl, lower haloalkyl, 5- or 6-membered heterocyclo, lower hydroxylalkyl, lower aralkyl, acyl, phenylcarbonyl, lower alkoxyalkyl, 5- or 6-membered heteroaryloxy, aminocarbonyl, lower alkylaminocarbonyl, lower alkylamino, lower aminoalkyl, lower alkylaminoalkyl, phenyloxy, and lower aralkoxy; or a pharmaceutically-acceptable salt or prodrug thereof.  
     
     
         5 . The method of    claim 4    wherein A is selected from furyl, oxazolyl, isoxazolyl, imidazolyl, and pyrazolyl; wherein R 1  is phenyl substituted at a substitutable position with one or more radicals selected from hydroxy, nitro, triflate, halo, and formyl; wherein R 2  is methyl or amino; and wherein R 3  is a radical selected from hydrido, oxo, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl, carboxymethyl, carboxyethyl, cyanomethyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, cyclohexyl, phenyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, pyrazinyl, hydroxylmethyl, hydroxylpropyl, benzyl, formyl, phenylcarbonyl, methoxymethyl, furylmethyloxy, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, aminomethyl, N,N-dimethylaminomethyl, N-methyl-N-ethylaminomethyl, benzyloxy, and phenyloxy; or a pharmaceutically-acceptable salt or prodrug thereof.  
     
     
         6 . The method of    claim 5    wherein the agent is selected from compounds, and pharmaceutically acceptable salts and prodrug thereof, of the group consisting of 
 4-[3-(hydroxymethyl)-5-(4-nitrophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[3-(difluoromethyl)-5-(4-hydroxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[5-(4-hydroxyphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[3-(hydroxymethyl)-5-(4-hydroxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-hydroxy-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;  
 4-[2-(4-hydroxypyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;  
 4-[5-methyl-3-(4-hydroxyphenyl)isoxazol-4-yl]benzenesulfonamide;  
 4-[5-hydroxymethyl-3-(4-hydroxyphenyl)isoxazol-4-yl]benzenesulfonamide;  
 4-[2-methyl-4-(4-hydroxyphenyl)-5-oxazolyl]benzenesulfonamide;  
 4-[5-(4-hydroxyphenyl)-2-(trifluoromethyl)-4-oxazolyl]benzenesulfonamide;  
 4-[3-(difluoromethyl)-5-(3-iodo-4-hydroxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[5-(3-iodo-4-hydroxyphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[3-(hydroxymethyl)-5-(3-iodo-4-hydroxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[3-(difluoromethyl)-5-(4-nitrophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[5-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[3-(difluoromethyl)-5-(4-nitrophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-nitro-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;  
 4-[2-(4-nitropyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;  
 4-[5-methyl-3-(4-nitrophenyl)isoxazol-4-yl]benzenesulfonamide;  
 4-[5-hydroxymethyl-3-(4-nitrophenyl)isoxazol-4-yl]benzenesulfonamide;  
 4-[2-methyl-4-(4-nitrophenyl)-5-oxazolyl]benzenesulfonamide; and  
 4-[5-(4-nitrophenyl)-2-(trifluoromethyl)-4-oxazolyl]benzenesulfonamide.  
 
     
     
         7 . The method of    claim 2   , wherein the isotope is capable of being detected by PET.  
     
     
         8 . The method of    claim 7   , wherein the compound is labeled with one or more isotopes selected from  11 C,  123 I,  73 Se,  76 Br,  77 Br, and  18 F.  
     
     
         9 . The method of    claim 7   , wherein the compound is labeled with  11 C or  18 F.  
     
     
         10 . The method of    claim 1    wherein the detected cyclooxygenase-2 is associated with a condition selected from inflammation, arthritis, neoplasia and central nervous system disorders.  
     
     
         11 . The method of    claim 1    wherein the agent is selected from compounds, and pharmaceutically acceptable salts thereof, of the group consisting of 
 4-[3-(hydroxymethyl)-5-[4-( 18 F)fluorophenyl]-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[3-(difluoromethyl)-5-[4-( 11 C)methoxyphenyl]-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[5-[4-( 11 C)methoxyphenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[3-(hydroxymethyl)-5-[4-( 11 C)methoxyphenyl]-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-( 11 C)methoxy-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;  
 4-[2-[4-( 11 C)methoxypyridin-3-yl]-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;  
 4-[5-methyl-3-[4-( 11 C)methoxyphenyl]isoxazol-4-yl]benzenesulfonamide;  
 4-[5-hydroxymethyl-3-[4-( 11 C)methoxyphenyl]isoxazol-4-yl]benzenesulfonamide;  
 4-[2-methyl-4-[4-( 11 C)methoxyphenyl]-5-oxazolyl]benzenesulfonamide;  
 4-[5-[4-( 11 C)methoxyphenyl]-2-(trifluoromethyl)-4-oxazolyl]benzenesulfonamide;  
 4-[3-(difluoromethyl)-5-[3-( 125 I) iodo-4-( 11 C)methoxyphenyl]-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[5-[3-( 125 I)iodo-4-( 11 C)methoxyphenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[3-(hydroxymethyl)-5-[3-( 125 I)iodo-4-( 11 C)methoxyphenyl]-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[3-(difluoromethyl)-5-[4-( 18 F)fluorophenyl]-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[5-[4-( 18 F)fluorophenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-[3-(difluoromethyl)-5-[4-( 18 F)fluorophenyl]-1H-pyrazol-1-yl]benzenesulfonamide;  
 4-( 18 F)fluoro-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;  
 4-[2-(4-( 18 F)fluoropyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;  
 4-[5-methyl-3-[4-( 18 F)fluorophenyl]isoxazol-4-yl]benzenesulfonamide;  
 4-[5-hydroxymethyl-3-[4-( 18 F)fluorophenyl]isoxazol-4-yl]benzenesulfonamide;  
 4-[2-methyl-4-[4-( 18 F)fluorophenyl]-5-oxazolyl]benzenesulfonamide; and  
 4-[5-[4-( 18 F)fluorophenyl]-2-(trifluoromethyl)-4-oxazolyl]benzenesulfonamide.  
 
     
     
         12 . A method of localizing and quantifying cyclooxygenase-2 in a mammal, said method comprising 
 a) preparing a labeled compound, which selectively binds to cyclooxygenase-2 and which contains an isotope capable of emitting radiation;    b) administering to said mammal a diagnostically effective amount of the labeled compound; and    c) detecting an emission from the compound administered to the mammal so that the cyclooxygenase-2 in the mammal is localized.    
     
     
         13 . The method of    claim 12    wherein the emission is detected by an technique selected from MRI, SPECT and PET.  
     
     
         14 . The method of    claim 13    wherein the emission is detected by PET.  
     
     
         15 . The method of    claim 12    wherein the isotope is capable of emitting gamma or positron radiation.  
     
     
         16 . The method of    claim 15    wherein the isotope is selected from isotopes of carbon, oxygen, nitrogen, selenium, bromine, iodine and fluorine.  
     
     
         17 . The method of    claim 16   , wherein the compound is labeled with one or more isotopes selected from  11 C,  123 I,  73 Se,  76 Br,  77 Br, and  18 F.  
     
     
         18 . The method of    claim 17    wherein the isotope is  18 F or  11 C.  
     
     
         19 . A method of preparing a labeled cyclooxygenase-2 inhibitor, said method comprising halide exchange of a nitro radical or alkylation of alcohols  
     
     
         20 . A method of detecting neoplasia in a mammal, said method comprising a) preparing a compound which selectively binds to cyclooxygenase-2 and which is labeled with an isotope capable of emitting gamma or positron radiation b) administering to said mammal a diagnostically effective amount of the labeled compound; and c) detecting an emission from the compound administered to the mammal so that the neoplasia in the mammal is localized.  
     
     
         21 . The method of    claim 20   , wherein the compound is labeled with one or more isotopes selected from  11 C,  123 I,  73 Se,  76 Br,  77 Br, and  18 F.  
     
     
         22 . A method of localizing and quantifying cyclooxygenase-2 in a mammal, the method comprising: 
 a) preparing a compound which selectively binds to cyclooxygenase-2 and which is labeled with an isotope capable of emitting gamma radiation;    b) administering to said mammal a diagnostically effective amount of the labeled compound; and    c) detecting the gamma emission from the compound administered to the mammal so that the cyclooxygenase-2 in the mammal is localized.    
     
     
         23 . The method of    claim 22   , wherein the compound is labeled with one or more isotopes selected from  125 I.  
     
     
         24 . The method of    claim 23    wherein the cyclooxygenase-2 concentration is associated with a condition selected from inflammation, arthritis, neoplasia and central nervous system disorders.  
     
     
         25 . A pharmaceutical composition for detecting a concentration of cyclooxygenase-2 comprising a pharmaceutically-acceptable carrier and optimally, at least one pharmaceutically-acceptable adjuvant; and an active substance comprising a diagnostically-effective amount of a compound which is capable of being detected in vivo.  
     
     
         26 . A pharmaceutical composition for detecting a concentration of cyclooxygenase-2 comprising a pharmaceutically-acceptable carrier and optimally, at least one pharmaceutically-acceptable adjuvant; and an active substance comprising a diagnostically-effective amount of a compound which is labeled with an isotope capable of emitting gamma or positron radiation.