Optical imaging of rheumatoid arthritis

Abstract

The present invention concerns the use of indocarbocyanine dyes, in particular indotricarbocyanine dyes for the diagnosis of inflammatory diseases, in particular rheumatoid arthritis, methods of diagnosing inflammatory diseases and an apparatus useful to carry out the method of diagnosing.

1 . A method for the diagnosis of an inflammatory disease comprising
 (i) administering to a subject a diagnostically effective amount of
 (a) an indocarbocyanine dye of formula (I) 
   
       
         
           
           
               
               
           
         
         
           wherein C stands for a radical (II) or (III) 
         
       
       
         
           
           
               
               
           
         
         
           wherein the position that is labelled with the star means the point of linkage with radical A and wherein A stands for a group (IV), (V), (VI), (VII), or (VIII) 
         
       
       
         
           
           
               
               
           
         
         
           wherein 
           R 1  and R 2 , independently of one another, stand for a C 1 -C 4 -sulfoalkyl chain or a saturated or unsaturated, branched or straight-chain C 1 -C 50 -alkyl chain, which optionally is substituted by 0 to 15 oxygen atoms and/or by 0 to 3 carbonyl groups and/or with 0 to 5 hydroxyl groups or optionally interrupted by 0 to 15 oxygen atoms and/or by 0 to 3 carbonyl groups and/or can be substituted with 0 to 5 hydroxyl groups; 
           R 3  stands for a straight-chain carbohydrate chain with up to 20 carbon residues, which is substituted with one or more —OH, —COOH, —SO 3  groups and/or optionally interrupted one or more times by —O—, —S—, —CO—, —CS—, —CONH, —NHCO—, NHCSNH—, —SO 2 —, —PO 4   − —, -aryl- and/or —NH— group; 
           R 4  stands for the group —COOE 1 , —CONE 1 E 2 , —NHCOE 1 , —NHCONHE 1 , —NE 1 E 2 , —OE 1 , —OSO 3 E 1 , —SO 3 E 1 , —SO 2 NHE 1  or -E 1 , wherein
 E 1  and E 2 , independently of one another, stand for a hydrogen atom, a C 1 -C 4 -sulfoalkyl chain, a saturated or unsaturated, branched or straight-chain C 1 -C 50 -alkyl chain, which optionally is interrupted by 0 to 15 oxygen atoms and/or by 0 to 3 carbonyl groups and/or is substituted with 0 to 5 hydroxyl groups; 
 
           R 5  stands for a hydrogen atom, or a fluorine, chlorine, bromine or iodine atom, methyl, ethyl, propyl or iso-propyl; 
           b means the number 2 or 3; and 
           X and Y, independently of one another, stand for O, S, ═C(CH 3 ) 2  or —(CH═CH)—, or a salt or solvate of thereof or 
           (b) an indocarbocyanine dye which is Cy7, indocyanine green (ICG), an analog of ICG, or indotricarbocyanine (ITC), 
           (ii) exposing a region of the body to be imaged to light of a wavelength between 700 nm and 900 nm and 
           (iii) measuring fluorescence within 500 seconds after administration of said dye, 
           wherein no targeting moiety is attached to the dye (a) or (b). 
         
       
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . A method according to  claim 1 , wherein the inflammatory disease is arthritis, inflammatory bowel disease, septic shock, osteoporosis, neuropathic pain, viral infection, bacterial infection, insulin-dependent diabetes, non-insulin dependent diabetes, periodontal disease, restenosis, alopecia areta, psoriasis, acute pancreatitis, allograft rejection, allergies, allergic inflammation in the lung, atherosclerosis, multiple sclerosis, cachexia, Alzheimer's disease, stroke, Crohn's disease, ischemia, congestive heart failure, pulmonary fibrosis, hepatitis, Guillain-Barre Syndrome, or systemic lupus erythematosus. 
     
     
         6 . A method according to  claim 5 , wherein the arthritis is rheumatoid arthritis, osteoarthritis, psoriatic arthritis, traumatic arthritis, bacterial arthritis, post-infectious arthritis, lyme disease (Borreliose), ankylosing spondyliitis and or rubella arthritis. 
     
     
         7 . A method according to  claim 1 , wherein the indocarbocyanine dye is administered in an amount of 10 mg/kg body weight or less. 
     
     
         8 . A method of diagnosing an inflammatory disease comprising:
 (a) administering an indocarbocyanine dye, preferably by bolus injection   (b) exposing a region of the body to light of a wavelength between 700 nm and 900 nm   (c) measuring fluorescence in the region of the body at multiple time points which are less than 500 seconds after administration of said dye,   
       wherein the indocarbocyanine dye has the formula (I) 
       
         
           
           
               
               
           
         
         wherein C stands for a radical (II) or (III) 
       
       
         
           
           
               
               
           
         
         wherein the position that is labelled with the star means the point of linkage with radical A and wherein A stands for a group (IV), (V), (VI), (VII), or (VIII) 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2 , independently of one another, stand for a C 1 -C 4 -sulfoalkyl chain or a saturated or unsaturated, branched or straight-chain C 1 -C 50 -alkyl chain, which optionally is substituted by 0 to 15 oxygen atoms and/or by 0 to 3 carbonyl groups and/or with 0 to 5 hydroxyl groups or optionally interrupted by 0 to 15 oxygen atoms and/or by 0 to 3 carbonyl groups and/or can be substituted with 0 to 5 hydroxyl groups; 
         R 3  stands for a straight-chain carbohydrate chain with up to 20 carbon residues, which is substituted with one or more —OH, —COOH, —SO 3  groups and/or optionally interrupted one or more times by —O—, —S—, —CO—, —CS—, —CONH, —NHCO—, NHCSNH—, —SO 2 —, —PO 4   − —, -aryl- and/or —NH— group; 
         R 4  stands for the group —COOE 1 , —CONE 1 E 2 , —NHCOE 1 , —NHCONHE 1 , —NE 1 E 2 , —OE 1 , —OSO 3 E 1 , —SO 3 E 1 , —SO 2 NHE 1  or -E 1 , wherein
 E 1  and E 2 , independently of one another, stand for a hydrogen atom, a C 1 -C 4 -sulfoalkyl chain, a saturated or unsaturated, branched or straight-chain C 1 -C 50 -alkyl chain, which optionally is interrupted by 0 to 15 oxygen atoms and/or by 0 to 3 carbonyl groups and/or is substituted with 0 to 5 hydroxyl groups; 
 
         R 5  stands for a hydrogen atom, or a fluorine, chlorine, bromine or iodine atom, methyl, ethyl, propyl or iso-propyl; 
         b means the number 2 or 3; and 
         X and Y, independently of one another, stand for O, S, ═C(CH 3 ) 2  or —(CH═CH)—, or 
         wherein the indocarbocyanine dye is Cy7, indocyanine green (ICG), an analog of ICG, or indotricarbocyanine (ITC) 
         as well as a salt and solvate thereof 
         wherein no targeting moiety is attached to the dye. 
       
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . A method according to  claim 8 , wherein the inflammatory disease is arthritis, inflammatory bowel disease, septic shock, osteoporosis, neuropathic pain, viral infection, bacterial infection, insulin-dependent diabetes, non-insulin dependent diabetes, periodontal disease, restenosis, alopecia areta, psoriasis, acute pancreatitis, allograft rejection, allergies, allergic inflammation in the lung, atherosclerosis, multiple sclerosis, cachexia, Alzheimer's disease, stroke, Crohn's disease, inflammatory bowel disease, ischemia, congestive heart failure, pulmonary fibrosis, hepatitis, Guillain-Barre Syndrome, and or systemic lupus erythematosus. 
     
     
         12 . A method according to  claim 11 , wherein the arthritis is rheumatoid arthritis, osteoarthritis, psoriatic arthritis, traumatic arthritis, bacterial arthritis, post-infectious arthritis, lyme disease (Boneliose), ankylosing spondyliitis or rubella arthritis. 
     
     
         13 . A method according to  claim 8 , wherein the indocarbocyanine dye is administered in an amount of 10 mg/kg body weight or less. 
     
     
         14 . A method according to  claim 8 , wherein the indocarbocyanine dye is injected into the region of the body to be diagnosed or into a blood vessel or the lymphatic system, which provides blood or lymph to the region of the body to be diagnosed. 
     
     
         15 . A method according to  claim 14 , wherein the indocarbocyanine dye is injected into the vein of the arm. 
     
     
         16 . A method according to  claim 8 , wherein the light in step (b) is applied continuously amplitude modulated or pulsed. 
     
     
         17 . A method according to  claim 8 , wherein the light has a wavelength of between 600 nm and 2.2 μm. 
     
     
         18 . A method according to  claim 8 , wherein the fluorescence is measured at multiple time points at least for 20 s, 30 s, 40 s, 50 s, 60 s, or 120 s after administration of the indocarbocyanine. 
     
     
         19 . A method according to  claim 8 , wherein the fluorescence in the region of body is detected at each time point as one image and/or by scanning the region of the body. 
     
     
         20 . A method according to  claim 8 , wherein the fluorescence is detected in intervals of 5 s or less. 
     
     
         21 . A method according to  claim 8 , wherein a fluorescent standard is provided on or in the vicinity of the imaged body region to normalize the measured fluorescence. 
     
     
         22 . A method according to  claim 8 , wherein a computer program is used to determine a time resolved pattern of circulation, preferably a pattern of blood circulation within the region of the body. 
     
     
         23 . A method according to  claim 22 , wherein the pattern of blood circulation in a patient suspected of having an inflammatory disease is compared to the pattern of blood circulation in a healthy patient and wherein alterations of the pattern of blood circulation are indicative of disease. 
     
     
         24 . A method according to  claim 8 , wherein the region of the body is the hand, foot, knee, elbow, skin or shoulder. 
     
     
         25 . (canceled) 
     
     
         26 . A method according to  claim 8 , wherein the indocarbocyanine wavelength of excitation maximum differs from the wavelength of the fluorescence maximum by at least 10 nm. 
     
     
         27 . A device for carrying out a method of  claim 8 , wherein the light is a laser. 
     
     
         28 . A device according to  claim 27 , wherein the fluorescence is detected in a transmission and/or reflexion assembly. 
     
     
         29 . A device according to  claim 27 , wherein the device comprises a long pass filter, which suppresses the excitation wavelength by at least OD 7. 
     
     
         30 . A device according to  claim 27 , wherein the device is a camera, if a plane of the body region is irradiated or the device has a scanning spot detector, if spots of the body region are irradiated. 
     
     
         31 . A device according to  claim 27 , comprising a computer system capable of determining the change of the indocarbocyanine dye within the body region. 
     
     
         32 . A method according to  claim 7 , wherein the indocarbocyanine dye is administered in an amount of 1 mg/kg body weight or less. 
     
     
         33 . A method according to  claim 7 , wherein the indocarbocyanine dye is administered in an amount of 0.1 mg/kg body weight or less. 
     
     
         34 . A method according to  claim 33 , wherein the indocarbocyanine dye is administered in an amount of 1 mg/kg body weight or less. 
     
     
         35 . A method according to  claim 33 , wherein the indocarbocyanine dye is administered in an amount of 0.1 mg/kg body weight or less. 
     
     
         36 . A method according to  claim 1 , wherein an increase of fluorescence is detected within less than 300 seconds after administration of the indocarbocyanine dye. 
     
     
         37 . A method according to  claim 8 , wherein an increase of fluorescence is detected within less than 300 seconds after administration of the indocarbocyanine dye. 
     
     
         38 . A method of  claim 1 , for the diagnosis of arthritis, inflammatory bowel disease, septic shock, osteoporosis, neuropathic pain, viral infection, bacterial infection, insulin-dependent diabetes, non-insulin dependent diabetes, periodontal disease, restenosis, alopecia areta, psoriasis, acute pancreatitis, allograft rejection, allergies, allergic inflammation in the lung, atherosclerosis, multiple sclerosis, cachexia, Alzheimer's disease, stroke, Crohn's disease, ischemia, congestive heart failure, pulmonary fibrosis, hepatitis, Guillain-Barre Syndrome, or systemic lupus erythematosus comprising
 (i) administering to a subject a diagnostically effective amount of a dye which is Cy7, indocyanine green (ICG), an analog of ICG, or indotricarbocyanine (ITC) dye, wherein no targeting moiety is attached to the dye,   (ii) exposing a region of the body to be imaged to light of a wavelength between 700 nm and 900 nm, and   (ii) detecting an increase of fluorescence at the arthritic site at multiple time points less than 500 seconds after administration of said dye.   
     
     
         39 . A method according to claim38, wherein the arthritis is rheumatoid arthritis, osteoarthritis, psoriatic arthritis, traumatic arthritis, bacterial arthritis, post-infectious arthritis, lyme disease (Borreliose), ankylosing spondyliitis or rubella arthritis.