Non-invasive diagnostic agents and methods of diagnosing infectious disease

Abstract

The present invention is directed to novel non-invasive diagnostic tools to diagnose numerous infectious disease states or conditions. The present invention represents a clear advance in the art which presently relies on tissue biopsy for diagnoses of these disease states. The novel imaging probe is capable of detecting infected cells, as well tissue. This represents a quantum step forward in the diagnosis and staging of NHL using non-invasively molecular imaging techniques. This novel probe will also be useful to monitor patients response to therapeutic treatments and other interventions or therapies used in the treatment of these disease states or conditions. Compounds according to the present invention may be used as diagnostic tools for a number of conditions and diseases states as well as therapeutic agents for treating such conditions and disease states. Pharmaceutical compositions are also described.

1 .- 72 . (canceled) 
     
     
         73 . A method of diagnosing the existence of a disease which is mediated through ICAM-1/LFA-1 receptors in tissue of a patient in which levels of said receptors are suspected of being elevated comprising administering to said patient an effective amount of at least one compound according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
       where Y is a chemical linker which links the nitrogen to a chelate group or a tricarbonyl complex X, wherein X incorporates or complexes with a radioisotope, or a pharmaceutically acceptable salt thereof, measuring the amount of said compound which binds to said tissue in said patient, and comparing said measurement from said measuring step with a standard, wherein an elevated measurement in comparison to said standard is indicative of the existence of said disease in said patient and said disease is a cardiovascular disease, atherosclerosis, ischemia, infarct or a cerebrovascular accident. 
     
     
         74 . The method according to  claim 73  wherein said ischemia or infarct is stroke, cerebrovascular ischemia, cerebrovascular infarct, myocardial ischemia or infarct. 
     
     
         75 . The method according to  claim 73  wherein said disease is cardiovascular ischemia, coronary atherosclerosis, angina or heart failure. 
     
     
         76 . The method according to  claim 73  wherein said disease is atherosclerosis or cardiovascular ischemia. 
     
     
         77 . The method according to  claim 73  wherein said atherosclerosis is coronary atherosclerosis. 
     
     
         78 . The method according to  claim 73  wherein X incorporates a radioisotope selected from the group consisting of  90 Y,  111 In,  177 Lu,  225 Ac,  213 Bi,  67 Ga,  68 Ga,  64 Cu,  67 Cu,  71 As,  72 As,  76 As,  77 As,  65 Zn,  76 Br,  48 V,  49 V,  203 Pb,  209 Pb,  212 Pb,  166 Ho,  153 Pm.  201 Tl,  188 Re,  186 Re,  99m Tc or a mixture thereof. 
     
     
         79 . The method according to  claim 73  wherein Y is a —(CH 2 ) n Z— group where n is 4, Z is a NR group and R is H, and which group links the nitrogen of said NR group to a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) group and wherein said DOTA group incorporates or complexes with a radioisotope selected from the group consisting of  90 Y,  111 In,  177 Lu,  67 Ga,  68 Ga, and  213 Bi, or a pharmaceutically acceptable salt thereof. 
     
     
         80 . The method according to  claim 79  wherein said radioisotope is  90 Y,  213 Bi,  177 Lu or  111 In. 
     
     
         81 . The method according to  claim 79  wherein said radioisotope is  213 Bi,  90 Y,  177 Lu or  111 In. 
     
     
         82 . The method according to  claim 79  wherein said radioisotope is  213 Bi. 
     
     
         83 . A method of monitoring the treatment of a ICAM-1/LFA-1 mediated disease in tissue or inflamed tissues of a patient comprising administering to said patient undergoing a course of treatment for said disease an effective amount of at least one compound according to the chemical structure: 
       
         
           
           
               
               
           
         
       
       where Y is a chemical linker which links the nitrogen to a chelate group or tricarbonyl complex X, wherein X incorporates or complexes with a radioisotope, or
 a pharmaceutically acceptable salt thereof; 
 measuring the amount of said compound which binds to said tissue in said patient at two different times or more during treatment; and comparing the measurements obtained in said measuring step at said different times with a standard from uninfected tissue and/or infected tissue, wherein said measurements obtained from said patient are compared to said standard(s) and optionally, to each other, such that said comparison is indicative of the progress or absence of progress in the treatment of said disease, wherein said disease is a cardiovascular disease, atherosclerosis, ischemia, infarct or a cerebrovascular accident. 
 
     
     
         84 . The method according to  claim 83  wherein said ischemia or infarct is stroke, cerebrovascular ischemia, cerebrovascular infarct, myocardial ischemia or infarct. 
     
     
         85 . The method according to  claim 83  wherein said disease is cardiovascular ischemia, coronary atherosclerosis, angina or heart failure. 
     
     
         86 . The method according to  claim 83  wherein said disease is atherosclerosis or cardiovascular ischemia. 
     
     
         87 . The method according to  claim 83  wherein said atherosclerosis is coronary atherosclerosis. 
     
     
         88 . The method according to  claim 83  wherein X incorporates a radioisotope selected from the group consisting of  90 Y,  111 In,  177 Lu,  225 Ac,  213 Bi,  67 Ga,  68 Ga,  64 Cu,  67 Cu,  71 As,  72 As,  76 As,  77 As,  65 Zn,  76 Br,  48 V,  49 V,  203 Pb,  209 Pb,  212 Pb,  166 Ho,  153  Pm.  201 Tl,  188 Re,  186 Re,  99m Tc or a mixture thereof. 
     
     
         89 . The method according to  claim 83  wherein Y is a —(CH 2 ) n Z— group where n is 4, Z is a NR group and R is H, and which group links the nitrogen of said NR group to a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) group and wherein said DOTA group incorporates or complexes with a radioisotope selected from the group consisting of  90 Y,  177 In,  177 Lu,  67 Ga,  68 Ga, and  213 Bi, or a pharmaceutically acceptable salt thereof. 
     
     
         90 . The method according to  claim 89  wherein said radioisotope is  90 Y,  177 Lu,  213 Bi,  177 Lu or  111 In. 
     
     
         91 . The method according to  claim 89  wherein said radioisotope is  213 Bi,  90 , or  177 Lu. 
     
     
         92 . The method according to  claim 89  wherein said radioisotope is  213 Bi. 
     
     
         93 . A method of treating and monitoring an ICAM-1/LFA-1 mediated disease in tissue or inflamed tissues of a patient comprising treating said disease in said patient and during said treating of said disease, administering to said patient an effective amount of at least one compound according to the chemical structure: 
       
         
           
           
               
               
           
         
       
       where Y is a chemical linker which links the nitrogen to a chelate group or tricarbonyl complex X, wherein X incorporates or complexes with a radioisotope, or
 a pharmaceutically acceptable salt thereof; and 
 measuring the amount of said compound which binds to said tissue in said patient at different times during said treatment and comparing the measurements obtained in said measuring step at said different times with a standard from infected tissue, wherein said measurements obtained from said patient are compared to said standard(s) and optionally, to each other, such that said comparison is indicative of the progress or absence of progress in the treatment of said disease, wherein said wherein said disease is a cardiovascular disease, atherosclerosis, ischemia, infarct or a cerebrovascular accident. 
 
     
     
         94 . The method according to  claim 93  wherein said ischemia or infarct is stroke, cerebrovascular ischemia, cerebrovascular infarct, myocardial ischemia or infarct. 
     
     
         95 . The method according to  claim 93  wherein said disease is cardiovascular ischemia, coronary atherosclerosis, angina or heart failure. 
     
     
         96 . The method according to  claim 93  wherein said disease is atherosclerosis or cardiovascular ischemia. 
     
     
         97 . The method according to  claim 93  wherein said atherosclerosis is coronary atherosclerosis. 
     
     
         98 . The method according to  claim 93  wherein X incorporates a radioisotope selected from the group consisting of  90 Y,  111 In,  177 Lu,  225 Ac,  213 Bi,  67 Ga,  68 Ga,  64 Cu,  67 Cu,  71 As,  72 As,  76 As,  77 As,  65 Zn,  76 Br,  48 V,  49 V,  203 Pb,  209 Pb,  212 Pb,  166 Ho,  153 Pm.  201 Tl,  188 Re,  186 Re,  99m Tc or a mixture thereof. 
     
     
         99 . The method according to  claim 93  wherein Y is a —(CH 2 ) n Z— group where n is 4, Z is a NR group and R is H, and which group links the nitrogen of said NR group to a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) group and wherein said DOTA group incorporates or complexes with a radioisotope selected from the group consisting of  90 Y,  111 In,  177 Lu,  67 Ga,  68 Ga, and  213 Bi, or a pharmaceutically acceptable salt thereof. 
     
     
         100 . The method according to  claim 99  wherein said radioisotope is  90 Y,  177 Lu,  213 Bi,  177 Lu or  111 In. 
     
     
         101 . The method according to  claim 89  wherein said radioisotope is  213 Bi,  90 Y, Or  177 Lu. 
     
     
         102 . The method according to  claim 89  wherein said radioisotope is  213 Bi. 
     
     
         103 . The method according to  claim 91  wherein said therapy is modified after said monitoring.