Hsp90-targeted inflammation and infection imaging and therapy

Abstract

The present invention provides new methods for inflammation and infection imaging and related medical applications thereof. In some embodiments, the present invention provides a method for the diagnosis of inflammation and/or infection. In some embodiments, the present invention provides a method for the treatment or prevention of inflammation and/or infection. In some embodiments, the present invention provides methods for monitoring the effect of inflammation and/or infection treatment, and/or methods for monitoring an inflammation and/or infection treatment regimen. In some embodiments, the present invention provides a method for selecting subjects for an inflammation and/or infection treatment. In some embodiments, the present invention provides a method for determining the dosage of a drug for the treatment of inflammation and/or infection.

What is claimed is: 
     
         1 . A method of imaging a tissue affected by an inflammation and/or infection in a subject in need thereof, comprising steps of:
 (a) administering to the subject a labeled compound that binds to Hsp90; and   (b) imaging the tissue by detecting the labeled compound in the subject.   
     
     
         2 . A method of imaging a tissue affected by an inflammation and/or infection in a subject in need thereof, comprising steps of:
 (a) administering to the subject a labeled compound of any of formula I to IX as described in the specification; and   (b) imaging the tissue by detecting the labeled compound in the subject.   
     
     
         3 . The method of any one of the preceding claims, further comprising detecting the presence of the inflammation and/or infection in the tissue by analyzing an image obtained in step (b). 
     
     
         4 . The method of any one of the preceding claims, wherein the labeled compound is a labeled compound of formula I: 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salt thereof, wherein: 
         each Y is independently CH or N; 
         R is hydrogen, a C 1  to C 10  alkyl, alkenyl, alkynyl, or an alkoxyalkyl group, optionally comprising one or more heteroatoms, or a targeting moiety connected to N9 via a linker;
 X 4  is hydrogen or halogen; 
 X 3  is CH 2 , CF 2 , S, SO, SO 2 , O, NH, or NR 2 , wherein R 2  is alkyl; 
 X 2  is halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido, dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, C(O)O-alkyl, NH 2 , OH, CN, SO 2 X 5 , NO 2 , NO, C(S)R, NHSO 2 X 5 , or C(O)R, where X 5  is F, NH 2 , alkyl, or H, and R 2  is alkyl, NH 2 , NH-alkyl, or O-alkyl; and 
 X 1  represents two substituents, which may be the same or different, disposed in the 4′ and 5′ positions on the aryl group, wherein X 1  is selected from halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido, dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, COO-alkyl, NH 2 OH, CN, SO 2 X 5 , NO 2 , NO, C(S)R, NHSO 2 X 5 , or C(O)R, where X 5  is F, NH 2 , alkyl, or H, and R 2  is alkyl, NH 2 , NH-alkyl, or O-alkyl, C 1  to C 6  alkyl or alkoxy, or wherein X 1  has the formula —O—(CH 2 )—O—, wherein n is an integer from 1 to 2, and one of the oxygens is bonded at the 5′-position and the other at the 4′-position of the aryl ring 
 
       
       wherein each hydrogen is optionally and independently substituted with a group that can be detected by a medical imaging technique, and/or at least one atom in the compound is optionally enriched in an isotope that can be detected by a medical imaging technique. 
     
     
         5 . The method of any one of the preceding claims, wherein the labeled compound is labeled through substituting at least one hydrogen atom in the compound with at least one group that produces higher signal intensity than the at least one hydrogen atom. 
     
     
         6 . The method of any one of the preceding claims, wherein at least one atom in the labeled compound is enriched in an isotope that can be detected by a medical imaging technique. 
     
     
         7 . The method of any one of the preceding claims, wherein the labeled compound binds to one or more isoforms of Hsp90. 
     
     
         8 . The method of any one of the preceding claims, wherein the labeled compound binds to a stress-specific form of Hsp90. 
     
     
         9 . The method of any one of the preceding claims, wherein the labeled compound binds to a stress-specific form of Hsp90 selectively over a housekeeping form of Hsp90. 
     
     
         10 . The method of  claim 9 , wherein a ratio of binding stress-specific Hsp90 to a housekeeping form of Hsp90 of about 1.5 or greater indicates that an inflammation/infection subject will be susceptible to Hsp90 inhibition therapy. 
     
     
         11 . The method of any one of the preceding claims, wherein the labeled compound has a K D  of less than about 1 mM, about 100 μM, about 10 μM, or about 1 μM. 
     
     
         12 . The method of any one of the preceding claims, wherein the labeled compound inhibits Hsp90. 
     
     
         13 . The method of  claim 12 , wherein the labeled compound has an IC 50  of less than about 1 mM, about 100 μM, about 10 μM, or about 1 μM. 
     
     
         14 . The method of any one of the preceding claims, wherein the imaging process comprises tomography. 
     
     
         15 . The method of  claim 14 , wherein the imaging process comprises positron emission tomography (PET). 
     
     
         16 . The method of  claim 15 , wherein PET is combined with another imaging technique. 
     
     
         17 . The method of  claim 15 , wherein PET is combined with X-ray Computed Tomography (CT), Magnetic Resonance Imaging (MRT), or single-photon emission computed tomography (SPECT). 
     
     
         18 . The method of  claim 14 , wherein the imaging process comprises single-photon emission computed tomography (SPECT). 
     
     
         19 . The method of any one of the preceding claims, further comprising collecting electrocardiography (ECG) data. 
     
     
         20 . The method of  claim 19 , wherein ECG data are collected prior to, concurrent with, and/or subsequent to the imaging process. 
     
     
         21 . The method of  claim 20 , comprising collecting ECG data during the imaging process. 
     
     
         22 . The method of any one of the preceding claims, wherein the step of imaging comprises imaging by multiple modalities. 
     
     
         23 . The method of any one of the preceding claims, wherein detecting the labeled compound in the subject comprises measuring signal intensity from the lung of the subject. 
     
     
         24 . The method of any one of the preceding claims, wherein detecting the labeled compound in the subject comprises measuring signal intensity from the colon of the subject. 
     
     
         25 . The method of any one of the preceding claims, wherein detecting the labeled compound in the subject comprises measuring signal intensity from the skin of the subject. 
     
     
         26 . The method of any one of the preceding claims, wherein detecting the labeled compound in the subject comprises measuring signal intensity from the macrophages of the subject. 
     
     
         27 . The method of any one of the preceding claims, wherein detecting the labeled compound in the subject comprises measuring signal intensity from the stroma of the subject. 
     
     
         28 . The method of any one of the preceding claims, wherein detecting the labeled compound in the subject comprises measuring signal intensity from the cardiac tissue of the subject. 
     
     
         29 . The method of any one of the preceding claims, wherein the inflammation and/or infection is associated with Hsp90. 
     
     
         30 . The method of any one of the preceding claims, wherein the inflammation and/or infection is associated with stress-specific Hsp90. 
     
     
         31 . The method of any one of the preceding claims, wherein the labeled compound is administered before, during, or after administration of a non-radioactive therapeutic compound. 
     
     
         32 . The method of any one of the preceding claims, wherein the labeled compound has a physical half-life of at least about 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48, 72, 96, or 100.3 hours. 
     
     
         33 . The method of any one of the preceding claims, wherein the imaging measures the accessibility of Hsp90 in the tissue affected by the inflammation and/or infection to a therapeutic compound. 
     
     
         34 . The method of any one of the preceding claims, wherein the imaging measures the concentrations of a labeled and/or non-labeled therapeutic compound in the tissue affected by the inflammation and/or infection. 
     
     
         35 . The method of  claim 34 , wherein the imaging measures the concentration of non-labeled therapeutic compound by use of a radiotracer amount of labeled compound. 
     
     
         36 . The method of  claim 34 , wherein the imaging measures tissue concentrations of radioactivity for labeled-compound administered at a therapeutically effective amount. 
     
     
         37 . The method of any one of the preceding claims, wherein the imaging measures the occupancy or saturation of Hsp90 by a therapeutic compound in the tissue affected by the inflammation and/or infection, or the ability of a therapeutic compound to displace the labeled compound in the tissue affected by the inflammation and/or infection. 
     
     
         38 . A method for the treatment of a tissue affected by, or prevention of an tissue from, an inflammation and/or infection, comprising steps of
 (a) administering a labeled compound of any of formula I to IX to a subject in need thereof, and   (b) imaging the tissue by detecting the labeled compound in the subject.   
     
     
         39 . A method for the treatment of a tissue affected by, or prevention of an tissue from, an inflammation and/or infection, comprising the step of administering a labeled compound of any of formula I to IX to a subject in need thereof. 
     
     
         40 . A method for the treatment of a tissue affected by, or prevention of an tissue from, an inflammation and/or infection, comprising the step of administering a non-radioactive therapeutic compound of formula X. 
     
     
         41 . A method for monitoring the effect of an inflammation and/or infection treatment in a subject in need thereof, comprising steps of:
 (a) administering a labeled compound of any of formula I to IX to the subject who is scheduled for the inflammation and/or infection treatment, currently undergoing the inflammation and/or infection treatment, or has completed or discontinued the inflammation and/or infection treatment;   (b) imaging a tissue affected by the inflammation and/or infection by detecting the labeled compound; and   (c) recommending to the subject an appropriate avoidance, continuation, modification, or termination in the inflammation and/or infection treatment.   
     
     
         42 . A method for monitoring an inflammation and/or infection treatment regimen, comprising steps of:
 (a) administering a labeled compound of any of formula I to IX to a subject under the inflammation and/or infection treatment regimen;   (b) imaging a tissue affected by the inflammation and/or infection by detecting the labeled compound in the subject;   (c) analyzing the images from step (b); and   (d) maintaining, modifying, or discontinuing the inflammation and/or infection treatment regimen.   
     
     
         43 . A method for selecting subjects for an inflammation and/or infection treatment, comprising steps of:
 (a) administering a labeled compound of any of formula I to IX to a subject;   (b) imaging a tissue affected by the inflammation and/or infection by detecting the labeled compound in the subject;   (c) analyzing the images from step (b); and   (d) including or excluding the subject for the treatment.   
     
     
         44 . A method for selecting subjects for an inflammation and/or infection treatment, comprising steps of:
 (a) administering to a subject a labeled compound that binds to stress-specific Hsp90; and   (b) imaging a tissue affected by the inflammation and/or infection by detecting the labeled compound in the subject;   
       wherein increased uptake of the labeled compound indicates more likelihood for the subject to benefit from the treatment. 
     
     
         45 . The method of  claim 44 , wherein the treatment comprises the use of a compound that binds to Hsp90. 
     
     
         46 . The method of  claim 45 , wherein the treatment comprises the use of a compound that binds to stress-specific Hsp90. 
     
     
         47 . The method of any one of  claims 38 ,  39 , or  41 - 44 , wherein the treatment comprises the use of the non-labeled counterpart of the labeled compound. 
     
     
         48 . The method of  claim 47 , wherein the non-labeled counterpart is of formula X. 
     
     
         49 . The method of  claim 47 , wherein the non-labeled counterpart is compound A: 
       
         
           
           
               
               
           
         
       
     
     
         50 . The method of any one of  claims 40  or  47 - 49 , where the method further comprises a standard of care treatment of the inflammation or infection. 
     
     
         51 . The method of any one of  claims 47 - 49 , wherein the method further comprises co-administration of anti-inflammatory agents, antihistamines, immunosuppressive agents, anti-viral agents, anti-fungal agents, antibacterial agents, anti-parasitic agents, or a combination thereof. 
     
     
         52 . A method for determining the dosage of a drug for the treatment of an inflammation and/or infection, comprising steps of:
 (a) administering a labeled compound of any of formula I to IX to a subject;   (b) imaging a tissue affected by the inflammation and/or infection by detecting the labeled compound in the subject;   (c) analyzing the images from step (b); and   (d) administering to the subject a suitable amount of the drug.   
     
     
         53 . The method of  claim 52 , further comprising administering a non-radioactive therapeutic amount of a compound that binds to Hsp90. 
     
     
         54 . The method of  claim 53 , wherein analyzing the images in step (c) is done with comparison to images obtained when administering only the labeled compound. 
     
     
         55 . The method of  claim 52  or  53 , wherein the labeled compound is administered before, during, or after administration of a non-radioactive therapeutic compound. 
     
     
         56 . The method of  claim 52 , wherein the drug is a therapeutic compound that binds to Hsp90. 
     
     
         57 . The method of any one of the preceding claims, wherein the labeled compound is a labeled compound having the structure of:
 wherein Y′ is —CH 2 — or S;   X 4  is hydrogen or halogen; and R is an amino alkyl moiety, optionally substituted on the amino nitrogen with one or two carbon-containing substituents selected independently from the group consisting of alkyl, alkenyl and alkynyl substituents, wherein the total number of carbons in the amino alkyl moiety is from 1 to 9.   
     
     
         58 . The method of any one of the preceding claims, wherein the labeled compound is labeled compound A: 
       
         
           
           
               
               
           
         
       
     
     
         59 . The method of  claim 58 , wherein compound A is labeled at 2′-iodo. 
       
         
           
           
               
               
           
         
       
     
     
         60 . The method of  claim 58 , wherein compound A is labeled through substituting a hydrogen atom with a group that can be detected by a medical imaging technique. 
     
     
         61 . The method of any one of the preceding claims, wherein the labeled compound is radiolabelled. 
     
     
         62 . The method of any one of the preceding claims, wherein the labeled compound comprises an isotope which decays by positron emission. 
     
     
         63 . The method of any one of the preceding claims, wherein the labeled compound comprises an isotope selected from  124 I,  11 C,  15 O,  13 N, and  18 F. 
     
     
         64 . The method of any one of the preceding claims, wherein the labeled compound comprises  124 I. 
     
     
         65 . The method of any one of the preceding claims, wherein the labeled compound comprises an isotope that decays by electron capture. 
     
     
         66 . The method of any one of the preceding claims, wherein the labeled compound comprises an isotope selected from  123 I and  131 I. 
     
     
         67 . The method of any one of the preceding claims, wherein the labeled compound comprises one or more  19 F. 
     
     
         68 . The method of any one of the preceding claims, wherein the labeled compound comprises a nanotube containing contrast reagents for MRI. 
     
     
         69 . The method of any one of  claims 1 - 56 , wherein the labeled compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         70 . The method of  claim 31 , wherein the non-radioactive therapeutic compound has the structure of formula X: 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salt thereof, wherein: 
         each Y is independently CH or N; 
         R is hydrogen, a C 1  to C 10  alkyl, alkenyl, alkynyl, or an alkoxyalkyl group, optionally comprising one or more heteroatoms, or a targeting moiety connected to N9 via a linker;
 X 4  is hydrogen or halogen; 
 X 3  is CH 2 , CF 2 , s, SO, SO 2 , O, NH, or NR 2 , wherein R 2  is alkyl; 
 X 2  is halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido, dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, C(O)O-alkyl, NH 2 , OH, CN, SO 2 X 5 , NO 2 , NO, C(S)R, NHSO 2 X 5 , or C(O)R, where X 5  is F, NH 2 , alkyl, or H, and R 2  is alkyl, NH 2 , NH-alkyl, or O-alkyl; and 
 X 1  represents two substituents, which may be the same or different, disposed in the 4′ and 5′ positions on the aryl group, wherein X 1  is selected from halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido, dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, COO-alkyl, NH 2 OH, CN, SO 2 X 5 , NO 2 , NO, C(S)R, NHSO 2 X 5 , or C(O)R, where X 5  is F, NH 2 , alkyl, or H, and R 2  is alkyl, NH 2 , NH-alkyl, or O-alkyl, C 1  to C 6  alkyl or alkoxy, or wherein X 1  has the formula —O—(CH 2 )—O—, wherein n is an integer from 1 to 2, and one of the oxygens is bonded at the 5′-position and the other at the 4′-position of the aryl ring; 
 
       
       or the non-radioactive therapeutic compound is a non-radioactive counterpart of a compound having the structure of any of formula III to IX. 
     
     
         71 . The method of  claim 70 , wherein the non-radioactive therapeutic compound is 
       
         
           
           
               
               
           
         
       
     
     
         72 . The method of any of the preceding claims, wherein the imaging is non-invasive. 
     
     
         73 . The method of any one of the preceding claims, further comprising identifying abnormal signal compared to a reference, wherein the abnormal signal indicates an inflammation and/or infection in the tissue. 
     
     
         74 . The method of any one of the preceding claims, further comprising identifying decreased signal compared to a reference, wherein the decreased signal indicates amelioration of an inflammation and/or infection in the tissue. 
     
     
         75 . The method of any one of the preceding claims, wherein the subject is a cancer patient.