Cationic steroid antimicrobial diagnostic, detection, screening and imaging methods

Abstract

The invention relates to diagnostic, detection, screening and imaging methods. In various embodiments, methods of diagnosis, detection, screening and imaging include administering a cationic steroid antimicrobial or CSA to a subject having or at risk of having an infection or a hyperproliferative disorder (e.g., a tumor, cancer or neoplasia) in an amount effective to diagnose or detect the infection or the hyperproliferative disorder (e.g., a tumor, cancer or neoplasia) in the subject. In a particular aspect, a detectable CSA, namely CSA-13 labeled with 99m Tc is used to detect the presence of an infection.

1 - 26 . (canceled) 
     
     
         27 . A detectably labelled cationic steroidal antimicrobial (CSA) for use in detecting an infection, or diagnosing a subject having or at risk of having an infection, the detectably labelled CSA comprising:
 a steroid backbone;   a plurality of amine or guanidine groups covalently attached to the steroid backbone;   and a detectable label incorporated into the structure of the CSA or covalently linked or conjugated to the CSA, wherein the detectable label comprises a radioisotope, a metal, or a metal oxide,   wherein the CSA is configured to bind to cell membranes of viruses, fungi, and bacteria.   
     
     
         28 . The detectably labelled CSA of  claim 27 , wherein the CSA is a compound having a structure of Formula V, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       where:
 each of fused rings A, B, C, and D is independently saturated, or is fully or partially unsaturated, provided that at least two of A, B, C, and D are saturated; 
 each of m, n, p, and q is independently 0 or 1; 
 each of R 1  through R 4 , R 6 , R 7 , R 11 , R 12 , R 15 , R 16 , R 17 , and R 18  is independently selected from the group consisting of hydrogen, hydroxyl, substituted or unsubstituted alkyl, hydroxyalkyl, alkyloxyalkyl, alkylcarboxyalkyl, alkylaminoalkyl, alkylamino-alkylamino, alkylamino-alkylamino-alkylamino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylaminoalkyl, haloalkyl, alkenyl, alkynyl, oxo, linking group attached to a second steroid, substituted or unsubstituted aminoalkyloxy, substituted or unsubstituted aminoalkyloxyalkyl, substituted or unsubstituted aminoalkylcarboxy, substituted or unsubstituted aminoalkylaminocarbonyl, substituted or unsubstituted aminoalkylcarboxamido, H 2 N—HC(Q 5 )-C(O)—O—, H 2 N—HC(Q 5 )-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy, P.G.-HN—HC(Q 5 )-C(O)—O—, guanidinoalkyloxy, quaternary ammonium alkylcarboxy, and guanidinoalkylcarboxy, where Q 5  is a side chain of an amino acid and P.G. is an amino protecting group: and 
 each of R 5 , R 8 , R 9 , R 10 , R 13 , and R 14  is independently deleted when one of fused rings A, B, C, or D is unsaturated so as to complete the valency of the carbon atom at that site, or selected from the group consisting of hydrogen, hydroxyl, substituted or unsubstituted alkyl, hydroxyalkyl, alkyloxyalkyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted aryl, haloalkyl, alkenyl, alkynyl, oxo, a linking group attached to a second steroid, substituted or unsubstituted aminoalkyloxy, substituted or unsubstituted aminoalkylcarboxy, substituted or unsubstituted aminoalkylaminocarbonyl, H 2 N—HC(Q 5 )-C(O)—O—, H 2 N—HC(Q 5 )-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy, P.G.-HN—HC(Q 5 )-C(O)—O—, guanidinoalkyloxy, and guanidinoalkylcarboxy, where Q 5  is a side chain of an amino acid and P.G. is an amino protecting group, 
 provided that at least three of R 1  through R 4 , R 6 , R 7 , R 11 , R 12 , R 15 , R 16 , R 17 , and R 18  are disposed on the same face of the ring system and are independently selected from the group consisting of substituted or unsubstituted aminoalkyl, substituted or unsubstituted aminoalkyloxy, alkylcarboxyalkyl, alkylamino-alkylamino, alkylamino-alkylamino-alkylamino, substituted or unsubstituted aminoalkylcarboxy, substituted or unsubstituted arylamino-alkyl, substituted or unsubstituted aminoalkyloxy-aminoalkylaminocarbonyl, substituted or unsubstituted aminoalkylarainocarbonyl, substituted or unsubstituted aminoalkylcarboxamido, quaternary ammonium alkylcarboxy, H 2 NHC(Q 5 )-C(O)—O—, H 2 N—HC(Q 5 )-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy, P.G.-HN—HC(Q 5 )-C(O)—O—, guanidinoalkyloxy, and guanidinoalkylcarboxy. 
 
     
     
         29 . The detectably labelled CSA of  claim 28 , wherein the detectable label comprises a radioisotope of carbon, hydrogen, nitrogen, oxygen, or sulfur included within the structure of the CSA. 
     
     
         30 . The detectably labelled CSA of  claim 28 , wherein the detectable label is a radioisotope covalently linked or conjugated to the CSA and selected from the group consisting of C, N, O, H, S, Cu, Fe, Ga, Ti, Sr, Y, Tc, In, Pm, Gd, Sm, Ho, Lu, Re, At, Bi, and Ac. 
     
     
         31 . The detectably labelled CSA of  claim 28 , wherein the detectable label is a radioisotope covalently linked or conjugated to the CSA and selected from the group consisting of  3 H,  10 B,  11 C,  14 C,  13 N,  15 O,  18 O,  18 F,  32 P,  35 S,  35 Cl,  45 Ti,  46 Sc,  51 Cr,  52 Fe,  59 Fe,  57 Co,  60 Co,  60 Cu,  61 Cu,  62 Cu,  64 Cu,  67 Cu,  67 Ga,  68 Ga,  72 As,  76 Br,  77 Br,  81m Kr,  82 Rb,  85 Sr,  89 Sr,  86 Y,  90 Y,  95 Nb,  94m Tc  99m Tc,  97 Ru,  103 Ru,  105 Rh,  109 Cd,  111 In,  113 Sn,  113m In,  114 In,  123 I  124 I,  125 I,  133 Xe,  137 Cs,  140 La,  141 Ce,  149 Pm,  153 Gd,  157 Gd,  153 Sm,  161 Tb,  166 Dy,  166 Ho,  169 Er,  169 Y,  175 Yb,  177 Lu,  186 Re,  188 Re,  201 Ti,  203 Pb,  211 At,  212 Bi,  225 Ac, and  226 Ra. 
     
     
         32 . The detectably labelled CSA of  claim 31 , wherein the radioisotope is selected from the group consisting of  99m Tc,  186 Re, and  188 Re. 
     
     
         33 . The detectably labelled CSA of  claim 31 , wherein the radioisotope is a beta emitter selected from the group consisting of  99m Tc,  60 Co,  137 Cs, and  226 Ra. 
     
     
         34 . The detectably labelled CSA of  claim 27 , wherein the detectable labelled CSA is configured to bind to cell membranes of at least bacterium and at least one virus:
 (a) wherein the at least bacterium is selected from the group consisting of  Bordetella pertussis, Borrelia burgdorferi, Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis, Campylobacter jejuni, Escherichia coli, Francisella tularensis, Haemophilus influenzae, Helicobacter pylori, Legionella pneumophila; Leptospira interrogans, Neisseria gonorrhoeae, Neisseria meningitides, Pseudomonas aeruginosa, Rickettsia rickettsii, Salmonella typhi, Salmonella typhimurium, Shigella sonnei, Treponema pallidum, Vibrio cholerae, Yersinia pestis, mycobacterium, listeria monocytogenes, helicobacter, bordetella, streptococcus, salmonella, Chlamydia, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Corynebacterium diphtheriae, Enterococcus faecalis, Enterococcus faecum, Listeria, monocytogenes, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis, Mycobacterium leprae, Mycobacterium tuberculosis, Mycoplasma pneumoniae ; and   (b) wherein the at least virus is selected from the group consisting of poxvirus, herpesvirus, hepatitis virus, immunodeficiency virus, flavivirus, papilloma virus (PV), polyoma virus, rhabdovirus, myxovirus, arenavirus, coronavirus, adenovirus, reovirus, picornavirus, togavirus, bunyavirus, parvovirus, and retrovirus.   
     
     
         35 . The detectably labelled CSA of  claim 27 , wherein the detectably labelled CSA is configured to be detected by magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), positron-emission tomography (PET), gamma-scintigraphy, computed tomography (CT), Computed Axial Tomography (CAT), or single photon emission tomography (SPECT). 
     
     
         36 . A method of detecting an infection, or diagnosing a subject having or at risk of having an infection, comprising:
 administering the detectably labelled CSA of  claim 27  to the subject under conditions whereby the detectably labelled CSA can bind to cell membranes of viruses, fungi, and bacteria that are causative of infection and present in the subject, and   detecting the detectably labelled CSA in the subject, including its location, to ascertain the presence or absence of an infection caused by any one of viruses, fungi, and bacteria, thereby detecting the infection, or diagnosing the subject as having or not having an infection.   
     
     
         37 . The method of  claim 36 , wherein detecting the radiolabeled CSA in the subject comprises imaging the radiolabeled CSA. 
     
     
         38 . The method of  claim 36 , wherein the CSA is selected from CSA-1 through CSA-400. 
     
     
         39 . The method of  claim 36 , wherein the CSA is selected from CSA-13, CSA-107, and CSA-100. 
     
     
         40 . The method of  claim 36 , wherein the method detects the presence or absence, type, kind, location, extent, severity, or progression of the infection. 
     
     
         41 . The method of  claim 36 , wherein the infection is a bacterial infection selected from the group consisting of  Bordetella, Bordetella pertussis; Borrelia, Borrelia burgdorferi; Brucella, Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis, Campylobacter, Campylobacter jejuni; Escherichia, Escherichia coli; Francisella, Francisella tularensis; Haemophilus, aemophilus luenzae; icobacter, Helicobacter pylori; Legionella, Legionella pneumophila; Leptospira, Leptospira interrogans; Neisseria, Neisseria gonorrhoeae, Neisseria meningitides; Pseudomonas, Pseudomonas aeruginosa; Rickettsia Rickettsia rickettsii, Salmonella, Salmonella typhi, Salmonella typhimurium; Shigella Shigella sonnei; Treponema, Treponema pallidum; Vibrio, Vibrio cholerae; Yersinia, Yersinia pestis a  mycobacterium, listeria monocytogenes, helicobacter, bordetella, streptococcus, salmonella, Chlamydia, Clostridium, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani; Corynebacterium, Corynebacterium diphtheriae; Enterococcus, Enterococcus faecalis, Enterococcus faecum; Listeria Listeria, monocytogenes; Staphylococcus, Staphylococcus aureus; Staphylococcus epidermidis, Staphylococcus saprophyticus; Streptococcus, Streptococcus agalactiae; Streptococcus pneumoniae; Streptococcus pyogenes, Chlamydia, Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis; Mycobacterium, Mycobacterium leprae, Mycobacterium tuberculosis; Mycoplasma, Mycoplasma pneumoniae.    
     
     
         42 . The method of  claim 36 , wherein the infection is a viral infection selected from the group consisting of a poxvirus, herpesvirus, hepatitis virus, immunodeficiency virus, flavivirus, papilloma virus (PV), polyoma virus, rhabdovirus, a myxovirus, an arenavirus, a coronavirus, adenovirus, reovirus, picornavirus, togavirus, bunyavirus, parvovirus, and retrovirus. 
     
     
         43 . The method of  claim 36 , wherein the infection is an infection of skin, dermis, breast, lung, nasopharynx, nose or sinuses, thyroid, head, neck, brain, spine, adrenal gland, thyroid, lymph, blood, gastrointestinal tract, genito-urinary tract, kidney, pancreas, adrenal gland, liver, bone, bone marrow, heart, muscle, or hematopoetic system. 
     
     
         44 . The method of  claim 36 , wherein detecting comprises magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), positron-emission tomography (PET), gamma-scintigraphy, computed tomography (CT), Computed Axial Tomography (CAT), or single photon emission tomography (SPECT). 
     
     
         45 . An ex vivo or in vitro method of detecting an infection, or diagnosing a subject having or at risk of having an infection, comprising:
 contacting the detectably labeled CSA of  claim 27  to a biological sample from a subject under conditions whereby the detectably labeled CSA can bind to cell membranes of viruses, fungi, and bacteria that are causative of infection and present in the biological sample; and   detecting the labeled CSA in the sample to ascertain the presence or absence of an infection in the sample, thereby of detecting an infection, or diagnosing the subject as having or not having an infection.   
     
     
         46 . The method of  claim 45 , wherein the biological sample comprises at least one of mucus, saliva, feces, blood, serum, plasma, cerebrospinal fluid, urine, or placenta blood, skin, dermis, breast, lung, nasopharynx, nose or sinuses, thyroid, head, neck, brain, spine, adrenal gland, thyroid, lymph, gastrointestinal tract, genito-urinary tract, kidney, pancreas, adrenal gland, liver, bone, bone marrow, heart, muscle, or a sample of the hematopoetic system.