Use of fluorinated derivatives of 4-aminopyridine in therapeutics and medical imaging

Abstract

The present disclosure provides novel compounds, including compounds that bind to potassium channels, methods for their manufacture, and methods for their use, including their use to diagnose and/or assess traumatic brain injury and use to treat dymeylinating diseases, and/or in vivo imaging of the central neverous system, and to diagnose and/or assess the progression of MS or other diseases.

1 . An imaging method comprising administering to a subject a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1 , R 2 , R 3 , and R 4  are each independently selected from the group consisting of H, (CH 2 ) n X, NH 2 , CH 2 OH, OCH 3 , CF 3 , OCHF 2 , and OCF 3 ; 
         at least one of R 1 , R 3 , and R 4  is H; 
         R 5  is selected from the group consisting of H, (CH 2 ) m X, C(CH 3 ) 3 , OH, COOCF 3 , and COO(CH 2 ) m X; 
         wherein n=0, 1, 2, 3, 4, or 5 and m=1, 2, 3, 4, or 5; 
         wherein X represents a fluorine atom or  18 F; 
         wherein the compound contains at least one  18 F,  11 C,  13 N, or  15 O isotope; and 
         wherein the compound is not [ 18 F]3-fluoro-4-aminopyridine; 
         or a pharmaceutical acceptable salt thereof, or a deuterated version thereof; 
         and detecting the compound in the subject. 
       
     
     
         2 . A method for diagnosing a demyelinating disease or evaluating the progression of a demyelinating disease comprising administering to a subject a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1 , R 2 , R 3 , and R 4  are each independently selected from the group consisting of H, (CH 2 ) n X, NH 2 , CH 2 OH, OCH 3 , CF 3 , OCHF 2 , and OCF 3 ; 
         at least one of R 1 , R 3 , and R 4  is H; 
         R 5  is selected from the group consisting of H, (CH 2 ) m X, C(CH 3 ) 3 , OH, COOCF 3 , and COO(CH 2 ) m X; 
         wherein n=0, 1, 2, 3, 4, or 5 and m=1, 2, 3, 4, or 5; 
         wherein X represents a fluorine atom or  18 F; 
         wherein the compound contains at least one  18 F,  11 C,  13 N, or  15 O isotope; and 
         wherein the compound is not [ 18 F]3-fluoro-4-aminopyridine; 
         or a pharmaceutical acceptable salt thereof, or a deuterated version thereof; 
         and detecting the compound in the subject by a radiodiagnostic method. 
       
     
     
         3 . The method of  claim 2 , wherein a dose is from about 0.005 to 50 mCi. 
     
     
         4 . The method of  claim 2 , further comprising quantifying an amount of the compound in the subject. 
     
     
         5 . The method of  claim 2 , wherein the demyelinating disease is multiple sclerosis, spinal cord compression, ischemia, acute disseminated encephalomyelitis, optic neuromyelitis, leukodystrophy, progressive multifocal leukoencephalopathy, metabolic disorders, toxic exposure, congenital demyelinating disease, peripheral neuropathy, encephalomyelitis, central pontine myelolysis, Anti-MAG Disease, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, or multifocal motor neuropathy (MMN). 
     
     
         6 . The method of  claim 2 , wherein the radiodiagnostic method is Positron Emission Tomography (PET), PET-Time-Activity Curve (TAC), PET-Magnetic Resonance Imaging (MRI), or PET/CT. 
     
     
         7 . The method of  claim 2 , wherein a demyelinated region in the subject is detected by detecting the compound. 
     
     
         8 . The method of  claim 2 , wherein the compound binds to potassium channels located at a demyelinated region in an axon in the subject. 
     
     
         9 . A method for diagnosing traumatic brain injury or evaluating the progression of traumatic brain injury in a subject comprising administering to the subject a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1 , R 2 , R 3 , and R 4  are each independently selected from the group consisting of H, (CH 2 ) n X, NH 2 , CH 2 OH, OCH 3 , CF 3 , OCHF 2 , and OCF 3 ; 
         at least one of R 1 , R 3 , and R 4  is H; 
         R 5  is selected from the group consisting of H, (CH 2 ) m X, C(CH 3 ) 3 , OH, COOCF 3 , and COO(CH 2 ) m X; 
         wherein n=0, 1, 2, 3, 4, or 5 and m=1, 2, 3, 4, or 5; 
         wherein X represents a fluorine atom or  18 F; 
         wherein the compound contains at least one  18 F,  11 C,  13 N, or  15 O isotope; and 
         wherein the compound is not [ 18 F]3-fluoro-4-aminopyridine; 
         or a pharmaceutical acceptable salt thereof, or a deuterated version thereof; 
         and detecting the compound in the subject by a radiodiagnostic method. 
       
     
     
         10 . The method of  claim 9 , wherein the subject is at risk for traumatic brain injury or a concussion. 
     
     
         11 . The method of  claim 9 , wherein the imaging is affected by a radiodiagnostic method. 
     
     
         12 . The method of  claim 11 , wherein the radiodiagnostic method is Positron Emission Tomography (PET), PET-Time-Activity Curve (TAC), PET-Magnetic Resonance Imaging (MRI), or PET/CT. 
     
     
         13 . The method of  claim 9 , further comprising quantifying the amount of the compound in the subject. 
     
     
         14 . The method of  claim 9 , wherein a demyelinated region in an axon in the subject is detected by detecting the compound and an increase in demyelination indicates traumatic brain injury. 
     
     
         15 . The method of  claim 9 , wherein the compound blocks potassium channels located at a demyelinated region in an axon in the subject.