Topical application of nerve labeling dyes for image-guided surgery

Abstract

The present invention relates to a topical agent that binds specifically to myelin basic protein and its method of use and determining myelination in the subject by detecting the agent present in the subject. A kit containing the agent or its derivatives for use in detecting myelin basic protein is also provided.

1 . A topical administered pharmaceutical agent comprising a compound of Formula I or a salt thereof, wherein Formula I is: 
       
         
           
           
               
               
           
         
         wherein R 1  is an alkyl group, R 2  is an electron donating group and R 3  is an electron withdrawing group; and 
         an aqueous pharmaceutical carrier comprising;
 at least two solvents selected from PEG-300, propylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, carbapol, and Laurocapram. 
 
       
     
     
         2 . The pharmaceutical agent of  claim 1  where, the aqueous pharmaceutical carrier comprises, based on volume;
 1-30% PEG-300, 1-20% propylene glycol, 1-10% polyvinyl pyrrolidone, and 0-10% Laurocapram. 
 
     
     
         3 . The pharmaceutical agent of  claim 1  where, the aqueous pharmaceutical carrier comprises based on volume; 10-30% PEG-300 and 5-20% Polyvinyl alcohol. 
     
     
         4 . The pharmaceutical agent of  claim 1  wherein R 1  is a lower alkyl groups from 1 to 6 carbon atoms, R 2  is a primary, secondary, or tertiary amine, or an alkoxy group. 
     
     
         5 . The pharmaceutical agent of  claim 1  wherein Formula I is: 
       
         
           
           
               
               
           
         
       
       where R 1  is an alkyl group, R 2  is an electron donating group, and R 4  and R 5  are independently hydrogen, alkyl, substituted alkyl, amine, substituted amine, or taken together form a heterocyclic ring or substituted heterocyclic ring structure. 
     
     
         6 . The pharmaceutical agent of  claim 5  where, the aqueous pharmaceutical carrier comprises, based on volume;
 1-30% PEG-300, 1-20% propylene glycol, 1-10% polyvinyl pyrrolidone, and 0-10% Laurocapram. 
 
     
     
         7 . The pharmaceutical agent of  claim 5  where, the aqueous pharmaceutical carrier comprises based on volume; 10-30% PEG-300 and 5-20% polyvinyl alcohol. 
     
     
         8 . The pharmaceutical agent of  claim 5 , wherein R 4  and R 5  taken together form a heterocyclic ring or a substituted heterocyclic ring. 
     
     
         9 . The pharmaceutical agent of  claim 8 , wherein R 4  and R 5  taken together form piperidine, piperazine, morpholine, an alkyl or alkoxyl substituted piperidine, piperazine, or morpholine. 
     
     
         10 . The pharmaceutical agent of  claim 8  where Formula I is: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The pharmaceutical agent of  claim 1  wherein Formula I is a salt further comprising an anion and said anion is a halide, a polyatomic anion, or a basic active compound. 
     
     
         12 . The agent of  claim 11  wherein the anion is a chloride. 
     
     
         13 . A method of imaging myelin basic protein in an open or minimally invasive surgical field by topical administration of a pharmaceutical agent comprising the steps of:
 contacting the surgical site with a pharmaceutical agent, said agent comprising a compound of Formula I or a salt thereof, wherein Formula I is:   
       
         
           
           
               
               
           
         
       
       wherein R 1  is an alkyl group, R 2  is an electron donating group and R 3  is an electron withdrawing group; and
 an aqueous pharmaceutical carrier comprising;
 at least two solvents selected from PEG-300, propylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, carbapol, and Laurocapram; and 
 
 detecting the agent by applying a light source tuned to the spectral excitation characteristics of the agent, and observing the subject through an optical filter tuned to the spectral emission characteristics of the agent; and 
 optionally determining the presence of myelin based on spectral excitation of the agent. 
 
     
     
         14 . The method of  claim 13  wherein the detecting is effected by fluorescence microscopy, laser-confocal microscopy, cross-polarization microscopy, autoradiography, or a combination thereof. 
     
     
         15 . The method of  claim 13  where, the aqueous pharmaceutical carrier comprises, based on volume;
 1-30% PEG-300, 1-20% propylene glycol, 1-10% polyvinyl pyrrolidone, and 0-10% Laurocapram. 
 
     
     
         16 . The method of  claim 13  where, the aqueous pharmaceutical carrier comprises based on volume; 10-30% PEG-300 and 5-20% polyvinyl alcohol. 
     
     
         17 . The method of  claim 13  wherein R 1  is a lower alkyl groups from 1 to 6 carbon atoms, R 2  is a primary, secondary, or tertiary amine, or an alkoxy group. 
     
     
         18 . The method of  claim 13  wherein Formula I is: 
       
         
           
           
               
               
           
         
       
       where R 1  is an alkyl group, R 2  is an electron donating group, and R 4  and R 5  are independently hydrogen, alkyl, substituted alkyl, amine, substituted amine, or taken together form a heterocyclic ring or substituted heterocyclic ring structure. 
     
     
         19 . The method of  claim 18  where, the aqueous pharmaceutical carrier comprises, based on volume;
 1-30% PEG-300, 1-20% propylene glycol, 1-10% polyvinyl pyrrolidone, and 0-10% Laurocapram. 
 
     
     
         20 . The method of  claim 18  where, the aqueous pharmaceutical carrier comprises based on volume; 10-30% PEG-300 and 5-20% polyvinyl alcohol.