Heptamethine cyanines for use as fluorescent markers of the biliary and renal systems

Abstract

Heptamethine cyanines for use as fluorescent markers of the biliary system are disclosed. Certain heptamethine cyanines exhibit biliary system specificity and methods for in vivo visualization of a biliary system of a subject are provided. The methods may be for diagnostic purposes and/or for visualization of biliary systems during surgery.

1 . A method for in vivo visualization of a biliary system of a subject, comprising:
 (i) administering to the subject a pharmaceutical composition comprising a fluorescence agent comprising a compound of Formula IIA in an amount sufficient to effect fluorescence detection of a portion of the biliary system upon irradiation with light having a wavelength in the range of 600 nm to 900 nm:   
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —CH 2 -, 
         R 2  is C 1 -C 3  alkyl, 
         R 13  to R 16  independently are C 1 -C 10  alkyl, 
         R 17  is C 1 -C 3  alkyl, 
         m is 2, 
         p is 3, 4, or 5, and 
         Z is a monatomic ion; 
         (ii) allowing time following the administration (i) for accumulation of the compound of Formula IIA in the biliary system; 
         (iii) irradiating the biliary system with light having a wavelength in the range of 600 nm to 900 nm (NIR) to produce a fluorescence signal of the compound of Formula IIA in the biliary system; 
         iv) visualizing at least one portion of the biliary system by detection of the fluorescence signal produced upon the irradiation (iii); 
         wherein 
         a contrast to background ratio (CBR) of the fluorescence signal to a background signal in a region of the biliary system being visualized is 1.5 or more within 20 minutes of the administration (i). 
       
     
     
         2 . The method according to  claim 1 , wherein administering the pharmaceutical composition (i) comprises at least one route selected from the group consisting of oral, buccal, systemic, injection, transdermal, rectal, inhalation and insufflation. 
     
     
         3 . The method according to  claim 1 , wherein the CBR remains 1.5 or more for at least 30 minutes. 
     
     
         4 . The method according to  claim 1 , wherein the pharmaceutical composition further comprises at least one selected from the group consisting of a pharmaceutically and physiologically acceptable fluid, an excipient, a non-toxic wetting agent, a non-toxic emulsifying agent, a preservative and a pH buffering agent. 
     
     
         5 . The method according to  claim 1 , wherein the light source for irradiating the target system is selected from the group consisting of a laser, a light-emitting diode (LED), a xenon lamp, a halogen bulb and a vertical-cavity surface-emitting laser (VSCEL). 
     
     
         6 . The method according to  claim 1 , wherein the effective amount of the compound of Formula IIA is from 1 μg/kg to 240 μg/kg body weight of the subject. 
     
     
         7 . The method according to  claim 1 , wherein an effective quantity of NIR light irradiating the biliary system is from 0.1 to 1000 mW/cm 2 . 
     
     
         8 . The method according to  claim 1  wherein the fluorescence agent consists of the compound of Formula IIA. 
     
     
         9 . The method according to  claim 1 , wherein
 the irradiation is performed externally with a light applicator selected from the group consisting of a micro-lens, a Fresnel lens and a diffuser, or   the irradiation is performed internally with an endoscope or a fiber optic catheter.   
     
     
         10 . The method according to  claim 1  wherein the compound of Formula IIA is the compound of the formula BL-760: 
       
         
           
           
               
               
           
         
         and the NIR light is of a wavelength of from 600 nm to 850 nm. 
       
     
     
         11 . The method according to  claim 10 , wherein a biliary:urinary specificity of the compound BL-760 is 100:0. 
     
     
         12 . The method according to  claim 1 , wherein determining bile leakage from a bile duct is based on detecting the fluorescence in the biliary system of the subject. 
     
     
         13 . A hepatobiliary surgery procedure of a patient, comprising:
 administering to the patient a pharmaceutical composition comprising the compound BL-760;   allowing time for the compound BL-760 to accumulate in the biliary system;   irradiating the biliary area and surrounding tissue with NIR of a wavelength from 600 nm to 850 nm to visualize the hepatic tissue or biliary tree by fluorescence of the BL-760 accumulated therein; and   performing surgery within the hepatobiliary area during the visualization of the hepatic tissue or biliary tree;   
       
         
           
           
               
               
           
         
       
     
     
         14 . A method for the detection of cancer in the hepatic tissue of a patient, comprising:
 administering to the patient a pharmaceutical composition comprising a compound of Formula IIA;   allowing time for the compound of Formula IIA to accumulate in the hepatic tissue;   irradiating the hepatic tissue with NIR of a wavelength of 600 nm to 850 nm to visualize the hepatic tissue by fluorescence of the compound of Formula IIA accumulated therein; and   determining, based on the fluorescence of the hepatic tissue, the presence of hepatocellular carcinoma or colorectal liver metastasis in the hepatic tissue of the patient;   
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —CH 2 -, 
         R 13  to R 16  independently are C 1 -C 10  alkyl, 
         R 17  is C 1 -C 3  alkyl, 
         m is 2, 
         p is 3, 4, or 5, and 
         Z is a monatomic ion.