Psma targeted fluorescent agents for image guided surgery

Abstract

Compositions and methods for visualizing tissue under illumination with near-infrared radiation, including compounds comprising near-infrared, closed chain, sulfo-cyanine dyes and prostate specific membrane antigen ligands are disclosed.

That which is claimed: 
     
         1 . A compound of the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A composition comprising compound (3): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein the composition is adapted for visualization of tissue under illumination with near-infrared radiation. 
       
     
     
         3 . The composition of  claim 2 , wherein the composition is adapted for administration to a subject. 
     
     
         4 . The composition of  claim 3 , wherein the composition comprises a unit dosage form of compound (3). 
     
     
         5 . The composition of  claim 4 , wherein the unit dosage form delivers to the subject an amount of compound (3) between about 0.01 and about 8 mg/kg. 
     
     
         6 . The composition of  claim 5 , wherein the unit dosage form delivers to the subject an amount of compound (3) of about 0.01 mg/kg, about 0.05 mg/kg, about 0.10 mg/kg, about 0.20 mg/kg, about 0.3 mg/kg, about 0.35 mg/kg, about 0.40 mg/kg, about 0.45 mg/kg, about 0.50 mg/kg, about 0.55 mg/kg, about 0.60 mg/kg, about 0.65 mg/kg, about 0.70 mg/kg, about 0.75 mg/kg, about 0.80 mg/kg, about 0.90 mg/kg, about 1 mg/kg, about 2, mg/kg, about 4 mg/kg, about 6 mg/kg, or about 8 mg/kg. 
     
     
         7 . The composition of  claim 2 , wherein the composition is in a single dose form. 
     
     
         8 . The composition of  claim 2 , wherein the composition is in dry form. 
     
     
         9 . The composition of  claim 2 , wherein the composition is lyophilized in a sterile container. 
     
     
         10 . The composition of  claim 2 , wherein the composition is contained within a sterile container. 
     
     
         11 . The composition of  claim 10 , wherein the sterile container comprises a machine detectable identifier. 
     
     
         12 . The composition of  claim 2 , further comprising one or more pharmaceutically acceptable excipients in an oral dosage form. 
     
     
         13 . The composition of  claim 2 , further comprising one or more pharmaceutically acceptable carriers in an injectable dosage form. 
     
     
         14 . The composition of  claim 2 , further comprising one or more pharmaceutically acceptable excipients in a dosage form for direct delivery to a surgical site. 
     
     
         15 . The use of a composition of  claim 2  for administration to a subject to obtain visualization of tissue expressing PSMA under illumination with near-infrared radiation. 
     
     
         16 . The use of  claim 15 , wherein the subject is a human subject. 
     
     
         17 . A method for visualization of tissue expressing PSMA, the method comprising administering to a subject a composition comprising compound (3): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein compound (3) is administered in an amount sufficient for imaging tissue under illumination with near-infrared radiation; 
         imaging the tissue under illumination with near-infrared radiation; and 
         obtaining at least one image of tissue from the subject. 
       
     
     
         18 . The method of  claim 17 , wherein the composition comprises a unit dosage form of compound (3). 
     
     
         19 . The method of  claim 18 , wherein the unit dosage form delivers to the subject an amount of compound (3) from about 0.01 mg/kg and about 8 mg/kg. 
     
     
         20 . The method of  claim 18 , wherein the composition is sterile, non-toxic, and adapted for administration to a subject. 
     
     
         21 . The method of  claim 17 , further comprising obtaining the image during administration, after administration, or both during and after administration of the composition. 
     
     
         22 . The method of  claim 17 , further comprising intravenously injecting a composition comprising compound (3) into the subject. 
     
     
         23 . The method of  claim 22 , wherein the composition is injected into a circulatory system of the subject. 
     
     
         24 . The method of  claim 17 , further comprising visualizing a subject area on which surgery is or will be performed. 
     
     
         25 . The method of  claim 24 , further comprising performing a surgical procedure of the subject area based on the visualization of the area. 
     
     
         26 . The method of  claim 24 , further comprising viewing a subject area on which an ophthalmic, arthroscopic, laparoscopic, cardiothoracic, muscular, or neurological procedure is or will be performed. 
     
     
         27 . The method of  claim 17 , further comprising diagnosing the subject with a condition or disease based on the visualization of the tissue expressing PSMA. 
     
     
         28 . The method of  claim 17 , further comprising obtaining ex vivo images of at least a portion of the subject. 
     
     
         29 . The method of  claim 17 , wherein the tissue being visualized comprises tumor tissue. 
     
     
         30 . The method of  claim 17 , wherein the tissue being visualized comprises cancerous tissue. 
     
     
         31 . The method of  claim 17 , wherein the tissue being visualized comprises prostate tissue. 
     
     
         32 . The method of  claim 17 , wherein the tissue being visualized comprises prostate tumor tissue. 
     
     
         33 . The method of  claim 17 , wherein the tissue being visualized comprises nerve tissue. 
     
     
         34 . The method of  claim 17  wherein the tissue being visualized comprises clear cell renal cell carcinoma.