99mTc-LABELED TRIPHENYLPHOSPHONIUM DERIVATIVE CONTRASTING AGENTS AND MOLECULAR PROBES FOR EARLY DETECTION AND IMAGING OF BREAST TUMORS

Abstract

99mTc-labeled triphenylphosphonium contrasting agents that target the mitochondria and are useful for early detection of breast tumors using scintimammographic imaging. 99mTc-Mito10-MAG3 possesses advantageous radiopharmaceutical properties. The uptake in the myocardium is reduced by one to two orders of magnitude compared to 99mTc-MIBI. 99mTc-Mito10-MAG3 exhibits fast blood clearance, with a blood half-life of less than 2 minutes in rats. A diminished myocardial uptake combined with a prompt reduction of cardiovascular blood pool signal to facilitate improved signal-to-background ratios.

We claim: 
     
         1 . A compound according to the structure: 
       
         
           
           
               
               
           
         
         wherein L is 99 mTc, 125I, 123I, 123/5/131I, 18F, 11C, 13N, 15O, 66/8Ga, 67Ga, 60Cu, 64Cu, 67Cu, 52Fe, 55Co, 61/2/4Cu, 62/3Zn, 70/1/4As, 75/6Br, 82Rb, 86Y, 89Zr, 110In, 111In, 120/4I, 201TI or 122Xe, L being chelated to R3, 
         wherein R1 is S, N or P, 
         wherein R2 is a branched or straight chain, cyclic, saturated or unsaturated, substituted or unsubstituted C1-25 group, 
         wherein R3 is a branched or straight chain, saturated or unsaturated, substituted or unsubstituted C1-30 moiety comprising one or more of carboxyl, amine, amide, ester, alcohol or thiol, 
         wherein R4, R5 or R6 are the same or independently a straight or branched chain, saturated or unsaturated, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl, and, 
         wherein X- is a salt-forming counterion, 
         or a solvate or hydrate thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein X— is Cl—, I— or F—. 
     
     
         3 . The compound of  claim 1 , wherein the salt-forming counterion is acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, mitrate, pamoate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate or triethiodide. 
     
     
         4 . The compound of  claim 1 , wherein R2 is a branched or straight chain, saturated or unsaturated, substituted or unsubstituted C4-15 alkyl. 
     
     
         5 . The compound of  claim 1 , wherein L is 99 mTc. 
     
     
         6 . The compound of  claim 1 , wherein R3-L is O-(2-18F-fluoroethyl)-L-tyrosine, 18F-fluoromisonidazole, 64Cu-diacetyl-bis(N-4-methylthiosemicarbazone), 3′-deoxy-3′-(18F)fluorothymidine (18F-FLT), 11C-thymidine, or 18F-1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)thymine. 
     
     
         7 . A process of making the compound of  claim 1  comprising:
 providing a compound according to the structure: 
 
       
         
           
           
               
               
           
         
         or a solvate or hydrate thereof, and, 
         radiolabeling the compound by chelating the compound with a radioisotope-containing reactant comprising 99 mTc. 
       
     
     
         8 . The process of  claim 7 , wherein the radioisotope-containing reactant comprises 99mTc pertechnetate. 
     
     
         9 . An injectable dosage form comprising the compound of  claim 1  and a pharmaceutically suitable injectable carrier system. 
     
     
         10 . A method of detecting breast cancer in a female human patient in need thereof comprising:
 injecting an injectable dosage form comprising the compound of  claim 1  and a pharmaceutically suitable injectable carrier system, and,   
       scintimammographically imaging the radioactivity of the radioisotope.