Hyperpolarized 1-13c-1,1-bis(acetoxy(methyl))-2,2'-cyclopropane as metabolic marker for mr

Abstract

1- 13 C-1,1-Bis(acetoxy(methyl))-2,2′-cyclopropane of formula (I): The compound can be hyperpolarized and used as a contrast agent in 13 C Magnetic Resonance diagnostic technique ( 13 C-MR) for the diagnosis of tumor.

1 . The compound 1- 13 C-1,1-Bis(acetoxy(methyl))-2,2′-cyclopropane, of formula (I) 
       
         
           
           
               
               
           
         
       
       said compound being enriched above natural abundance of  13 C in position 1 of the molecule. 
     
     
         2 . The deuterated compound of  claim 1  of formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound according to  claim 1  wherein said compound is hyperpolarized. 
     
     
         4 . An imaging medium comprising the compound according to  claim 3 . 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . A method of  13 C-MR detection of tumor comprising using the imaging medium according to  claim 4  and detecting signals of the at least one hyperpolarized metabolic product of a carboxylesterase conversion of said hyperpolarized compound. 
     
     
         10 . The method according to  claim 9 , wherein said at least one hyperpolarized metabolic product is 1- 13 C-1-(acetoxy(methyl))-1-(hydroxy(methyl))-2,2′-cyclopropane, 1- 13 C-1,1-(dihydroxy(methyl))-2,2′-cyclopropane or a mixture thereof. 
     
     
         11 . The method according to  claim 9  wherein a first signal obtained from a region of interest is compared with a second signal and the comparison is used to determine a difference between tumor and non-tumor tissue. 
     
     
         12 . A method for operating an MRI system comprising the steps of:
 a. submitting a subject who is affected or suspected to be affected by a tumor, who has been positioned in an MRI system and treated with the compound of  claim 3 , and wherein said compound has been metabolically converted into the corresponding hyperpolarized metabolic product(s) of a carboxylesterase conversion, to a radiation having a frequency selected to excite nuclear spin transitions in  13 C nuclei;   b. recording an MR signal from said excited nuclei; and   c. comparing a first MR signal deriving from a region of interest comprising said tumor or said suspected tumor with a second MR signal deriving from said subject or from a sample taken from said subject.   
     
     
         13 . The method according to  claim 12  further comprising the steps of:
 d. determining a difference between said first signal and second signal; 
 e. comparing said difference of step d) with a reference value, to produce a deviation value; and 
 f. determining if the deviation value is, in absolute value, higher than a predetermined value. 
 
     
     
         14 . The method according to  claim 13 , wherein said second signal is determined on a non-tumor tissue, further comprising the step of:
 g. providing an indication of possible tumor affection in case the deviation value is in absolute value higher than said predetermined value.   
     
     
         15 . The method according to  claim 13 , wherein said second signal is determined in the region of interest, at an earlier moment in time with respect to the first signal, and optionally stored in the system, said method further comprising the step of:
 g′. providing an indication of tumor variation in case the deviation is in absolute value higher than said predetermined value.   
     
     
         16 . The method according to  claim 13 , wherein said subject has undergone an anti-tumor treatment and wherein said second signal is determined in the region of interest, at an earlier moment in time with respect to said first signal, and optionally stored in the system, said method further comprising the step of:
 g″. providing an indication of efficacy of said treatment if this deviation is in absolute value higher than a predetermined value.   
     
     
         17 . The method according to  claim 16  wherein said second signal is determined before, after or at the beginning of the treatment. 
     
     
         18 . A process for the preparation of the compound of  claim 1  comprising the steps of:
 a) reacting 1- 13 C-1,1-Bis(hydroxy(methyl))-2,2′-cyclopropane with acetyl chloride, and 
 b) removing the excess of acetyl chloride and the formed hydrochloric gas. 
 
     
     
         19 . A compound according to  claim 2  wherein said compound is hyperpolarized. 
     
     
         20 . An imaging medium comprising the compound according to  claim 19 . 
     
     
         21 . A method of  13 C-MR detection of tumor comprising using the imaging medium according to  claim 20  and detecting signals of the at least one hyperpolarized metabolic product of a carboxylesterase conversion of said hyperpolarized compound. 
     
     
         22 . The method according to  claim 21 , wherein said at least one hyperpolarized metabolic product is 1- 13 C-1-(acetoxy(methyl))-1-(hydroxy(methyl))-2,2′-cyclopropane, 1- 13 C-1,1-(dihydroxy(methyl))-2,2′-cyclopropane or a mixture thereof. 
     
     
         23 . The method according to  claim 21  wherein a first signal obtained from a region of interest is compared with a second signal and the comparison is used to determine a difference between tumor and non-tumor tissue. 
     
     
         24 . A method for operating an MRI system comprising the steps of:
 a. submitting a subject who is affected or suspected to be affected by a tumor, who has been positioned in an MRI system and treated with the compound of  claim 19 , and wherein said compound has been metabolically converted into the corresponding hyperpolarized metabolic product(s) of a carboxylesterase conversion, to a radiation having a frequency selected to excite nuclear spin transitions in  13 C nuclei;   b. recording an MR signal from said excited nuclei; and   c. comparing a first MR signal deriving from a region of interest comprising said tumor or said suspected tumor with a second MR signal deriving from said subject or from a sample taken from said subject.   
     
     
         25 . The method according to  claim 24  further comprising the steps of:
 d. determining a difference between said first signal and second signal; 
 e. comparing said difference of step d) with a reference value, to produce a deviation value; and 
 f. determining if the deviation value is, in absolute value, higher than a predetermined value. 
 
     
     
         26 . The method according to  claim 25 , wherein said second signal is determined on a non-tumor tissue, further comprising the step of:
 g. providing an indication of possible tumor affection in case the deviation value is in absolute value higher than said predetermined value.   
     
     
         27 . The method according to  claim 25 , wherein said second signal is determined in the region of interest, at an earlier moment in time with respect to the first signal, and optionally stored in the system, said method further comprising the step of:
 g′. providing an indication of tumor variation in case the deviation is in absolute value higher than said predetermined value.   
     
     
         28 . The method according to  claim 25 , wherein said subject has undergone an anti-tumor treatment and wherein said second signal is determined in the region of interest, at an earlier moment in time with respect to said first signal, and optionally stored in the system, said method further comprising the step of:
 g″. providing an indication of efficacy of said treatment if this deviation is in absolute value higher than a predetermined value.   
     
     
         29 . The method according to  claim 28  wherein said second signal is determined before, after or at the beginning of the treatment. 
     
     
         30 . A process for the preparation of the compound of  claim 2  comprising the steps of:
 c) reacting the corresponding deuterated analog of 1- 13 C-1,1-Bis(hydroxy(methyl))-2,2′-cyclopropane with acetyl chloride, and 
 d) removing the excess of acetyl chloride and the formed hydrochloric gas.