Mri imaging of amyloid plaque using liposomes

Abstract

Provided are aromatic compounds, phospholipid-polymer-aromatic conjugates comprising the aromatic compounds, and liposome compositions including the phospholipid-polymer-aromatic conjugates. The liposomal compositions may be useful for imaging of Alzheimer's Disease, for example, imaging of the amyloid-β plaque deposits characteristic of Alzheimer's Disease.

1 . A liposomal composition, comprising:
 a membrane, comprising:
 a phospholipid-polymer-aromatic conjugate, the aromatic moiety in the phospholipid-polymer-aromatic conjugate being represented by Structural Formula I:
   —X—Ar—R 1 -Het  (I)
 
 
   wherein:
 X is —R 2 —O— or —R 2 —N(R 3 )—; 
 R 1  is C 2 -C 6  alkyl or alkenyl; 
 R 2  is a linking group comprising 1 to 6 carbon atoms that is one of: alkylene or alkoxyalkylene; 
 R 3  is hydrogen, C 1 -C 6  alkyl, or C 1 -C 6  alkoxyalkyl; 
 Ar is a monocyclic or polycyclic group comprising at least one aromatic or heteroaromatic ring; 
 Het is a monocyclic or polycyclic group comprising at least one heteroaromatic ring; 
 R 2  is substituted with zero, one or more of: hydroxyl, C 1 -C 6  alkyl, and C 1 -C 6  hydroxyalkyl; and 
 Ar, Het, R 1 , and R 3  other than hydrogen are independently substituted with zero, one or more of: halogen; —OH; alkyl, —O-alkyl, aryl, —O-aryl or —(O-alkylene) 1-6  optionally substituted with —OH or halogen; —NH 2 ; —NH-alkyl; —N-dialkyl; carboxyl; sulfonyl; carbamoyl; and glycosyl. 
   
     
     
         2 . The liposomal composition of  claim 1 , the aromatic moiety in the phospholipid-polymer-aromatic conjugate being represented by: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The liposomal composition of  claim 1 , the aromatic moiety in the phospholipid-polymer-aromatic conjugate being represented by: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The liposomal composition of  claim 1 , the aromatic moiety in the phospholipid-polymer-aromatic conjugate being represented by: 
       
         
           
           
               
               
           
         
         pyrimidine P being substituted with zero, one, or more of —OH, —O-alkyl, and —NH 2 . 
       
     
     
         5 . The liposomal composition of  claim 1 , the aromatic moiety in the phospholipid-polymer-aromatic conjugate being represented by: 
       
         
           
           
               
               
           
         
         pyrimidine P being substituted with zero, one, or two of —OH, —OMe, or —NH 2 . 
       
     
     
         6 . The liposomal composition of  claim 1 , the aromatic moiety in the phospholipid-polymer-aromatic conjugate being represented by one of: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The liposomal composition of  claim 1 , the phospholipid-polymer moiety in the phospholipid-polymer-aromatic conjugate being represented by one of the following structural formula: 
       
         
           
           
               
               
           
         
         n being an integer from about 60 to about 100; and 
         m being one of: 12, 13, 14, 15, 16, 17, or 18. 
       
     
     
         8 . The liposomal composition of  claim 1 , further comprising a nonradioactive magnetic resonance imaging (MRI) contrast enhancing agent that is at least one of encapsulated by or bound to the membrane. 
     
     
         9 . The liposomal composition of  claim 1 , the membrane further comprising a first phospholipid and a second phospholipid, the second phospholipid being derivatized with a hydrophilic polymer. 
     
     
         10 . The liposomal composition of  claim 1 , the membrane further comprising:
 DPPC;   cholesterol;   diethylenetriaminepentaacetic acid)-bis(stearylamide), gadolinium salt;   1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]; and   the phospholipid-polymer-aromatic conjugate being represented by one of the following structural formulae:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         n being an integer from about 70 to about 90; and 
         m being 14 or 16. 
       
     
     
         11 . A method for imaging amyloid deposits in a patient, the method comprising:
 introducing into the patient a detectable quantity of a liposomal composition, the liposomal composition comprising:
 a membrane, comprising:
 a phospholipid-polymer-aromatic conjugate, the aromatic moiety in the phospholipid-polymer-aromatic conjugate being represented by Structural Formula I:
   —X—Ar—R 1 -Het  (I)
 
 
 
 wherein:
 X is —R 2 —O— or —R 2 —N(R 3 )—; 
 R 1  is C 1 -C 6  alkyl or alkenyl; 
 R 2  is a linking group comprising 1 to 6 carbon atoms that is one of: 
 
 alkylene or alkoxyalkylene;
 R 3  is hydrogen, C 1 -C 6  alkyl, or C 1 -C 6  alkoxyalkyl; 
 Ar is a monocyclic or polycyclic group comprising at least one aromatic or heteroaromatic ring; 
 Het is a monocyclic or polycyclic group comprising at least one heteroaromatic ring; 
 R 2  is substituted with zero, one or more of: hydroxyl, C 1 -C 6  alkyl, and C 1 -C 6  hydroxyalkyl; and 
 Ar, Het, R 1 , and R 3  other than hydrogen are independently substituted with zero, one or more of: halogen; —OH; alkyl, —O-alkyl, aryl, —O-aryl or —(O-alkylene) 1-6  optionally substituted with —OH or halogen; —NH 2 ; —NH-alkyl; —N-dialkyl; carboxyl; sulfonyl; carbamoyl; and glycosyl; 
 
 a nonradioactive magnetic resonance imaging (MRI) contrast enhancing agent at least one of encapsulated by or bound to the membrane; 
   allowing sufficient time for the liposomal composition to be associated with one or more amyloid deposits; and   detecting the liposomal composition associated with the one or more amyloid deposits.   
     
     
         12 . The method of  claim 11 , the detecting comprising detecting using magnetic resonance imaging. 
     
     
         13 . The method of  claim 11 , the nonradioactive magnetic resonance imaging (MRI) contrast enhancing agent being encapsulated by and bound to the membrane. 
     
     
         14 . The method of  claim 13 , the liposomal composition characterized by per-particle relaxivity in mM −1  s −1  of at least about one or more of about: 100,000, 125,000, 150,000, 165,000, 180,000, 190,000, and 200,000. 
     
     
         15 . The method of  claim 11 , the aromatic moiety in the phospholipid-polymer-aromatic conjugate being represented by one of: 
       
         
           
           
               
               
           
         
         pyrimidine P being substituted with zero, one, or more of —OH, —O-alkyl, and —NH 2 . 
       
     
     
         16 . The method of  claim 11 , the membrane further comprising:
 DPPC;   cholesterol;   diethylenetriaminepentaacetic acid)-bis(stearylamide), gadolinium salt;   1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]; and   the phospholipid-polymer-aromatic conjugate being represented by one of the following structural formulae:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         n being an integer from about 70 to about 90; and 
         m being 14 or 16. 
       
     
     
         17 . The method of  claim 11 , further comprising diagnosing the patient with Alzheimer's disease according to detecting the liposomal composition associated with the one or more amyloid deposits. 
     
     
         18 . The method of  claim 11 , further comprising:
 identifying the patient as potentially having Alzheimer's disease according to detecting the liposomal composition associated with the one or more amyloid deposits;   subjecting the patient to an analysis for tau neurofibrillary tangles; and   upon determining the presence of tau neurofibrillary tangles in conjunction with detecting the liposomal composition associated with the one or more amyloid deposits, diagnosing the patent with Alzheimer's disease.   
     
     
         19 . A kit for imaging amyloid deposits in a patient, the kit comprising:
 a liposomal composition, the liposomal composition comprising:
 a membrane, comprising:
 a phospholipid-polymer-aromatic conjugate, the aromatic moiety in the phospholipid-polymer-aromatic conjugate being represented by Structural Formula I:
   —X—Ar—R 1 -Het  (I)
 
 
 
 wherein:
 X is —R 2 —O— or —R 2 —N(R 3 )—; 
 R 1  is C 2 -C 6  alkyl or alkenyl; 
 R 2  is a linking group comprising 1 to 6 carbon atoms that is one of: 
 
 alkylene or alkoxyalkylene;
 R 3  is hydrogen, C 1 -C 6  alkyl, or C 1 -C 6  alkoxyalkyl; 
 Ar is a monocyclic or polycyclic group comprising at least one aromatic or heteroaromatic ring; 
 Het is a monocyclic or polycyclic group comprising at least one heteroaromatic ring; 
 R 2  is substituted with zero, one or more of: hydroxyl, C 1 -C 6  alkyl, and C 1 -C 6  hydroxyalkyl; and 
 Ar, Het, R 1 , and R 3  other than hydrogen are independently substituted with zero, one or more of: halogen; —OH; alkyl, —O-alkyl, aryl, —O-aryl or —(O-alkylene) 1-6  optionally substituted with —OH or halogen; —NH 2 ; —NH-alkyl; —N-dialkyl; carboxyl; sulfonyl; carbamoyl; and glycosyl; 
 
 a nonradioactive magnetic resonance imaging (MRI) contrast enhancing agent at least one of encapsulated by or bound to the membrane; 
   Instructions, the instructions directing a user to
 introduce into the patient a detectable quantity of the liposomal composition; 
 allow sufficient time for the liposomal composition to be associated with one or more amyloid deposits; and 
 detect the liposomal composition associated with the one or more amyloid deposits. 
   
     
     
         20 . The kit of  claim 19 , the instructions further directing the user to diagnose the patient with Alzheimer's disease according to detection of the liposomal composition associated with the one or more amyloid deposits.