Targeted contrast agents for MRI of amyloid deposition

1. A liposomal composition, comprising:

a first phospholipid;

a sterically bulky excipient that is capable of stabilizing the liposomal composition;

a second phospholipid that is derivatized with a first polymer;

a macrocyclic gadolinium-based imaging agent; and

a third phospholipid that is derivatized with a second polymer, the second polymer being conjugated to a targeting ligand, the targeting ligand being represented by:

wherein,

Pyrimidine “P” may be substituted with zero, one, or more of —OH, O-alkyl, and —NH 2 ;

R 2 is a linking group comprising C 1 -C 6 alkyl or C 1 -C 6 alkoxyalkyl; and

R 3 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxyalkyl, and R 3 other than hydrogen is substituted with zero, one, or more —OH, and

wherein the third phospholipid that is derivatized with a second polymer comprises:

or a salt thereof, wherein the variable n is any integer from about 70 to about 90, and wherein the variable m is one of: 12, 13, 14, 15, 16, 17, or 18.

2. The liposomal composition of claim 1 , wherein the first phospholipid comprises hydrogenated soy L-α-phosphatidylcholine (“HSPC”).

3. The liposomal composition of claim 1 , wherein the sterically bulky excipient that is capable of stabilizing the liposomal composition comprises cholesterol (“Chol”).

4. The liposomal composition of claim 1 , wherein the second phospholipid that is derivatized with a first polymer comprises 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(methoxy (polyethylene glycol)-2000) (“DSPE-mPEG2000”).

5. The liposomal composition of claim 1 , wherein the macrocyclic gadolinium-based imaging agent comprises:

6. The liposomal composition of claim 1 , wherein the macrocyclic gadolinium-based imaging agent is selected from the group consisting of:

7. The liposomal composition of claim 5 , wherein the macrocyclic gadolinium-based imaging agent is conjugated to a fourth phospholipid to comprise:

or a salt thereof, and wherein the variable x is one of: 12, 13, 14, 15, 16, 17, or 18.

8. The liposomal composition of claim 7 , wherein the variable x is 16 (the conjugate: “Gd(III)-DOTA-DSPE”).

9. The liposomal composition of claim 1 , wherein the targeting ligand comprises:

10. The liposomal composition of claim 1 , wherein the conjugate of the third phospholipid, the second polymer, and the targeting ligand comprises:

(“ET3-73”).

11. A liposomal composition, comprising:

a macrocyclic gadolinium-based imaging agent conjugated to a first phospholipid comprising:

or a salt thereof, and wherein the variable x is one of: 12, 13, 14, 15, 16, 17, or 18; and

a second phospholipid that is derivatized with a polymer, the polymer being conjugated to a targeting ligand, the conjugate of the second phospholipid, the polymer, and the targeting ligand comprising:

or a salt thereof, wherein the variable n is any integer from about 70 to about 90, and wherein the variable m is one of: 12, 13, 14, 15, 16, 17, or 18.

12. A liposomal composition, comprising:

liposomes, the liposomes comprising;

HSPC;

Chol;

DSPE-mPEG2000;

Gd(III)-DOTA-DSPE; and

ET3-73.

13. The liposomal composition of claim 12 , wherein a molar ratio (%) of components in the liposomal composition is HSPC:Chol:DSPE-mPEG2000:Gd(III)-DOTA-DSPE:ET3-73=about 31.5:about 40:about 2.5:about 25:about 1.

14. The liposomal composition of claim 12 , wherein a molar ratio (%) of components in the liposomal composition is HSPC:Chol:DSPE-mPEG2000:Gd(III)-DOTA-DSPE:ET3-73=about 32.5:about 40:about 2:about 25:about 0.5.

15. The liposomal composition of claim 12 , wherein the average diameter (D 50 ) of the liposomes in the liposomal composition is between about 100 nm to about 140 nm.

16. The liposomal composition of claim 12 , wherein the liposomal composition has a pH of between 6.4 and 8.4.

17. The liposomal composition of claim 12 , comprising a free gadolinium content of less than 2.5 μg/mL.

18. The liposomal composition of claim 12 , wherein the liposomes have an osmolality of between 200-400 mOsmol/kg.