Targeted contrast agents for mri of alpha-synuclein deposition
Abstract
A liposomal composition (“ADx-003”) is provided, ADx-003 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 Formula I: wherein X is —CH 2 —, —CH 2 —CH 2 —, —CHO—, or —O—CO—; Y is —CH—CH═CH— or A and B are independently selected from C and N; R 1 , R 2 , R 3 , and R 4 are independently selected from —H, halogen, —OH, and —CH 3 ; and R 5 , R 6 , and R 7 are independently selected from —H, halogen, —OH, —OCH 3 , —NO 2 , —N(CH 3 ) 2 , C 1 -C 6 alkyl, or a substituted or unsubstituted C 4 -C 6 aryl group, except that when A and/or B is N the adjacent R 5 and/or R 7 is —H, or a pharmaceutically acceptable salt thereof.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound according to Formula I:
wherein
X is —CH 2 —, —CH 2 —CH 2 —, —CHO—, or —O—CO—;
Y is —CH—CH═CH— or
A and B are independently selected from C and N;
R 1 , R 2 , R 3 and R 4 are independently selected from —H, Halogen, —OH, and -Me; and
R 5 , R 6 , and R 7 are independently selected from —H, Halogen, —OH, —OMe, —NO 2 , —NMe 2 , C 1 -C 6 alkyl, or a substituted or unsubstituted C 4 -C 6 aryl group, except that when A and/or B is N the adjacent R 5 and/or R 7 is —H, or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein the compound has the structure:
3 . The compound of claim 1 , wherein the compound has the structure:
4 . The compound of claim 1 , wherein the compound has the structure:
5 . A phospholipid-polymer-targeting ligand conjugate, wherein:
the phospholipid-polymer comprises:
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; and
the targeting ligand comprises a compound according to Formula I:
wherein
X is —CH 2 —, —CH 2 —CH 2 —, —CHO—, or —O—CO—;
Y is —CH—CH═CH— or
A and B are independently selected from C and N;
R 1 , R 2 , R 3 and R 4 are independently selected from —H, Halogen, —OH, and -Me; and
R 5 , R 6 , and R 7 are independently selected from —H, Halogen, —OH, —OMe, —NO 2 , —NMe 2 , C 1 -C 6 alkyl, or a substituted or unsubstituted C 4 -C 6 aryl group, except that when A and/or B is N the adjacent R 5 and/or R 7 is —H, or a pharmaceutically acceptable salt thereof.
6 . The phospholipid-polymer-targeting ligand conjugate of claim 5 , comprising:
wherein n is 77 or 79.
7 . The phospholipid-polymer-targeting ligand conjugate of claim 5 , comprising:
wherein n is 77 or 79.
8 . The phospholipid-polymer-targeting ligand conjugate of claim 5 , comprising:
wherein n is 77 or 79.
9 . 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 a compound according to Formula I:
wherein
X is —CH 2 —, —CH 2 —CH 2 —, —CHO—, or —O—CO—;
Y is —CH—CH═CH— or
A and B are independently selected from C and N;
R 1 , R 2 , R 3 and R 4 are independently selected from —H, Halogen, —OH, and -Me; and
R 5 , R 6 , and R 7 are independently selected from —H, Halogen, —OH, —OMe, —NO 2 , —NMe 2 , C 1 -C 6 alkyl, or a substituted or unsubstituted C 4 -C 6 aryl group, except that when A and/or B is N the adjacent R 5 and/or R 7 is —H, or a pharmaceutically acceptable salt thereof.
10 . The liposomal composition of claim 9 , wherein the first phospholipid comprises hydrogenated soy L-α-phosphatidylcholine (“HSPC”).
11 . The liposomal composition of claim 9 , wherein the sterically bulky excipient that is capable of stabilizing the liposomal composition comprises cholesterol (“Chol”).
12 . The liposomal composition of claim 9 , 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”).
13 . The liposomal composition of claim 9 , wherein the macrocyclic gadolinium-based imaging agent comprises:
14 . The liposomal composition of claim 9 , 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.
15 . The liposomal composition of claim 14 , wherein the variable x is 16 (the conjugate: “Gd(III)-DOTA-DSPE”).
16 . The liposomal composition of claim 9 , wherein the targeting ligand comprises:
17 . The liposomal composition of claim 9 , wherein the targeting ligand comprises:
18 . The liposomal composition of claim 9 , wherein the targeting ligand comprises:
19 . The liposomal composition of claim 9 , 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.
20 . The liposomal composition of claim 9 , wherein the conjugate of the third phospholipid, the second polymer, and the targeting ligand comprises:
wherein n is 77 or 79.Cited by (0)
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