PAMAM dendrimer based CEST imaging agents and uses thereof

Patent metadata

Field	Value
Publication number	US-10898594-B2
Application number	US-201615771786-A
Country	US
Kind code	B2
Filing date	Oct 27, 2016
Priority date	Oct 27, 2015
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

PAMAM dendrimer based CEST imaging agents, pharmaceutical compositions comprising the same and methods of uses thereof are disclosed.

First claim

That which is claimed:

1. A compound of formula (I):

wherein:
each A is

wherein each A′ is independently selected from the group consisting of

a metal chelating moiety (D) optionally comprising a metal or a radiometal suitable for treating or imaging, a therapeutic agent (T), a targeting agent (TG), an imaging agent (IM), PEG-X wherein PEG is polyethylene glycol and X is

or a targeting agent (TG), and —NR-L-W—(CH 2 ) m -SA, provided that at least one of A′ is —NR-L-W—(CH 2 ) m -SA,
L is a linking group selected from the group consisting of —(CH 2 ) m —, —C(═O)—(CH 2 ) m —, —(CH 2 —CH 2 —O) t —, —C(═O)—(CH 2 —CH 2 —O) t —, —(O—CH 2 —CH 2 ) t —, —C(═O)—(O—CH 2 —CH 2 ) t —, —C(═O)—(CHR 2 ) m —NR 3 —C(═O)—(CH 2 ) m —, —C(═O)—(CH 2 ) m —O—C(═O)—NR 3 —(CH 2 ) p —, —C(═O)—(CH 2 ) m —NR 3 —C(═O)—O—CH 2 ) p —, —C(═O)—(CH 2 ) m —NR 3 —C(═O)—NR 3 —(CH 2 ) p —, —C(═O)—(CH 2 ) m —NR 3 —C(═O)—(CH 2 ) p —, —C(═O)—(CH 2 ) m —C(═O)—NR 3 —(CH 2 ) p —, —C(═O)—(CH 2 ) m —NR 3 —C(═O)—NR 3 —(CH 2 ) p —, —C(═O)—(CH 2 ) m —NR 1 —C(═O)—NR 3 —(CH 2 ) p —, —C(═O)—(CH 2 ) m —O—C(═O)—NR 3 —, —C(═O)—CH 2 ) m —O—C(═O)—NR 3 —(CH 2 ) p —, —C(═O)—(CH 2 ) m —NR 3 —C(═O)—O—(CH 2 ) p —, polyethylene glycol, glutaric anhydride, albumin, lysine, and amino-acid,
W is selected from the group consisting of —NR—C(═O)—, —C(═O)—NR—, —S—, —O—, and —SO 2 —;
SA is

each R is independently selected from the group consisting of H and C 1 -C 4 alkyl;
each R 1 is independently selected from the group consisting of H, Na, C 1 -C 4 alkyl, and a protecting group;
each R 2 is independently selected from the group consisting of hydrogen, and —COOR 1 ,
each R 3 is independently selected from the group consisting of hydrogen, substituted or unsubstituted linear or branched alkyl, alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl;
m and p are each independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8;
t is a integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12;
n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
or a salt or a stereoisomer thereof.

2. The compound of claim 1 , wherein n is 5.

3. The compound of claim 1 , wherein the ratio of SA:D:Am is about 42:4:82.

4. The compound of claim 1 , wherein the ratio of SA:D:Ac:Am is about 42:4:56:26.

5. The compound of claim 1 , wherein the ratio of SA:D:PP:Am is about 42:4:40:42.

6. The compound of claim 1 , wherein TG is selected from the group consisting of: cRGD, folic acid, peptide, peptidomimetic, antibody, and antibody fragments.

7. The compound of claim 6 , wherein the antibody or antibody fragment is selected from the group consisting of integrins, folate receptor, somatostatin receptor, EGFR, tenascin, CXCR7, PD-L1, CSF1R, c-Met, HGF, Fab, Fab′, F(ab′)2, single chain antibody, nanobody, minibody, diabody, and CXCR4.

8. The compound of claim 1 , wherein D is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , wherein the metal is selected from the group consisting of Cu, Ga, Zr, Y, Tc, In, Lu, Bi, At, Ac, R, and Sr.

10. The compound of claim 9 , wherein the metal is a radiometal and is selected from the group consisting of 64 Cu, 67 Cu, 68 Ga, 60 Ga, 89 Zr, 86 Y, 94m Tc, 111 In, 67 Ga, 99m Tc, 177 Lu, 213 Bi, 212 Bi, 90 Y, 211 At, 225 Ac, 223 R, and 89 Sr.

11. The compound of claim 1 , wherein the compound is selected from the group consisting of:

12. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier, diluent, or excipient.

13. A method for producing a magnetic resonance imaging (MRI) of a target, comprising: administering and/or
contacting the target with an effective amount of a magnetic resonance imaging contrast agent; and
imaging the target using a Chemical Exchange Saturation Transfer (CEST) or frequency labeled exchange (FLEX) based MRI technique to produce the MR image of the target,
wherein the MRI contrast agent is a compound of formula (I), or a salt or stereoisomer thereof:

wherein:
each A is

wherein each A′ is independently selected from the group consisting of

a metal chelating moiety (D) optionally comprising a metal or a radiometal suitable for treating or imaging, a therapeutic agent (T), a targeting agent (TG), an imaging agent (IM), PEG-X wherein PEG is polyethylene glycol and X is

or a targeting agent (TG), and —NR-L-W—(CH 2 ) m -SA, provided that at least one of A′ is —NR-L-W—(CH 2 ) m -SA,
L is a linking group selected from the group consisting of —(CH 2 ) m —, —C(═O)—(CH 2 ) m —, —(CH 2 —CH 2 —O) t —, —C(═O)—(CH 2 —CH 2 —O) t —, —(O—CH 2 —CH 2 ) t —, —C(═O)—(O—CH 2 —CH 2 ) t —, —C(═O)—(CHR 2 ) m —NR 3 —C(═O)—(CH 2 ) m —, —C(═O)—(CH 2 ) m —O—C(═O)—NR 3 —(CH 2 ) p —, —C(═O)—(CH 2 ) m —NR 3 —C(═O)—O—CH 2 ) p —, —C(═O)—(CH 2 ) m —NR 3 —C(═O)—NR 3 —(CH 2 ) p —, —C(═O)—(CH 2 ) m —NR 3 —C(═O)—(CH 2 ) p —, —C(═O)—(CH 2 ) m —C(═O)—NR 3 —(CH 2 ) p —, —C(═O)—(CH 2 ) m —NR 3 —C(═O)—NR 3 —(CH 2 ) p —, —C(═O)—(CH 2 ) m —NR 1 —C(═O)—NR 3 —(CH 2 ) p —, —C(═O)—(CH 2 ) m —O—C(═O)—NR 3 —, —C(═O)—CH 2 ) m —O—C(═O)—NR 3 —(CH 2 ) p —, —C(═O)—(CH 2 ) m —NR 3 —C(═O)—O—(CH 2 ) p —, polyethylene glycol, glutaric anhydride, albumin, lysine, and amino-acid;
W is selected from the group consisting of —NR—C(═O)—, —C(═O)—NR—, —S—, —O—, and —SO 2 —;
SA is

each R is independently selected from the group consisting of H an

Assignees

• Univ Johns Hopkins

Inventors

• Lesniak Wojciech
• Nimmagadda Sridhar
• Oskolkov Nikita
• Mcmahon Michael
• Song Xiaolei
• Pomper Martin G

Classifications

• C08G79/08

  a linkage containing boron · CPC title

• C08G83/00

  Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00 · CPC title

• A61K49/14

  Peptides, e.g. proteins · CPC title

• A61K49/106

  the complex-forming compound being cyclic, e.g. DOTA · CPC title

• A61K49/16

  Antibodies; Immunoglobulins; Fragments thereof · CPC title