Novel Substrate Based PET Imaging Agents

• US 20100074843A1
• Filed: 04/30/2009
• Published: 03/25/2010
• Est. Priority Date: 04/30/2008
• Status: Active Grant

• Current Assignee: Siemens Medical Solutions USA Incorporated (Siemens AG)
• Original Assignee: Siemens Medical Solutions USA Incorporated (Siemens AG)
• Inventors: Scott, Peter J.H., Kolb, Hartmuth C., Chen, Gang, Mocharla, Vani P., Gangadharmath, Umesh B., Liang, Qianwa, Chen, Kai, Walsh, Joseph C., Kasi, Dhanalakshmi
• Granted Patent: US 9,005,577 B2
• Time in Patent Office: Days
• US Class Current: 424/1.690
• CPC Class Codes: A61K 51/088 conjugates with carriers being peptides, polyamino acids or proteins antibodies A61K51/10
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: G01N 2333/96466 Cysteine endopeptidases (3.4.22)
• CPC Class Codes: G01N 33/60 involving radioactive labelled substances

Abstract

The present application is directed to radiolabeled imaging agents comprising a radiolabel, and a substrate, pharmaceutical compositions comprising radiolabeled imaging agents, and methods of using the radiolabeled imaging agents. The present application is further directed to methods of preparing the radiolabeled imaging agent. Such imaging agents can used in imaging studies, such as Positron Emitting Tomography (PET) or Single Photon Emission Computed Tomography (SPECT).

Claims

1. An imaging agent comprising a compound of formula I:

2. The imaging agent of claim 1 wherein,

X is a bond or a linker connected to an N-terminus of a peptide substrate;

Y is a bond or a linker;

RL is a radiolabel,

Sub is a peptide substrate;

CPV is a cell permeating vector;

Z is a capping group;

m, p, and s are independently 0-4;

n is 0;

t is 1; and

u is 1.

3. The imaging agent of claim 1 wherein,

X_m is a bond or X²X³X⁴, wherein X² is a (C_1-10)alkylenyl group, aryl group or heteroaryl group, X³ is a heteroaryl group or —

C═

N—

O—

, X⁴ is a (C_1-10)alkylenyl group, wherein one of the (C_1-10)alkylenyl carbon atoms is optionally replaced with —

CO—

, —

CONR″

—

, —

NR″

CO—

, —

NR″

—

, —

O—

or —

S—

;

Y is a bond or a linker;

RL is a radiolabel selected from the group consisting of ¹¹C or ¹⁸F;

Sub is a peptide substrate selected from the group consisting of -DEVD-, -DE(N-alkyl V)D, -DEVDD, -DNLD-, -DQTD-, -DMQD-, -YVDA-, -YEVD-, -LEVD-, LEHD-, -DQMD-, VDQQD-, -VDVDA-, -VEID-, -VQVD-, -YVADGW-, -VDVAD-, -VDVADGW-, -RGVDQQDGKNHW-, -GVDQQDGKNW-, -VDQQDGKNW-, -DQQDGKNW-, -QQDGKNW-, -VDQQDGKW-, -VDQQDW-, -VDQQDW-, -WEHD-, -YVAD-, -AEVD-, -IETD-, -AEVD, -VEHD-, -XEXDAMC-, -DEVDAMC, -VEHDAMC-, -VADFMK-, -YEVDGW-, -LEVDGW-, -VDQMDGW-, -VDVADGW-, -VQVDGW-, -VDQVDGW-, -DEVDAMC-, -VD-fmk-, -VAD-fmk-, -YVAD-fmk-, -ID-fmk-, -LD-fmk, -FD-fmk-, -AD-fmk-, -GD-fmk-, -KD-fmk-, -ED-fmk- and -DEVDAFC-;

CPV is selected from the group consisting of polyethyleneimine, PEG, PEI-PEG, PEG-PEI, Lys4, polyamines, histidylated poly-L-lysine, polyarginine, polyornithine, cationic liposomes and lipids, saccharide derivatives and polylysine;

Z is a capping group;

p is 0-4;

n is 0;

s is 1;

t is 1; and

u is 1.

4. The imaging agent of claim 1 wherein,

X_m is X²X³X⁴, wherein X² is a (C_2-6)alkylenyl group or aryl, X³ is a heteroaryl group or —

C═

N—

O—

, X⁴ is a (C_1-10)alkylenyl group, wherein one of the (C_1-10)alkylenyl carbon atoms is optionally replaced with —

CO—

;

Y is a bond or a linker;

RL is ¹⁸F;

Sub is a peptide substrate selected from the group consisting of -DEVD-, -DE(N-alkyl V)D-, -DEVDD-, -DNLD-, -DQTD-, -DMQD-, -YVDA-, -YEVD-, -LEVD-, -LEHD-, -DQMD-, VDQQD-, -VDVDA-, -VEID-, -VQVD-, -YVADGW- and -VDVAD;

CPV is selected from the group consisting of a polyethyleneimine, PEG, PEI-PEG, PEG-PEI, Lys4, polyamines, histidylated polyarginine, polyornithine, cationic liposomes and lipids, saccharide derivatives and polylysine;

Z is a capping group;

p is 0-4;

n is 0;

s is 1;

t is 1; and

u is 1.

5. The imaging agent of claim 1 wherein,

X_m is X²X³X⁴, wherein X² is —

(CH₂)₂—

, X³ is a triazole, X⁴ is —

CH₂C(O)—

;

Y is a -AlaNH—

;

RL is ¹⁸F;

Sub is -DEVD;

CPV is (—

CH₂CH₂O—

)₄;

Z is —

CH₂CH₂CO₂H;

n is 0;

s is 1;

t is 1; and

u is 1.

6. The imaging agent of claim 1 wherein,

X is a bond or a linker connected to an N-terminus of a peptide substrate;

Y is a bond or a linker;

RL is a radiolabel;

Sub is a peptide substrate;

CPV is a cell permeating vector;

Z is a capping group;

m, p, and n are independently 0-4;

s is 0;

t is 1; and

u is 1.

7. The imaging agent of claim 1 wherein,

X_m is X²X³X⁴, wherein X² is C₁-C₆alkylene, X³ is a heteroaryl group, X⁴ is a (C_1-10)alkylenyl group, wherein one of the (C_1-10)alkylenyl carbon atoms is optionally replaced with —

CO—

;

Y is a bond or a linker;

RL is ¹⁸F;

Sub is a peptide substrate selected from the group consisting of -DEVD-, -DE(N-alkyl V)D-, -DEVDD-, -DNLD-, -DQTD-, -DMQD-, -YVDA-, -YEVD-, -LEVD-, -LEHD-, -DQMD-, VDQQD, -VDVDA-, -VEID-, -VQVD-, -YVADGW- and -VDVAD;

CPV is selected from the group consisting o a polyethyleneimine, PEG, PEI-PEG, PEG-PEI, Lys4, polyamines, histidylated poly-L-lysine, polyarginine, polyornithine, cationic liposomes and lipids, saccharide derivatives and polylysine;

Z is a capping group;

p is 0-4;

n is 1;

s is 0;

t is 1; and

u is 1.

8. The imaging agent of claim 1 wherein the compound of formula (I) is

9. The imaging agent of claim 1 wherein,

X_m is X²X³X⁴, wherein X² is C₁-C₆alkylene, X³ is a heteroaryl group, X⁴ is a (C_1-10)alkylenyl group, wherein one of the (C_1-10)alkylenyl carbon atoms is optionally replaced with —

CO—

;

Y is a bond or a linker;

RL is ¹⁸F;

Sub is a peptide substrate selected from the group consisting of -DEVD-, -DE(N-alkyl V)D-, -DEVDD-, -DNLD-, -DQTD-, -DMQD-, -YVDA-, -YEVD-, -LEVD-, -LEHD-, -DQMD-, VDQQD-, -VDVDA-, -VEID-, -VQVD, -YVADGW- and -VDVAD;

CPV is independently selected from the group consisting of a polyethyleneimine, PEG, PEI-PEG, PEG-PEI, Lys4, polyamines, histidylated poly-L-lysine, polyarginine, polyornithine, cationic liposomes and lipids, saccharide derivatives and polylysine;

Z is a capping group;

p is 0-4;

n is 1;

s is 1;

t is 1; and

u is 1.

10. The imaging agent of claim 1 wherein the compound of formula (I) is

11. The imaging agent of claim 1, wherein the radiolabel is selected from the group consisting of ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁶¹Cu, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ⁶⁸Ga, ¹²⁴I, ¹²⁵I, ¹³¹I, ⁹⁹Tc, ⁷⁵Br, ¹⁵³Gd and ³²P.

12. The imaging agent of claim 11, wherein the radiolabel is selected from the group consisting of ¹¹C and ¹⁸F.

13. The imaging agent of claim 1, wherein the radiolabel is a PET or SPECT based isotope.

14. The imaging agent of claim 13, wherein the PET or SPECT based isotope is selected from the group consisting of ¹⁸F, ⁶⁴Cu and ^99mTc.

15. The imaging agent of claim 1, wherein the radiolabel is linked to the substrate using click chemistry, chelation chemistry, oxime formation, or amide-based conjugation chemistry.

16. The imaging agent of claim 1, wherein the substrate comprises a peptide fragment.

17. The imaging agent of claim 16, wherein the peptide fragment is selected from the group consisting of a dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide and nonapeptide.

18. The imaging agent of claim 17, wherein the peptide fragment is selected from the group consisting of -DEVD-, -DE(N-alkyl V)D-, -DEVDD-, -DNLD-, -DQTD-, -DMQD-, -YVDA-, -YEVD-, -LEVD-, -LEHD-, -DQMD-, VDQQD-, -VDVDA-, -VEID-, -VQVD-, -YVADGW-, -VDVAD-, -VDVADGW-, -RGVDQQDGKNHW-, -GVDQQDGKNW-, -VDQQDGKNW-, -DQQDGKNW-, -QQDGKNW-, -VDQQDGKW-, -VDQQDGW-, -VDQQDW-, -WEHD-, -YVAD-, -AEVD-, -IETD-, -AEVD-, -WEHD-, -VEHD-, -XEXDAMC-, -DEVDAMC, -VEHDAMC-, -VADFMK-, -YEVDGW-, -LEVDGW-, -VDQMDGW-, -VDVADGW-, -VQVDGW-, VDQVDGW-, -DEVDAMC, -VD-fmk-, -VAD-fmk-, -YVAD-fmk-, -ID-fmk-, -L-D-fmk, -FD-fmk-, -AD-fmk-, -GD-fmk-, -KD-fmk-, -ED-fmk- and -DEVDAFC-.

19. The imaging agent of claim 1 wherein the substrate comprises a nucleic acid or polynucleotide.

20. The imaging agent of claim 1, wherein the cell-permeating vector is selected from the group consisting of a polyethyleneimine, PEG, PEI-PEG, PEG-PEI, (Lys)_4-, TAT peptide fragment, or saccharide derivative.

21. The imaging agent of claim 1, wherein the cell-permeating vector is an amphiphilic moiety.

22. The imaging agent of claim 21, wherein the amphiphilic moiety is selected from the group consisting of polyethyleneimine, polyamines, histidylated poly-L-lysine, polyarginine, polyornithine, cationic liposomes and lipids, and polylysine.

23. A method for a imaging reporter in vivo, the method comprising contacting the imaging agent of any one of claims 1 to 22 to a cell and imaging the reporter in-vivo.

24. The method of claim 23, wherein the reporter is a protease or nuclease.

25. The method of claim 24, wherein the protease is Caspase 3.

26. A method for detecting or diagnosing a disease involving abnormal apoptosis in a mammal, the method comprising administering an imaging agent of any one of claims 1 to 22 to the mammal, and detecting the presence of retained radioactivity in the mammal.

27. The method of claim 26, wherein the detecting step employs a nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT) for monitoring a distribution of the imaging agent within the body or within a portion thereof.

28. A method of visualizing caspase activity in a body of a patient, the method comprising:

(a) administering to the patient the imaging agent of any one of claims 1 to 19; and

(b) employing a nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT) for visualizing a distribution of the imaging agent within the body or within a portion thereof.