Technetium labelled peptides

Patent metadata

Field	Value
Publication number	US-9259496-B2
Application number	US-201214002021-A
Country	US
Kind code	B2
Filing date	Mar 2, 2012
Priority date	Mar 4, 2011
Publication date	Feb 16, 2016
Grant date	Feb 16, 2016

Abstract

The present invention relates to technetium imaging agents comprising radiolabeled c-Met binding peptides suitable for SPECT or PET imaging in vivo. The c-Met binding peptides are labelled via chelator conjugates. Also disclosed are pharmaceutical compositions, methods of preparation of the agents and compositions, plus methods of in vivo imaging using the compositions, especially for use in the diagnosis of cancer.

First claim

What is claimed is:

1. An imaging agent which comprises a radioactive x Tc complex of a chelator conjugate of a c-Met binding peptide, said chelator conjugate being of Formula I:
Z 1 -[cMBP]-Z 2   (I)

where:

x Tc is the radioisotope 94m Tc or 99m Tc;
cMBP is an 18 to 30-mer c-Met binding cyclic peptide of Formula II:
-(A) x -Q-(A′) y -  (II)

where Q is the amino acid sequence (SEQ-1): -Cys a -X 1 -Cys c -X 2 -Gly-Pro-Pro-X 3 -Phe-Glu-Cys d -Trp-Cys b -Tyr-X 4 -X 5 -X 6 -
wherein X 1 is Asn, His or Tyr;
X 2 is Gly, Ser, Thr or Asn;
X 3 is Thr or Arg;
X 4 is Ala, Asp, Glu, Gly or Ser;
X 5 is Ser or Thr;
X 6 is Asp or Glu;
and Cys a-d are each cysteine residues such that residues a and b as well as c and d are cyclised to form two separate disulfide bonds;
one of A and A′ is any amino acid other than Cys, and the other one of A or A′ is a linker peptide selected from: -Gly-Gly-Gly-Lys- (SEQ-4), -Gly-Ser-Gly-Lys- (SEQ-5) or -Gly-Ser-Gly-Ser-Lys- (SEQ-6) wherein a Z 3 group is attached to the epsilon amine group of the Lys residue of said linker peptide and Z 3 is conjugated to x Tc;
x and y are independently integers of value 0 to 13, and are selected such that [x+y]=1 to 13;
Z 1 is attached to the N-terminus of cMBP, and is —NH(C═O)R G where —(C═O)R G has R G selected from: C 1-6 alkyl, or C 3-10 aryl groups or comprises a polyethyleneglycol (PEG) building block;
Z 2 is attached to the C-terminus of cMBP and is a primary amide;
Z 3 is a chelator of Formula (III):

wherein E 1 -E 6 are each independently an R′ group;
each R′ is independently H or C 1-4 alkyl, C 3-7 alkylaryl, C 2-7 alkoxyalkyl, C 1-4 hydroxyalkyl, C 1-4 fluoroalkyl, C 2-7 carboxyalkyl or C 1-4 aminoalkyl, or two or more R′ groups together with the atoms to which they are attached form a carbocyclic, heterocyclic, saturated or unsaturated ring;
L is a synthetic linker group of formula -(A″) m - wherein each A″ is independently —CR2-, —CR═CR—, —C═C—, —CR 2 CO 2 —, —CO 2 CR 2 —, —NRCO—, —CONR—, —NR(C═O)NR—, —NR(C═S)NR—, —SO 2 NR—, —NRSO 2 —, —CR2OCR2-, —CR 2 SCR 2 —, —CR 2 NRCR 2 —, a C 4-8 cycloheteroalkylene group, a C 4-8 cycloalkylene group, a C 5-12 arylene group, or a C 3-12 heteroarylene group, or a monodisperse polyethyleneglycol (PEG) building block;
each R is independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxyalkyl or C 1-4 hydroxyalkyl; and
m is an integer of value 1 to 10.

2. The imaging agent of claim 1 , wherein Q comprises the amino acid sequence of either SEQ-2 or SEQ-3:

(SEQ-2)

Ser-Cys a -X 1 -Cys c -X 2 -Gly-Pro-Pro-X 3 -Phe-Glu-Cys d -

Trp-Cys b -Tyr-X 4 -X 5 -X 6 ;

(SEQ-3)

Ala-Gly-Ser-Cys a -X 1 -Cys c -X 2 -Gly-Pro-Pro-X 3 -Phe-

Glu-Cys d -Trp-Cys b -Tyr-X 4 -X 5 -X 6 -Gly-Thr.

3. The imaging agent of claim 1 , wherein X 3 is Arg.

4. The imaging agent of claim 1 , where cMBP has the amino acid sequence (SEQ-7):

Ala-Gly-Ser-Cys a -Tyr-Cys c -Ser-Gly-Pro-Pro-Arg-Phe-

Glu-Cys d -Trp-Cys b -Tyr-Glu-Thr-Glu-Gly-Thr-Gly-Gly-

Gly-Lys.

5. The imaging agent of claim 1 , where the chelator is of Formula IIIA:

where q is an integer of value 1 to 6, and A″ is as defined for Formula III.

6. The imaging agent of claim 1 , where x Tc is 99m Tc.

7. A method of preparation of the imaging agent of claim 1 which comprises reacting the chelator conjugate with x Tc as defined in claim 1 .

8. A radiopharmaceutical composition comprising the imaging agent of claim 1 together with a pharmaceutically acceptable carrier.

9. A kit for the preparation of a radiopharmaceutical composition which comprises the chelator conjugate of claim 1 in sterile, solid form.

10. A method of imaging a mammalian body comprising administering to said body the imaging agent of claim 1 , or the radiopharmaceutical composition of claim 8 , and generating an image of at least a part of said body using PET or SPECT.

11. The method of claim 10 wherein the images are of sites of c-Met overexpression or localization.

12. The method of claim 11 wherein the site of c-Met overexpression or localization is a cancer or precancerous lesion.

13. The method of claim 10 which is performed repeatedly to monitor the efficacy of cancer therapy of a human or animal body administered a drug or radiation, said imaging occurring before, after, and optionally during said drug or radiation administration.

Assignees

• Iveson Peter Brian
• Indrevoll Bard
• Newton Ben
• Bhalla Rajiv
• Johannesen Edvin Wilhelm
• Ge Healthcare Ltd

Inventors

• Iveson Peter Brian
• Indrevoll Bard
• Newton Ben
• Bhalla Rajiv
• Johannesen Edvin Wilhelm

Classifications

• A61K51/088 Primary

  conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10) · CPC title

• A61K51/08 Primary

  Peptides, e.g. proteins {, carriers being peptides, polyamino acids, proteins} · CPC title

• A61K51/02

  characterised by the carrier {, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus} · CPC title

• A61K51/04

  Organic compounds · CPC title