Peptide radiotracer compositions

Patent metadata

Field	Value
Publication number	US-9533059-B2
Application number	US-201113816589-A
Country	US
Kind code	B2
Filing date	Aug 11, 2011
Priority date	Aug 18, 2010
Publication date	Jan 3, 2017
Grant date	Jan 3, 2017

Abstract

The present invention relates to imaging agent compositions comprising radiolabelled c-Met binding peptides suitable for positron emission tomography (PET) imaging in vivo. The c-Met binding peptides are labelled with the radioisotope 18 F. 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 management of cancer.

First claim

The invention claimed is:

1. An imaging agent composition which comprises (i) a 18 F-radiolabelled c-Met binding cyclic peptide and (ii) an unlabelled c-Met binding cyclic peptide;
wherein the unlabelled c-Met binding cyclic peptide has the same amino acid sequence as the radiolabelled c-Met binding cyclic peptide;
wherein the unlabelled c-Met binding cyclic peptide is present in the composition at no more than 50 times the molar amount of the 18 F-labelled c-Met binding cyclic peptide; and
wherein the c-Met binding cyclic peptide is an 18 to 30-mer cyclic peptide of Formula I:
Z 1 -[cMBP]-Z 2   (I)

where cMBP is of Formula II:
-(A) x -Q-(A′) y -  (II);

and Q is the amino acid sequence SEQ ID NO: 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;
A and A′ are independently any amino acid other than Cys, with the proviso that at least one of A and A′ is present and is Lys;
x and y are independently integers of value 0 to 13, and are chosen such that [x+y]=1 to 13;
Z 1 is attached to the N-terminus of cMBP, and is H or M IG ;
Z 2 is attached to the C-terminus of cMBP and is OH, OB c , or M IG ,
where B c is a biocompatible cation;
each M IG is independently a metabolism inhibiting group which is a biocompatible group which inhibits or suppresses in vivo metabolism of the cMBP; and
wherein the labelled cMBP is labelled at the Lys residue of the A or A′ groups with 18 F, and
wherein the unlabelled c-Met binding cyclic peptide excludes the c-Met binding cyclic peptide labelled with 19 F, where said 19 F labelled c-Met binding cyclic peptide and 18 F-radiolabelled c-Met binding cyclic peptide differ only in the isotopes of the fluorine atom.

2. The imaging agent composition of claim 1 , where cMBP is of Formula IIA:
-(A) x -Q-(A′) z -Lys-  (IIA)

wherein: z is an integer of value 0 to 2 and [x+z]=0 to 12, and cMBP comprises only one Lys residue.

3. The imaging agent composition of claim 1 , wherein cMBP comprises the amino acid sequence of either SEQ ID NO: 2 or SEQ ID NO: 3:

(SEQ ID NO: 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 ID NO: 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.

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

5. The imaging agent composition of claim 1 , wherein either the -(A) x - or -(A′) y - groups comprise a linker peptide which is chosen from:

(SEQ ID NO: 4)

-Gly-Gly-Gly-Lys-,

(SEQ ID NO: 5)

-Gly-Ser-Gly-Lys-

or

(SEQ ID NO: 6)

-Gly-Ser-Gly-Ser-Lys-.

6. The imaging agent composition of claim 5 , where cMBP has the amino acid sequence (SEQ ID NO: 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.

7. The imaging agent composition of claim 1 , where both Z 1 and Z 2 are independently M IG .

8. The imaging agent composition of claim 7 , where Z 1 is acetyl and Z 2 is a primary amide.

9. The imaging agent composition of claim 1 , wherein cMBP is labelled at epsilon amine group of the Lysine residue of the A or A′ groups with 18 F.

10. The imaging agent composition of claim 1 , wherein cMBP is labelled at epsilon amine group of the carboxy terminal Lysine with 18 F.

11. The imaging agent composition of claim 1 , further comprising 4-aminobenzoic acid as radioprotectant and 5-10% v/v ethanol as solubilizer.

12. The imaging agent composition of claim 1 , wherein the 18 F-radiolabelled c-Met binding cyclic peptide has the following structure:

wherein n=18 and Formula I is radiolabelled at the Lysine residue of the A or A′ groups of the cMBP.

13. The imaging agent composition of claim 1 , wherein the 18 F-radiolabelled c-Met binding cyclic peptide has the following structure:

wherein n=18 and Formula I is radiolabelled at the Lysine residue of the A or A′ groups of the cMBP.

14. The imaging agent composition of claim 1 , which is maintained at or above pH 7.5 and/or further comprises a solubiliser.

15. The imaging agent composition of claim 1 , which further comprises one or more radioprotectants.

16. A pharmaceutical composition which comprises the imaging agent composition of claim 1 together with a biocompatible carrier, in a sterile form suitable for mammalian administration.

Assignees

• Iveson Peter Brian
• Bhalla Rajiv
• Indrevall Bard
• Getvoldsen Gareth
• Ge Healthcare Ltd

Inventors

• Iveson Peter Brian
• Bhalla Rajiv
• Indrevall Bard
• Getvoldsen Gareth

Classifications

• A61K49/00 Primary

  Preparations for testing in vivo · CPC title

• A61K38/16

  Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)} · CPC title

• A61K51/088 Primary

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

• A61K38/1833

  Hepatocyte growth factor; Scatter factor; Tumor cytotoxic factor II · CPC title

• C07K7/64

  Cyclic peptides containing only normal peptide links · CPC title