WO1998047541B1

WO1998047541B1 - Contrast agents

Info

Publication number: WO1998047541B1
Application number: PCT/GB1998/001197
Authority: WO
Filing date: 1998-04-24
Publication date: 1998-11-26
Anticipated expiration: 1999-10-24

Abstract

The invention provides a composition of matter of the formula (I): V - L - R, where V is a vector moiety having affinity for an angiogenesis-related endothelias cell receptor, L is a linker moiety or a bond and R is a detectable moiety, characterised in that V is a non-peptidic organic group, or V is peptidic and R is a macromolecular or particulate species providing a multiplicity of labels detectable in in vivo imaging.

Claims

110AMENDED CLAIMS[received by the International Bureau on 12 October 1998 (12.10.98); original claims 1-14 replaced by new claims 1-16 (4 pages)]

1. A composition of matter of formula I

V - L - R (I)

where V is a vector moiety having affinity for an angiogenesis-related endothelial cell receptor, L is a linker moiety or a bond and R is a detectable moiety, characterised in that V is a non-peptidic organic group, or V is peptidic and R is a macromolecular or particulate species providing a multiplicity of labels detectable in in vivo imaging.

2. A composition of matter as claimed in claim 1 wherein V is a non-peptidic organic moiety.

3. A composition of matter as claimed in claim 1 wherein V is a peptide or peptoid moiety.

4. A composition of matter as claimed in claim 1 wherein V is a vector for integrin receptor.

5. A composition of matter as claimed in claim 1 wherein V is a vector for fibronectin receptor.

6. A composition of matter as claimed in claim 1 wherein V is a vector for the VEGF receptor.

7. A composition of matter as claimed in claim 1 wherein V is a vector for the urokinase plasminogen activator receptor (UPAR) .

8. A composition of matter as claimed in claim 1 wherein V is selected from the list of vector moieties comprising: 111

N²- [3S-hydroxy-4- (N-hydroxyamino) 2R- isobutylsuccinyl] -L- (4- oxymethylcarboxy)phenylalanine-N¹-methylamide,

N- (4-octylphenyl) -3- (2-carboxyethyl) -6, 7-dihydro- 5H-thiazolo [3 , 2-a] pyrimidine-2-carboxamide,

N²- [3S-hydroxy-4-hydroxyamino) -2R- isobutylsuccinyl] -L-phenylalanine-IS^-methylamide,

N- (6-aminohexyl) - [4- (6 , 7-dimethoxy-quinazolin-4- ylamino) henyl] acetamide hydrochloride ,

3-0x0-2- [2- (pyridin-2-ylamino) -ethyl] -2 , 3-dihydro- lH-isoindole-5-carboxylic acid [2- (2-amino- ethylcarbamoyl) -ethyl] -amide, and

N- (6-amino-hexyl) -2- {3- [2- (4-chloro-benzyloxy) -2 - (2 , 4-dichloro-phenyl) -ethyl] -3H-imidazol-l-yl } - acetamide .

9. A composition of matter as claimed in claim 1 wherein V-L-R is selected from the following residues:

Gd (III), ^99mTc or ^nιIn chelates of the DTPA derivatives of the vector moieties as claimed in claim 8.

10. A composition of matter as claimed in any one of claims 1 to 8 wherein R is a radionuclide .

11. A composition of matter as claimed in claim 10 wherein R is an iodine or metal radionuclide.

12. A pharmaceutical composition comprising a composition of matter of formula I as defined in any one of claims 1 to 11 together with at least one 112

pharmaceutically acceptable carrier or excipient .

13. The use of a composition of matter of formula I as defined in any one of claims 1 to 11 for the manufacture of a contrast medium for use in a method of diagnosis involving administration of said contrast medium to an animate subject and generation of an image of at least part of said subject.

14. A method of generating an image of an animate human or non-human animal subject involving administering a contrast agent to said subject and generating an image of at least a part of said subject to which said contrast agent has distributed, characterised in that as said contrast agent is used a composition of matter of formula I as defined in any one of claims 1 to 11.

15. A method of monitoring the effect of treatment of a human or non-human animal subject with a drug to combat or provoke effects associated with angiogenesis , said method involving administering to said subject a composition of matter of formula I as defined in any one of claims 1 to 11 and detecting the uptake of said agent by angiogenesis related endothelial cell receptors, said administration and detection optionally but preferably being effected repeatedly, eg. before, during and after treatment with said drug.

16. A process for the preparation of a composition of a matter of formula I as defined in any one of claims 1 to 11, said process comprising conjugating (i) an organic compound having binding affinity for an endothelial cell receptor associated with angiogenesis to (ii) a compound detectable in a diagnostic imaging procedure or a chelant compound and if necessary metallating chelant groups in the resultant conjugate 113

with a metal ion detectable in a diagnostic imaging procedure .

114

STATEMENT UNDER ARTICLE 19

New claim 4 relates to compositions of the invention wherein V is a vector for the fibronectin receptor. Reference is made to page 3 of the application, line 20.

New claim 5 relates to compositions of the invention wherein V is a vector for integrin receptors. Reference is made to page 3 of the application, lines 29-32.

New claims 6 to 16 correspond to former claims 4 to 14, renumbered in view of the insertion of new claims 4 and 5.

New claim 9 (former claim 7) has been amended by correction of the erroneous mention of ¹³¹I₂ to the correct ^{ι n}In. ¹³¹I₂ was a typographical mistake and was obviously an error because ¹³¹I₂ does not form chelates whereas ^mIn does. Reference is made to page 61 of the application, lines 16 and 25.