Nitrogen-containing macrocyclic conjugates as radiopharmaceuticals

Patent metadata

Field	Value
Publication number	US-9701694-B2
Application number	US-200913132194-A
Country	US
Kind code	B2
Filing date	Dec 2, 2009
Priority date	Dec 2, 2008
Publication date	Jul 11, 2017
Grant date	Jul 11, 2017

Abstract

The present invention relates to compounds that are useful as metal ligands and which either contain a molecular recognition moiety or can be bound to a molecular recognition moiety and methods of making these compounds. Once the compounds that contain a molecular recognition moiety are coordinated with a suitable metallic radionuclide, the coordinated compounds are useful as radiopharmaceuticals in the areas of radiotherapy and diagnostic imaging. The invention therefore also relates to methods of diagnosis and therapy utilising the radiolabelled compounds of the invention.

First claim

What is claimed is:

1. A compound of formula (I),

wherein:
L is a nitrogen containing macrocyclic metal ligand of the formula:

V is selected from the group consisting of N and CR 4 ;
each R x and R y are independently H or CH 3 ;
each p is independently an integer selected from the group consisting of 2, 3, and 4;
R 4 is optionally substituted C 1 -C 12 alkyl;
X is a group of the formula —(CH 2 ) n 13 , wherein n is 1, 2, 3 or 4;
Y is a molecular recognition moiety, wherein the molecular recognition moiety is selected from the group consisting of an antibody, a protein, a peptide, a carbohydrate, a nucleic acid, an oligonucleotide, an oligosaccharide and a liposome;
or a pharmaceutically acceptable salt or complex thereof.

2. The compound according to claim 1 wherein X is —CH 2 CH 2 CH 2 —.

3. The compound according to claim 1 wherein L is a macrocyclic metal ligand of the formula:

wherein R x , R y and p are as defined in claim 1 .

4. The compound according to claim 1 , wherein L is a group of the formula:

5. The compound according to claim 1 , wherein each molecular recognition moiety includes a spacer portion and a recognition portion, wherein the spacer portion joins the recognition portion to the remainder of the molecule.

6. The compound according to claim 1 , wherein the nitrogen-containing macrocyclic metal ligand is coordinated with a metal ion.

7. The compound according to claim 6 wherein the metal ion is a radionuclide selected from the group consisting of Cu, Tc, Gd, Ga, In, Co, Re, Fe, Au, Ag, Rh, Pt, Bi, Cr, W, Ni, V, Ir, Zn, Cd, Mn, Ru, Pd, Hg, and Ti.

8. The compound according to claim 7 , wherein the metal ion is a radionuclide selected from the group consisting of 60 Cu, 62 Cu, 64 Cu and 67 Cu.

9. A pharmaceutical composition comprising the compound according to claim 1 .

10. A method of producing a compound of formula (I):

wherein:
L is a nitrogen-containing macrocyclic metal ligand of the formula:

V is selected from the group consisting of N and CR 4 ;
each R x and R y are independently H or CH 3 ;
each p is independently an integer selected from the group consisting of 2, 3, and 4;
R 4 is optionally substituted C 1 -C 12 alkyl;
X is a group of the formula —(CH 2 ) n —, wherein n is 1, 2, 3 or 4;
Y is selected from a molecular recognition moiety, wherein the molecular recognition moiety is selected from the group consisting of an antibody, a protein, a peptide, a carbohydrate, a nucleic acid, an oligonucleotide, an oligosaccharide and a liposome;

the method comprising:
(a) reacting an amino substituted metal chelating ligand or a metal complex thereof of the formula:
L-NH 2

 wherein L is a nitrogen-containing macrocyclic metal ligand; with an activated dicarbonyl compound; and
(b) isolating the compound of formula (I) or a metal complex thereof.

11. A method of radioimaging a subject, the method comprising the step of administering an effective amount of the compound according to claim 6 to the subject.

12. The compound according to claim 1 , wherein:
L is a nitrogen containing macrocyclic ligand of the formula:

V is CR 4 ;
R 4 is CH 3 ;
each R x and R y are independently H;
p is 2;
X is —CH 2 CH 2 CH 2 —; and
Y is Tyr 3 -octreotate,
or a pharmaceutically acceptable salt or complex thereof.

13. A compound of formula (I) according to claim 12 , wherein the nitrogen containing macrocyclic metal ligand is coordinated with a metal ion.

14. A compound of formula (I) according to claim 12 , wherein the nitrogen containing macrocyclic metal ligand is coordinated with a metal ion which is selected from the group consisting of 60 Cu, 62 Cu, 64 Cu and 67 Cu.

Assignees

• Donnelly Paul Stephen
• Ma Michelle Therese
• Scanlon Denis Bernard
• Univ Melbourne

Inventors

• Donnelly Paul Stephen
• Ma Michelle Therese
• Scanlon Denis Bernard

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K51/088

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

• A61K49/10

  Organic compounds · CPC title

• A61K51/082

  the peptide being a RGD-containing peptide · CPC title

• A61K51/00

  Preparations containing radioactive substances for use in therapy or testing in vivo · CPC title