Radioactively labelled amino acid analogues, their preparation and use

• US 7,189,383 B2
• Filed: 08/01/2003
• Issued: 03/13/2007
• Est. Priority Date: 08/02/2002
• Status: Expired due to Fees

• Current Assignee: Vrije Universiteit Brussel
• Original Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Inventors: Mertens, John J. R.
• Primary Examiner(s): Saeed; Kamal A.
• Assistant Examiner(s): CHU, YONG LIANG
• Application Number:
  US10/523,184
• Publication Number:
  US 20060127306A1
• Time in Patent Office: 1,320 Days
• Field of Search: 424/9.4, 514/345, 514/358, 546/300, 546/329, 546/346
• US Class Current: 424/9.4
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 49/0438 Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
• CPC Class Codes: A61K 51/0406 Amines, polyamines, e.g. spermine, spermidine, amino acids, (bis)guanidines
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The present invention relates to Halogenated amino acid analogues for use in diagnosis, which compounds have the general formula (I) wherein: R is (C₁–C₆) alkyl optionally substituted with thioether or ether oxygen atom when n=0, or a substituted aromatic or heteraromatic ring when n=1–6; and m=0 or 1; and X is a halogen atom. The invention further relates to precursor compounds for these analogues, to a method of preparing these analogues, to a pharmaceutical composition comprising these analogues and to the use of these analogues and compositions in the diagnosis of cancer

Claims

1. A halogenated amino acid compound of formula:

3. The compound of claim 1, wherein the halogen is ¹⁸F.

4. The compound of claim 1, wherein the halogen is ¹²³I.

5. The compound of claim 1, wherein the analogue is selected from the group consisting of:

[¹⁸F] labeled L,D-2-amino-3-(2-fluoromethyl-phenyl)-propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(3-fluoromethyl-phenyl)-propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(4-fluoromethyl-phenyl)-propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(2-fluoroethyl-phenyl)-propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(3-fluoroethyl-phenyl)-propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(4-fluoroethyl-phenyl) propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(3-fluoromethyl-pyridin-2-yl) -propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(4-fluoromethyl-pyridin-2-yl)-propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(5-fluoromethyl-pyridin-2-yl)-propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(6-fluoromethyl-pyridin-2-yl) propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(3-fluoroethyl-pyridin-2-yl) -propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(4-fluoroethyl-pyridin-2-yl)-propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(5-fluoroethyl-pyridin-2-yl)-propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(6-fluoroethyl-pyridin-2-yl)-propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(2-fluoromethyl-4-hydroxy-phenyl)-propionic acid;

[¹⁸F] labeled L,D-2-amino-3- (5-fluoromethyl-3-hydroxy-phenyl) -propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(6-fluoromethyl-3-hydroxy-phenyl)-propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(2-fluoroethyl-4-hydroxy-phenyl)-propionic acid;

[⁸F] labeled L,D-2-amino-3-(5-fluoroethyl-3-hydroxy-phenyl) -propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(6-fluoroethyl-3-hydroxy-phenyl)-propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(3-fluoromethyl-5-hydroxy-pyridin-2-yl) -propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(3-fluoroethyl-5-hydroxy-pyridin-2-yl) -propionic acid;

[¹⁸F] labeled L,D-2-amino-3- (3-fluoromethyl-6-hydroxy-pyridin-2-yl) -propionic acid;

[¹⁸F] labeled L,D-2-amino-3- (4-fluoromethyl-6-hydroxy-pyridin-2-yl)-propionic acid;

[¹⁸F] labeled L,D-2-amino-3- (3-fluoroethyl-6-hydroxy-pyridin-2-yl)-propionic acid;

[¹⁸F] labeled L,D-2-amino-3-(4-fluoroethyl-6-hydroxy-pyridin-2-yl)-propionic acid.

6. A pharmaceutical composition comprising the compound of claim 1 and at least one of an excipient, carrier and diluent.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is used as a tracer in at least one of Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (MRI).

8. A method for preparing the compound of claim 1, the method comprising:

providing a precursor having the general formula

9. The method of claim 8 wherein the substitution comprises aliphatic nucleophilic substitution of tosyl, mesityl, or triflate with radioactive fluorine.

10. The method of claim 8 wherein the leaving group is a halogen, and the substitution comprises exchange of the leaving group with radioactive fluorine.

2. A halogenated amino acid compound of formula: