Non-invasive diagnostic imaging technology for mitochondria dysfunction using radiolabeled lipophilic salts

• US 7,112,318 B2
• Filed: 02/06/2003
• Issued: 09/26/2006
• Est. Priority Date: 02/06/2002
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Scheffel, Ursula A., Ravert, Hayden T., Dannals, Robert Francis, Frost, James J., Madar, Igal
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US10/360,566
• Publication Number:
  US 20040033197A1
• Time in Patent Office: 1,328 Days
• Field of Search: 424/1.11, 424/1.65, 424/9.1, 424/9.3, 424/9.4, 424/9.5, 424/9.6, 424/9.7, 424/9.8, 424/1.77, 424/1.81, 424/1.85, 424/1.89, 424/9.2, 534/7, 534 10- 16, 568/8, 568/16, 568/17
• US Class Current: 424/1.89
• CPC Class Codes: A61B 6/507 for determination of haemodynamic parameters, e.g. perfusion CT
• CPC Class Codes: A61B 6/508 for non-human patients
• CPC Class Codes: A61K 51/04 Organic compounds
• CPC Class Codes: A61K 51/0476 complexes from monodendate ligands, e.g. sestamibi
• CPC Class Codes: A61K 51/0489 Phosphates or phosphonates, e.g. bone-seeking phosphonates; phospholipids: A61K51/0408; nucleotides or nucleic acids: A61K51/0491
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The invention provides a series of lipophilic phosphonium cations (PhCs) labeled with ¹⁸F for non-invasive assessment of ΔΨm, lipophilic ammonium cation analogs of the PhCs, and methods of using same for imaging and detection of mitochondrial-related pathologies in patients using PET or SPECT.

Claims

1. A compound comprising at least one pharmaceutically acceptable anion and a cation represented by the following formula:

2. The compound of claim 1 wherein R¹ is aralkyl.

10. An imaging method comprising:

contacting cells or tissues with a compound of any one of claims 1–

9; and

making a radiographic image.

11. The method of claim 10 wherein a tumor is imaged.

12. The method of claim 10 wherein the compound preferentially accumulates in mitochondria of tumor cells.

13. The method of claim 11 wherein the tumor is neoplasm.

14. The method of claim 11 wherein the tumor is a lung tumor.

15. The method of claim 11 wherein the tumor is a breast tumor.

16. The method of claim 11 wherein the tumor is a prostate tumor.

17. The method of claim 11 wherein the tumor imaging method is capable of distinguishing between tissue inflammation and tumors.

18. The method of claim 10 wherein myocardial cells or tissue is imaged.

19. The method of claim 10 wherein the compound is detected by positron emission tomography.

20. The method of claim 10 wherein the subject is a human.

3. A compound comprising at least one pharmaceutically acceptable anion and a cation represented by the following formula:

4. The compound of claim 3 wherein at least one of Ar¹, Ar², and Ar³ is aryl.

5. The compound of claim 3 wherein at least one of Ar¹, Ar², and Ar³ is phenyl.

6. The compound of claim 3 wherein each Ar¹, Ar², and Ar³ is phenyl.

7. The compound of claim 3 wherein m is 1.

8. A compound which selected from the group consisting of:

¹⁸F-4-fluorobenzyl-triphenylphosphonium;

¹⁸F-2-fluorobenzyl-triphenylphosphonium;

or

¹⁸F-3-fluorobenzyl-triphenylphosphonium.

9. A compound selected from the group consisting of

¹⁸F-2-fluoroethyl-triphenylphosphonium;

¹⁸F-2-fluoroethyl-tri-ortho-tolylphosphonium;

¹⁸F-2-fluoroethyl-tri-meta-tolylphosphonium;

¹⁸F-2-fluoroethyl-tri-para-tolylphosphonium;

¹⁸F-3-fluoropropyl-triphenylphosphonium;

¹⁸F-3-fluoropropyl-tri-ortho-tolylphosphonium;

¹⁸F-3-fluoropropyl-tri-meta-tolylphosphonium;

¹⁸F-3-fluoropropyl-tri-para-tolylphosphonium;

¹⁸F-4-fluorobutyl-triphenylphosphonium;

¹⁸F-4-fluorobutyl-tri-ortho-tolylphosphonium;

¹⁸F-4-fluorobutyl-tri-meta-tolylphosphonium;

¹⁸F-4-fluorobutyl-tri-para-tolylphosphonium;

¹⁸F-2-fluorobenzyl-tri-ortho-tolylphosphonium;

¹⁸F-2-fluorobenzyl-tri-meta-tolylphosphonium;

¹⁸F-2-fluorobenzyl-tri-para-tolylphosphonium;

¹⁸F-3-fluorobenzyl-tri-ortho-tolylphosphonium;

¹⁸F-3-fluorobenzyl-tri-meta-tolylphosphonium;

¹⁸F-3-fluorobenzyl-tri-para-tolylphosphonium;

¹⁸F-4-fluorobenzyl-tri-ortho-tolylphosphonium;

¹⁸F-4-fluorobenzyl-tri-meta-tolylphosphonium;

¹⁸F-4-fluorobenzyl-tri-para-tolylphosphonium;

¹⁸F-3-fluoro-4-formyl-benzyl-triphenylphosphonium;

¹⁸F-3-fluoro-4-formyl-benzyl-tri-ortho-tolylphosponium;

¹⁸F-3-fluoro-4-formyl-benzyl-tri-meta-tolylphosphonium;

¹⁸F-3-fluoro-4-formyl-benzyl-tri-para-tolylphosphonium;

(¹⁸F-4-fluorobenzyl)-(2-chloroethyl)-diphenylphosphonium;

(¹⁸F-4-fluorobenzyl)-(3-chloropropyl)-diphenylphosphonium;

(¹⁸F-4-fluorobenzyl)-(4-chlorobutyl)-diphenylphosphonium;

(¹⁸F-4-fluorobenzyl)-(6-chloropentyl)-diphenylphosphonium;

(¹⁸F-4-fluorobenzyl)-(5-chlorohexyl)-diphenylphosphonium;

¹⁸F-2-fluoroethyl-tri(4-pyridyl)phosphonium;

¹⁸F-3-fluoropropyl-tri(4-pyridyl)phosphonium;

¹⁸F-4-fluorobutyl-tri(4-pyridyl)phosphonium;

¹⁸F-2-fluorobenzyl-tri(4-pyridyl)phosphonium;

¹⁸F-3-fluorobenzyl-tri(4-pyridyl)phosphonium;

¹⁸F-4-fluorobenzyl-tri(4-pyridyl)phosphonium;

or

¹⁸F-3-fluoro-4-formyl-benzyl-tri(4-pyridyl)phosphonium.