Porphyrin compounds for imaging tissue oxygen

• US 6,362,175 B1
• Filed: 10/15/1993
• Issued: 03/26/2002
• Est. Priority Date: 09/20/1991
• Status: Expired due to Term

• Current Assignee: Oxygen Enterprises, Ltd.
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Vinogradov, Sergei, Wilson, David F.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/137,624
• Time in Patent Office: 3,084 Days
• Field of Search: 540/145, 514/185, 514/410, 534/15, 128/654
• US Class Current: 514/185
• CPC Class Codes: A61B 2562/146 for optical coupling
• CPC Class Codes: A61B 5/14556 by fluorescence A61B5/14555 takes precedence
• CPC Class Codes: A61B 5/1459 invasive, e.g. introduced into the body by a catheter A61B5/1464 takes precedence
• CPC Class Codes: A61B 5/6833 Adhesive patches
• CPC Class Codes: A61B 5/6848 Needles
• CPC Class Codes: A61K 41/0071 PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07H 15/26 Acyclic or carbocyclic radicals, substituted by hetero rings
• CPC Class Codes: G01N 21/64 Fluorescence; Phosphorescence
• CPC Class Codes: G01N 21/6408 with measurement of decay time, time resolved fluorescence
• CPC Class Codes: G01N 21/6456 Spatial resolved fluorescence measurements; Imaging
• CPC Class Codes: G01N 21/6458 Fluorescence microscopy fluorescence microscopes per se G02B21/0076 and G02B21/16
• CPC Class Codes: G01N 31/225 for oxygen, e.g. including dissolved oxygen

Abstract

Methods and compounds for the measurement in vivo of oxygen in living tissue. The compounds preferably comprise a substituted porphyrin which is soluble in aqueous solution which is capable of absorbing an amount of energy and subsequently releasing the energy as phosphorescent light. In preferred embodiments, the porphyrin has an absorption band which is at a wavelength in the near infra-red window of living tissue and the phosphorescence is quenched by molecular oxygen according to the Stern-Volmer relationship.

Claims

1. A compound for the measurement of oxygen in living tissue comprising a substituted porphyrin which is capable of absorbing an amount of energy and subsequently releasing said energy as phosphorescent light, said substituted porphyrin having an absorption band at a wave-length in the near infra-red region in living tissue and said phosphorescence being quenched by molecular oxygen, said substituted porphyrin being soluble in an aqueous solution.

2. The compound of claim 1 wherein said compound has an absorption band at a wavelength of greater than about 600 nm.

3. The compound of claim 1 wherein said compound has an emission band at a wavelength in the near infra-red window of living tissue.

4. The compound of claim 3 wherein said compound has an emission band at a wavelength of greater than about 600 nm.

5. The compound of claim 3 wherein said absorption and emission bands are located in the range from about 600 nm to about 1300 nm.

6. The compound of claim 2 wherein said absorption band ranges from about 600 to about 640 nm.

7. The compound of claim 2 wherein said absorption band ranges from about 640 to about 720 nm.

8. The compound of claim 1 wherein said porphyrin is a metalloporphyrin.

9. A compound of claim 1 which is capable of phosphorescing and which has the formula

wherein:

R₁ is 2(3)-substituted aryl;

R₂ and R₃ are independently hydrogen or are linked together to form substituted or unsubstituted aryl; and

M is H₂ or a metal, said substituent group rendering the compound soluble in an aqueous solution.

10. The compound of claim 9 wherein M is a metal selected from the group consisting of Zn, Al, Sn, Y, La, Lu, Pd, Pt and derivatives thereof.

11. The compound of claim 10 wherein said derivatives are selected from the group consisting of LuOH, Pd, LaOH or Pt.

12. The compound of claim 9 wherein R₂ and R₃ are linked together to form a benzo system.

13. The compound of claim 12 wherein said benzo is selected from the group consisting of phenyl, naphthyl, anthryl, and phenanthryl.

14. The compound of claim 13 wherein the benzo of R₁ is a substituted phenyl.

15. The compound of claim 9 wherein said substituent group is a flexible, hydrophilic polymeric compound or a sugar compound.

16. The compound of claim 14 wherein said phenyl is further substituted with a substituent group at the 4-position.

17. The compound of claim 15 wherein said substituent is selected from the group consisting of a polyamide, polyethylene glycol, and polypropylene glycol.

18. The compound of claim 8 wherein the prophyrin is selected from the group consisting of tetrabenzoporphyrin, tetranapthoporphyrin, tetraanthraporphyrin, and derivatives thereof.

19. The compound of claim 18 wherein the metal is selected from the group consisting of Zn, Al, Sn, Y, La, Lu, Pd, Pt, and derivatives thereof.

20. The compound of claim 18 wherein the derivative is a meso-tetrapheylated compound.

21. The compound of claim 20 wherein the metalloporphyrin is (Pd) tetraphenyltetrabenzoporphyrin.

22. The compound of claim 20 wherein the metalloporphyrin is (Lu) tetraphenyltetranapwthoporphyrin.

23. The compound of claim 20 wherein the metalloporphyrin is (Pd) meso-tetra-(4-carboxylphenyl)porphyrin.

24. The compound of claim 23 which is modified with polyethylene glycol.

25. The compound of claim 14 wherein the porphyrin is phenyltetrabenzoporphyrin.

26. The compound of claim 20 wherein the porphyrin is meso-tetraphenyltetrabenzoporphyrin.

27. The compound of claim 20 wherein the porphyrin is meso-tetraphenyltetranaphthoporphyrin.

28. The compound of claim 17 wherein said substituent is selected from the group consisting of polyethylene glycol and polypropylene glycol.

29. The compound of claim 28 wherein said substituent is polyethylene glycol.

30. The compound of claim 28 wherein said substituent is polypropylene glycol.

31. The compound of claim 18 wherein the porphyrin is tetrabenzoporphyrin.

32. The compound of claim 31 wherein said substituent is selected from the group consisting of polyethylene glycol and polypropylene glycol.

33. The compound of claim 32 wherein said substituent is polyethylene glycol.

34. The compound of claim 32 wherein said substituent is polypropylene glycol.

35. The compound of claim 1 wherein said substituent is a flexible, hydrophilic polymeric compound.

36. A method for preparing a compound of claim 1 having the formula

37. The method of claim 36 where said providing step comprises reacting a carboxy-substituted porphyrin with a halogenating agent selected from the group consisting of an inorganic halogenating agent and an organic halogenating agent.

38. The method of claim 37 wherein said halogenating agent is selected from the group consisting of thionyl chloride and oxalyl chloride.

39. The method of claim 36 comprising reacting the compound of formula III with PEG at a temperature of about room temperature to about the reflux temperature of PEG.

40. The method of claim 39 comprising reacting the compound of formula III with PEG at a temperature of about 100°

C. to about 150°

C.

41. The method of claim 36 comprising reacting the compound of formula III with PEG for about several hours to about several days.

42. The method of claim 41 comprising reacting the compound of formula III with PEG for about 24 hours.

43. A method for measuring oxygenation of living tissue comprising providing in vivo a phosphorescent compound comprising a substituted porphyrin having an energy absorption band at a wavelength in the near infra-red window of said tissue and being soluble in an aqueous medium and wherein said phosphorescence is quenched by molecular oxygen, causing said compound to phosphoresce and observing quenching by oxygen in said tissue of said phosphorescing compound.

44. The method of claim 43 comprising providing in vivo a compound selected from the group consisting of tetrabenzoporphyrin, tetranaphthoporphyrin, tetraanthraporphyrin and derivatives thereof.

45. The method of claim 44 comprising providing in vivo a compound having the formula

wherein:

R₁ is substituted or unsubstituted aryl;

R₂ and R₃ are independently hydrogen or are linked together to form an aryl group; and

M is H₂ or a metal.

46. The method of claim 45 comprising diagnosing in the tissue of a patient a disease which causes an alteration of the oxygen pressure in said tissue.