Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1993-10-15
2002-03-26
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S410000, C534S015000, C128S126100
Reexamination Certificate
active
06362175
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to the imaging of the body portions of animals, and specifically to the field of phosphorimetry.
BACKGROUND OF THE INVENTION
This invention is based on the quenching by molecular oxygen of the luminescence of various chemical compounds. This quenching effect can be used for imaging the distribution and concentration of oxygen in body portions of animals, including humans. Such information is indicative of tissue structure and anomalies, defects and diseases associated therewith. For example, certain disease states are characterized by the alteration of oxygen pressure in the involved tissue. The reader is referred to U.S. Pat. No. 4,947,850 for further discussion of the Background of the present invention.
“Luminescence” is the emission of light radiation from a species after that species has absorbed radiation. Luminescence involves the conversion of a molecule to an unstable, excited state. The emission of light arises on the return of the compound to its normal state. “Photoluminescence” refers to luminescence which is associated with excitation by light of substantially short wavelengths. The light emitted from the excited species and which is confined to the period of excitation is fluorescence. The emitted light which persists after excitation has ceased is phosphorescence, or afterglow.
Phosphorescence of certain chemical compounds is quenched by oxygen according to the Stern-Volmer relationship which is stated as follows:
T
0
/T=
1
+k
Q
*T
0
PO
2
where T
0
and T are the phosphorescence lifetimes in the absence of oxygen, PO
2
is the oxygen pressure for a lifetime of T, and k
Q
is the quenching constant. The constant k
Q
is related to the frequency of collisions between the excited triplet state molecule and molecular oxygen and the probability of energy transfer occurring when these molecules collide.
Various and often countervailing considerations are associated with the design, selection and/or preparation of materials for use as phosphorescent probes to study tissue oxygenation. It is generally required that the probe comprises a phosphorescent chromophore, and that the probes be soluble in aqueous solution, for example, physiological media.
The phosphorescent chromophore is the phosphorescent portion of the probe molecule. The chromophore can be converted to the triplet state (T
1
) by light absorption, followed by return to the ground state either with light emission (phosphorescence and/or delayed fluorescence) or by energy transfer to molecular oxygen.
Phosphorescent oxygen probes which are currently in use are generally based on Group VIII metals, e.g., palladium (Pd) and platinum (Pt) derivatives of porphyrins. See D. F. Wilson et al.,
J. Appl. Physiol
., Vol. 70(6), pp. 2691-92 (1991). The Group VIII metalloporphyrins are advantageous in that they generally have high quantum yields which correspond to the fraction of excited molecules that phosphoresce. The Group VIII metalloporphyrins also possess desirable phosphorescence lifetimes and oxygen-quenching constants. However, these compounds possess serious drawbacks when considered for application to clinical measurements. In this connection, the absorption band of the Group VIII metal porphyrins is generally located at less than about 600 nanometers (nm). Other chromophores which occur naturally in living tissue, for example, hemoglobin, myoglobin and cytochrome, also have absorption bands at wavelengths less than about 600 nm. Due to the overlap in the wavelengths of the absorption bands, the naturally occurring chromophores absorb energy, for example, light, which is used to convert the Group VIII metalloporphyrins from the ground state to the triplet state. This prevents substantial excitation of the probe compounds.
Moreover, penetration of the excitation energy into the tissue is limited to about 50 to about 100 micrometers (&mgr;m) when the excitation light is about 400 nm, and about 500 to about 1,000 &mgr;m when the excitation light is about 560 nm. The penetration limitation is due, at least in part, to the tendency of chromophores which occur naturally in vivo, for example, hemoglobin, to absorb the excitation energy. The absorbance of the naturally-occurring chromophores generally decreases rapidly at wavelengths of greater than about 600 nm which is generally also the absorbance maxima of the currently used phosphorescing probe compounds.
The penetration limitation of excitation energy permits oxygen measurements of only the surface layer of tissue or substantially optically clear tissue, for example, eye tissue. The use of currently available phosphorescing compounds for imaging tissue oxygen is therefore generally limited to clinical pathologies of eye tissue and/or those lying right on or very near the surface of tissue.
Phosphorescent chromophores typically comprise a multiplicity of aromatic ring units. These aromatic ring units generally render the phosphorescent compounds substantially hydrophobic with little or no water solubility. However, it is generally required that phosphorescent compounds for imaging tissue oxygen be hydrophilic and soluble in aqueous solution, for example, physiological media. This aqueous solubility permits the compounds to circulate throughout the circulatory system of the host patient and be delivered to various tissue sites for subsequent excitation and examination and diagnosis of the involved tissue. The hydrophobicity of the currently available phosphorescing compounds generally limits their utility for clinical measurement of tissue oxygenation.
There is thus a need for phosphorescing compounds for studying tissue oxygenation which possess absorbance bands of greater than about 600 nm, this being the absorption maxima of prior art phosphorescing compounds. Moreover, there is a need for phosphorescing compounds for studying clinical pathologies at greater tissue depths and which are substantially soluble in aqueous solution, including physiological media.
SUMMARY OF THE INVENTION
In accordance with the above needs, the present invention provides improved methods and compounds for imaging internal body structures of animals, including humans. The methods and compounds of this invention provide numerous advantages over prior art methods and compounds. In a preferred embodiment, the present invention is directed to a compound for the measurement in vivo of oxygen in living tissue. The compound preferably comprises a chromophore which is capable of absorbing an amount of energy and subsequently releasing the energy as phosphorescent light. The chromophore preferably 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.
In a more preferred embodiment, the present invention is directed to a compound which is capable of phosphorescing and which has the formula
where R
1
is 2(3)-substituted aryl; R
2
and R
3
are independently hydrogen or are linked together to form substituted or unsubstituted aryl; and M is H
2
or a metal.
In additional embodiments, the present invention is directed to a method for measuring the oxygenation of living tissue. The method comprises providing in vivo a phosphorescent compound having an energy absorption band at a wavelength in the near infra-red window of the tissue. The method further comprises causing said compound to phosphoresce and observing quenching by oxygen of the phosphorescence.
Preferred embodiments of methods and compounds taught and claimed herein provide significant clinical tools for examining, diagnosing and treating disease states which result in altered oxygen pressures in affected tissue. Compounds of the present invention are substantially hydrophilic in aqueous solution, for example, physiological media, and possess absorbance bands which are at a wavelength in the near infra-red window of living tissue. In view of their solubility and absorbance characteristics, the present methods and compounds overcome the drawbacks associated with
Vinogradov Sergei
Wilson David F.
Dilworth Paxson LLP
McConathy Evelyn H.
Raymond Richard L.
The Trustees of the University of Pennsylvania
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