Organic compounds -- part of the class 532-570 series – Organic compounds – Radioactive metal containing
Reexamination Certificate
2000-04-14
2002-08-20
Nazario-Gonzalez, Porfirio (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Radioactive metal containing
C556S001000, C556S045000
Reexamination Certificate
active
06437103
ABSTRACT:
BACKGROUND OF THE INVENTION
Coronary artery disease (CAD) is the leading cause of death in the United States, accounting for roughly 24% of all deaths. The health care cost of cardiovascular diseases in 1999 is estimated by the AHA at $286.5 billion, a figure which includes direct costs, such as physicians, other professionals, hospital and nursing home services, the cost of medications, home health and lost productivity. Many of the deaths resulting from CAD may have been prevented if a valid, standardized technique existed which assessed the condition of the myocardium and allowed the use of appropriate therapy. Hence, there is a need for sensitive, reliable, and low cost techniques for early detection of heart disease and for monitoring the course of treatment.
Long-chain fatty acids are a major source of energy for the heart muscle and are rapidly metabolized by beta-oxidation under normal conditions. At rest and during exercise, non-esterified fatty acids supply approximately 65% of the energy requirement for myocardial metabolism while the remainder of myocardial energy needs are provided by glucose (15%), lactate and pyruvate (12%), and amino acids (5%) [Zieler et al. 1976, Neely et al. 1972, Opieet al. 1969, Mostet al. 1969]. Non-esterified fatty acids are taken up by the myocardium with an extraction of 40-60% and either transiently esterified to triglyceride or oxidized for energy [Schon et al. 1982, Poe et al. 1975, Machulla et al. 1978, Westera et al. 1980; Gately et al. 1983, Van der Wall et al. 1981]. In contrast, under conditions of reduced oxygen delivery to heart tissue such as ischemia and hypoxia, there is a dramatic decrease in fatty acid metabolism.
Fatty acid molecules have a unique structure and do not require carrier mediation for their transport. Fatty acids are bound to albumin and enter into the cell mainly by free diffusion through the capillary wall and sarcolemma into the intracellular space. This extraction is dependent mainly on the following parameters: the chain length of the fatty acid (double bonds and branching have secondary effects), the blood flow to the myocardium, the concentration of the fatty acid in plasma, and the metabolic state of the myocardial tissue. In addition, both lipophilic and carboxylic sides of the fatty acid molecule must be free of bonding in order to retain the transport and the biochemical properties of the molecule. Fatty acid interaction in the heart tissue is not of a receptor-ligand type. Therefore the rigidity of the fatty acid structure may not be the main determinant of their transport and biochemical degradation process.
Two compounds currently used in the U.S. and Europe for cardiac imaging are T1-201 (DuPont/Mallinckrodt) and Cardiolite (DuPont). Both agents are useful and provide important information on myocardial function. However, these radiopharmaceuticals have certain important limitations. The main drawbacks are: (1) these agents are mainly flow tracers and do not directly address the metabolic viability of the injured myocurdium, and (2) image sensitivity is low for single vessel obstruction, however, it is improved with increased damage.
Many fatty acids or their analogs have been labeled with positron and gamma emitting radionuclides to non-invasively assess changes in fatty acid metabolism [Schon et al. 1982, Machulla et al. 1978, Lerch et al. 1982, Schon et al. 1986, Weiss et al. 1976, Sobel et al. 1977, Goldstein et al. 1980, Livni et al., 1982, Dudczak et al. 1984, Reske et al. 1984, Livni et al. 1985, U.S. Pat. No. 4,746,505]. These fatty acids have the radiolabel on the carboxylic carbon, in the middle, or on the terminal alkyl carbon. As a result, all of these agents are always subject to loss of the label during the degradation steps of the fatty acid beta-oxidation process.
A significant departure from the structure of a normal fatty acid, e.g. palmitate, or iodophenyl, did not result in a significant change in the fatty acid behavior of the compound. For example, 15-(p-iodophenyl)pentadecanoic acid [Goodman et al. 1984] and, even more notably, a series of phenyleneiodophenyl fatty acids [Liefhold and Eisenhut, 1986] all demonstrated moderate myocardial uptake. Members of the latter group differed in molecular weight from palmitate (mol. wt=256) by about 260 Dalton.
Although fatty acids labeled with positron emitting radionuclides in conjunction with tomographic techniques may be an excellent means of quantifying in vivo regional myocardial metabolism, they remain the exclusive research tool of a limited number of institutions. Iodine-123 labeled BMPPA showed promise in animal and human studies [Goodman et al. 1984, Miller et al. 1985], however, since
123
I requires a cyclotron for production, it is unlikely that
123
I-labeled fatty acids (uncontaminated with I-124) will become widely available for routine diagnostic use.
The excellent nuclear properties of Tc-99m and its widespread availability from a generator have made this radionuclide the most frequently used nuclide in nuclear medicine. Several groups over the past 20 years have attempted to develop a myocardial imaging agent in which a technetium chelating moiety was incorporated into a long chain fatty acid [Eckelman et al.1975, Livni et al. 1981, Davison et al 1985, Kelso et al. 1988, Cumming et al. 1988, Mach et al. 1986, 1988, 1989]. In all these cases, the radiolabeled fatty acids contained structural modifications wherein one side of the molecule, carboxyl or w-alkyl moiety, was chemically involved in the chelate moiety. As a result, these agents did not show heart uptake.
An agent that allows for noninvasive delineation of myocardial metabolism and which could be routinely prepared at most clinical institutions or purchased from a distribution center would be of considerable benefit in the diagnosis and treatment of heart disease. Myocardial energy demand is met primarily by fatty acid oxidation. Radiolabeled fatty acids that display efficient myocardial uptake and adequate myocardial retention are attractive candidates for clinical evaluation of regional discrepancies in fatty acid metabolism which occur in ischemic heart disease and cardiomyopathies.
SUMMARY OF THE INVENTION
The instant invention features radiolabeled fatty acids which exhibit high uptake and retention in the myocardium. In preferred embodiments the radiolabel is selected from the group consisting of
99m
Tc, Re,
68
Ga,
67
Ga and
111
In. The instant claimed fatty acid analogs are designed to be transported into myocardial cells by the same long chain fatty acid carrier protein mechanism as natural fatty acids. In addition, the agents provide stable chelation of the metal and cannot be completely catabolized in vivo. In this manner, transport/delivery and metabolism can be imaged after the tracer is retained intracellularly. Particularly preferred imaging agents show a heart-to-lung ratio of at least 2:1 within 30 minutes of administration.
The transport mechanism of the molecules described herein is a function of lipophilicity and neutrality derived from the fatty acid structure and the metal complex, respectively. Variation of the 1,2-dithio-5,8-diazacyclodecan moiety position within the fatty acid chain results in molecules that mimic fatty acids with respect to transport, and consequently, with reduced lung uptake. Separation of stereoisomers also improves the myocardial uptake and kinetics. Particularly preferred stereoisomers (R or S) are substanially pure (e.g. greater than about 75% isomeric purity).
The instant claimed labeled fatty acid can be used alone or in conjunction with myocardial flow agents. Other features and advantages of the instant invention will be apparent from the following Detailed Description and Claims.
REFERENCES:
patent: 4524059 (1985-06-01), Elmaleh et al.
patent: 4615876 (1986-10-01), Troutner et al.
patent: 4746505 (1988-05-01), Jones et al.
patent: wo 97/19705 (1997-05-01), None
Yamamura, Norio et al. “Technetium-99m-Labeled Medium-Chain
Babich John W.
Elmaleh David R.
Maresca Kevin
Shoup Timothy
Biostream Inc.
Foley Hoag & Eliot LLP
Nazario-Gonzalez Porfirio
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