Comparison studies have shown the value of reticuloendothelial system, RES (e.g. liver, spleen and bone marrow), scanning with radionuclides as a diagnostic tool. The use of a variety of radioisotope labeled particles or colloids for scanning procedures is well documented in the literature, and the behavior of particles as a function of liver blood flow dynamics has been described in detail.
As with all scanning preparations in general, the most desirable agent is that which combines good target organ localization and high efficiency labeling characteristics with a short lived radioisotope. Stability of the labeled agent and ease of preparation are also essential to meet the particular demands of clinical usage. Safety to the patient is the foremost criterion by which agents meeting the above practical requirements must be judged.
Certain metal ion compounds (e.g. tin, titanium, iron and chromium), whose biological distribution, toxicity and fate in animals have been studied, can be readily prepared as colloidal particles, a size range not filtered out by the lung and ideal for obtaining high target to background ratios in the liver.
Generally, a RES scanning agent is chemically a radioactive colloid when administered intravenously. The colloid particles are phagocytized by the reticuloendothelial cells, such as the Kupffer cells, of the liver. These particles accumulate rapidly in the Kupffer cells and other RES cells and remain there long enough for scintillation scans of their distribution to be obtained. The position, size, shape of the liver or any space occupying lesion in the liver of sufficient size can be readily localized and determined by radioisotope uptake in healthy tissue and lack of uptake at the site of the lesions.
The metastable isotope Tc-99m has a 6 hour half-life and lacks primary particulate radiation. These properties reduce radiation exposure to the patient. This improves the quality of the scan and decreases the total time required to complete the procedure.
Because of the six-hour physical half-life of Tc-99m, the routine use of the Tc-99m labeled liver scanning agent requires daily compounding. Therefore, it is desirable to have a stable non-radioactive preparation for a liver agent containing all the components required to prepare the agent as needed.
Although Tc-99m compounds would appear to be ideal radio-pharmaceuticals for diagnostic use, providing or selecting technetium compounds or colloids with a view toward organ specificity and tolerable levels of toxicity is a complex task. Obviously, compounds with a very low LD.sub.50 are undesirable for human or veterinary use, even in the small amounts called for by diagnostic work. Compounds with insufficient in vivo stability may be poor diagnostic tools, since the radioactive ions or other chemical species with insufficient or undesirable organ specificity may be liberated. Stable compounds which become distributed generally throughout the organism, despite their stability, or which do not reach a desired destination in the organism are also poorly suited for many studies of organ function or structure, e.g. liver and gall bladder studies.
The problem of selecting or preparing a liver specific radio-pharmaceutical for liver morphology studies is particularly difficult. Any radio-pharmaceutical used for this purpose should ideally have 100% RES specificity and minimal uptake in other organs. One such agent is disclosed in U.S. Pat. No. 3,875,299. However, the tin colloid of that patent suffers the disadvantage of requiring water as the solvent which tends to cause hydrolysis and premature formation of the colloid and is highly sensitive to air oxidation.
USPTO Backgrounds
USPTO Backgrounds