JPS585887B2 - Housiyaseiiyakuhin Oyobisono Seizouhouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a radiopharmaceutical for scintigraphic organ visualization, consisting of 2-mercaptoinbutyric acid labeled with reduced technetium-99m, and a method for producing this radiopharmaceutical.

Previously, various dyes were labeled with radioactive isotopes of iodine to depict the liver and bile ducts together.

Imaging agents such as rose bengal labeled with iodine-131 have been found to be useful, but the relatively high radiation doses associated therewith have limited the extent to which they can be used.

The Journal of Nuclear Medicine (T
he journal of nuclear me
dicine), August 1972, Volume 13, No. 8, 6
On pages 52-654, the use of D-penicillamine labeled with technetium-99m is suggested as a bile scintigraphic agent, which is prepared in an acid solution, heated and neutralized before use.

The Journal of Nuclear Medicine 1
In June 1973, Vol. 14, No. 6, pp. 411-412, some technetium mercaptide derivatives are suggested as liver-specific imaging agents.

These technetium-labeled drugs would result in a reduction in the amount of radiation absorbed.

The present invention relates generally to such hepatobiliary imaging radiopharmaceuticals, and more particularly to novel liver-specific radiopharmaceuticals useful for studying the morphology and function of the liver, gallbladder, and bile ducts.

More particularly, the present invention involves the steps of preparing a reagent of a mixed aqueous solution of 2-mercaptoisobutyric acid and a reducing agent, and then adding to this reagent technetium-99m pertechnetate ion in a physiological salt solution. This invention relates to a method for producing a radiopharmaceutical comprising:

The drug consists of an aqueous solution of 2-mercaptoinbutyric acid chelated with reduced technetium-99m.

Preferably, stannous is used for reduction cutting of technetium-99m.

In this process, an imaging agent is produced by mixing a reagent containing 2-mercaptoisobutyric acid and stannous with oxidant-free technetium-99m pertechnetate, which is readily available in physiological salt solution. Manufactured simply and quickly.

When this labeled substance was intravenously injected into experimental animals and the biodegradation of the labeled substance in the experimental animals was investigated, it was found that the radioactivity disappeared rapidly, especially from the plasma that passed through the liver, and then almost all of the radioactivity disappeared. It can be seen that it is completely excreted into the bile duct.

The first object of the present invention is to produce a technetium-99m radiopharmaceutical that rapidly accumulates in the liver and is excreted from the liver into the bile ducts, so as to be useful in studies of liver and biliary morphology and function. It is.

Another object of the invention is to produce such radiopharmaceuticals in a simple and rapid labeling method without heating or complicated pH adjustment.

Other objects and advantages of this new medicament and its method of manufacture will become apparent from the following specific examples.

A radiopharmaceutical was prepared from a reagent made by mixing equal parts of an aqueous solution of 3mM 2-mercaptoisobutyric acid and an aqueous solution of 1mM stannous chloride.

To 1 part by volume of reagent is added 1 part of oxidant-free technetium-99m pertechnetate in physiological salt solution.

Shake the combined solution to mix thoroughly.

Technetium labeling is done quickly.

Immediately after mixing, the binding of technetium ni-99m is essentially complete and the drug can be immediately administered intravenously.

This radiopharmaceutical should be used within 2 hours of manufacture.

Other proportions of 2-mercaptoisobutyric acid and stannous chloride may also be used.

The biodistribution of labeled pharmaceutical products from reagents prepared by mixing equal volumes of 1mM stannous chloride and 2-mercaptoisobutyric acid at concentrations of 3, 5, 7.5, or 10mM does not result in biodistribution. No significant difference was observed.

Similarly, the reagents were 1 mM stannous chloride and 2-mercaptoisobutyric acid 3 adjusted to a pH range of 2-9 to pH 7.
No significant difference was observed in the biodistribution of radiopharmaceuticals produced by mixing equal volumes of various mM solutions.

pH of 3mM 2-mercaptoisobutyric acid of the above specific example
is about 2.9 and the pH range of the reagent is 2.5
or 3 or 5.

Even with varying concentrations of stannous chloride or technetium-9
Changing the ratio of reagent to 9m pertechnetate has no significant effect on its biodistribution.

After intravenous administration of this radiopharmaceutical to experimental animals, its radioactivity is distributed into the plasma, from which it is cleared exponentially by the liver.

Its half-life is less than 2 minutes.

The initial clearance rate is comparable to that obtained with intravenously administered radiocolloids in conspecific animals, and the liver extraction capacity is almost 100%.

The slope of the radioactivity disappearance curve in the plasma decreases after 5 minutes and becomes fairly flat at 30 minutes, at which point approximately 5% of the dose remains in the plasma.

Absorption for kidneys and spleen can be ignored.

For example, in laboratory rats, as early as 5 minutes after dosing, more than 75% of the remaining radioactivity is in the liver and 6% in the intestine.

Radioactivity in the liver is rapidly excreted into the intestines through the bile ducts.

Three hours after dosing, approximately 4% of the remaining radioactivity is found in the liver and 91% in the intestine.

Radioactivity in the kidneys and spleens of animals sacrificed 1 hour after dosing was negligible.

It was found that approximately 93% of the administered radioactivity was excreted from the body within 24 hours after administration.

Radiopharmaceuticals are particularly useful for studying liver and bile duct function.

NuclearChicag
o) In a scintigraph taken of a laboratory dog given an intravenous injection using a standard pinhole collimator attached to an H-P scintillation camera, the liver was clearly visible 7 minutes after dosing. and is comparable to that obtained using technetium-99m labeled colloids.

However, no radioactivity was observed in the spleen.

In 30 minutes, the gallbladder is visible, and 60 minutes after dosing, the radioactivity in the gallbladder becomes intense.

Scintigraphs taken 90 to 120 minutes after dosing show that the radioactivity in the common bile duct and ampullary region is well resolved.

The above examples and distribution data demonstrate this improved radiopharmaceutical and a simple method for rapidly manufacturing it.

In order to produce the said medicament, technetium-99m reducing agents other than stannous, namely ferrous ions, stannous titanium ions, zirconyl ions and stannous chromium ions and 2-mercaptoisobutyric acid itself are within the skill of the art. Known high concentrations or low pH or elevated temperatures can be used.

Liver and biliary scintigraphic agents were prepared by (a) heating technetium-99m pertechnetate in the presence of 2-mercaptoisobutyric acid at 100°C for 15 minutes, or (b)
) is produced by contacting technetium-99m pertechnetate with high concentrations (e.g., 10 mmol or more) of 2-mercaptoisobutyric acid for several hours.

It has been found that various radiopharmaceuticals that do not generally accumulate in normal tissues other than the target organ to be examined accumulate in infarcts and tumors. Can be useful.

Embodiments of the present invention are listed below.

(1) The method according to the claims, in which stannous is used as the reducing agent.

(2) The method according to any of claims or item (1) above, wherein stannous chloride is used as the reducing agent.

(3) The method according to any one of claims (1) and (2) above, wherein the molar ratio of 2-mercaptoisobutyric acid to stannous chloride is 3:1.

Claims (1)

[Claims] 1. A method for producing a radiopharmaceutical, which comprises the steps of preparing a reagent of a mixed aqueous solution of 2-mercaptoinbutyric acid and a reducing agent, and then adding technetium-99m pertechnetate ion in a physiological salt solution to this reagent.