CA1186225A - Radioactive diagnostic agent and its preparation - Google Patents
Radioactive diagnostic agent and its preparationInfo
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- CA1186225A CA1186225A CA000386019A CA386019A CA1186225A CA 1186225 A CA1186225 A CA 1186225A CA 000386019 A CA000386019 A CA 000386019A CA 386019 A CA386019 A CA 386019A CA 1186225 A CA1186225 A CA 1186225A
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Abstract
: A radioactive diagnostic agent for imaging of various organs, particularly of brain, which comprises a radioactive element such as 99mTC and a non-radioactive carrier comprising as the essential component glucosonebis(thiosemecarbazone) of the formula: < IMG >
Description
Radioactiv _diagnostic agent and its preparation The present invention relates to a radioactive diagnostic agent and its preparation. More particularly, it relates to a radioactive element-labeled compound for nuclear medical diagnosis, particularly for diagnosis of ailments of the brain, and its preparation process.
Radioactive diagnostic agents for nuclear medical diagnosis of ailments of the brain, such as imaging of the brain and brain functional study, are required to have the following properties: (1) they must be able to pass through the blood-brain barrier to reach the brain;
and t2) they must accumulate in the brain at a high con-centration within a short time and skay there over the period of time required for clinical study. Various studies have been carried out in an attempt to dis-cover radioactive diagnostic agents satisfyiny these requirements. Of the materials studied, 18F-labeled deoxyglucose (Gallagher et al.: J. Nuclear Medicine, ~ol. 19, pages 1154-1161 (1978)) and 123I-labeled phenylalkylamines (Winchell et al.: J. Nuclear Medicine, Vol. 21, pages 940~946 (1980)) are notable from the practical viewpoint. These compounds can pass through the blood-brain barrier and accumulate in the brain and are evaluated as practically useful for the purpose of imaging of brain and brain functional study.
However, 18F is a positron emitting nuclide, and special apparatus, such as a positron camera, is needed for imaging. Thus, ordinary scintillation cameras, which are widely employed in the field of nuclear medicine, are not usable. Further, the half life of 18F is only 1.8 hours, and therefore there are severe limitations imposed on the time available for manufacture, transportation and supply of the radioactive element or the labeled diagnostic agent. These drawbacks exist inherently in 18F-labeled deoxyglucose.
On the other hand, 123~-labeled phenylalkylamines can not give a sufficiently clear image upon the use of a collimator for low energy gamma-rays, which is most frequently employed in scintillation cameras. Further, lS 1 3I is relatively expensive, and the use of 123I-labeled phenylalkylamines in amounts sufficient for diagnosis is uneconomical.
As a result of an extensive study seeking for any substance suitable as a carrier for radioactive elements in the field of nuclear medicine, it has now been found that glucosone bis(thiosemicarbazone) (hereinafter re-ferred to as "GBT") of the formula:
H-C=N-NH-CS-NH
C=N-NH-CS-NH
HO-C-H
H-C-OH
H-C-OH
can form stable chelate compounds with various radioactive elements and the resulting chelate compounds (i.e. the radioactive element-labeled compounds) can pass through the blood-brain barrier. ~t has also been found that the radioactive element-labeled GBT can be used as a radio-active diagnostic agent which malces possible highly reliable diagnosis, particularly in the brain.
According to one aspect of the present invention, there .. .
t~ 7 is provided a non-radioactive carrier, which comprises as the essential component glucosone-bis(thiosemicarbazone) of the formula:
~-C=N-N~-CS-NH2 C=N-NH CS-NH2 HO-C-H
H-C-OH
H-C-OH
CH20H, said carrier being of pharmaceutically acceptable purity.
There is also provided a radioactive diagnostic agent which comprises a radioactive element and the said non-radioactive carrier.
~GT can be produced, for example, by oxidizing ~-D-glucose with cupric acetate to form a carbonyl group at the 2-position and reacting the resultant glucosone with thiosemicarbazide to introduce thiosemicarbazone groups into the 1- and 2~positions.
GBT may be used as a carrier in two different ways depending upon the kind or state of the radioactive element to be carried. When the radioactive element is in a valency state which is not required to be reduced or oxidized for the formation of a stable chelate compound, GBT is contacted with the radioactive element in an aqueous medium to form a radioactive element-labeled BGT as a chelate compound. This labeling manner may be applied to Gallium-67, Indium-lll, etc. When the radioactive element is in a valency state which is required to be reduced or oxidized for the formation of a stable chelate compound, GBT is contacted with the radioactive element in an aqueous medium in the presence of a reducing agent or an oxidiz-ing agent to form a radioactive element-labeled G~T as a chelate compound. This labeling manner may be applied to Technetium-99m, etc.
Therefore, the non-radioactive carrier of the invention may comprise GBT optionally with a reducing agent or an oxidizing agent for the radioactive element to be used for labeling.
A stannous salt, i.e. a salt of the divalent tin ion (Sn++), may be employed, for example, as the reducing agent. Specific examples are stannous halides (eOg.
stannous chloride, stannous fluoride), stannous sulfate, stannous nitrate, stannous acetate, stannous citrate, etc. Sn ion-bearing resins, e.g. ion-exchange resins charged with the Sn++ ion, are also usable.
In addition to GBT as the essential component and a reducing agent or an oxidizing agent as the optional com-ponent, the carrier of the invention may comprise anyother additive(s) when desired. Bxamples of such additive(s) are a pH controlling agent e.g. an acid, a base or a buffering substance, a reductive stabilizer e.g.
ascorbic acid, erythorbic acid or gentisic acid or a salt thereof, an isotonizing agent e.g. sodium chloride, a preserving agent e.g. benzyl alcohol, etc.
When preparing the non-radioactive carrier of the invention, GBT and, if used, other additives including a reducing agent or an oxidizing agent, may be mixed in any optional order. The carrier may be formulated in the form of a powder, particularly a lyophilized powder, or in the form of liquid preparation, particularly an aqueous solution.
For preparation of a radioactive diagnostic agent of the invention, a radioactive element may be contacted with the non-radioactive carrier, usually in an aqueous medium, whereby the radioactive element-labeled radioactive diag-nostic agent is prepared in s1tu. The radioactive element is usually employed in the form of salt, preferably a water-soluble salt, and is normally used as an aqueous solution, which may additionally comprise any conventional additive(s) eOg. an isotonizing agent (e.g. sodium chloride) or a preserving agent (e.g. benzyl alcohol).
For instance, technetium-99m is usually available in the form of a pertechnetate (wherein 9gmTc is heptavalent) and may be employed as an aqueous solution. When such an p~
aqueous solution is combined with the non-radioactive carrier comprising a reducing agent, e.g. a stannous salt, 99mTc is reduced by the reducing agent to a lower valency (i.e. tetravalent) state, and a 99mTc-labeled radioactive diagnostic agent is obtained comprising a chelate compound between GBT and 99mTc in a stable stateO
When the reducing agent in a water-insoluble form, e.g. an ion-exchange resin charged with the Sn++ ion, is used, it is eliminated from the resulting radioactive diagnostic agent by an appropriate separation procedure, e.g.
filtration prior to its administration.
The radioactive element in the radioactive diagnostic agent should have sufficient radioactivity and radioactiv-ity concentration to insure reliable diagnosis, although there are no particular predetermined limitations. For instance, when the radioactive element is 99mTc, the amount of the radioactive diagnostic agent to be admin-istered to a human adult may be from about 0.5 to 5.0 ml, which usually displays a radioactivity of 0.1 to 50 mCi.
The radioactive diagnostic agent of this invention is useful for nuclear medical diagnosis, particularly for imaging of the brain and brain functional study.
Practical and presently preferred embodiments of the invention are illustratively shown in the following Examples wherein percentages are by weight, unless otherwise defined.
Exam~le 1 Preparation of glucosone:-A solution of cupric acetate (20 g) in methanol (250 ml) was added to a solution of ~-D-glucose (~.5 g) in water (10 ml) and the resultant mixture was heated on a water bath for 1 hour. The reaction mixture was cooled, and the precipitate cuprous oxide was eliminated by filtration. Hydrogen sulfide gas was introduced into the filtrate for about 1 minute to precipitate the unreacted cupric acetate in the form of cupric sulfide. After elimination of the precipitate b~ filtration, the filtrate was treated with a small amount of activated charcoal and concentrated under reduced pressure to give glucosone in a syrupy state.
Example 2 Preparation of glucosone-bis(thiosemicarbazone) (GBT):-~ solution of thiosemicarbazide (4.5 g) in water (50 ml) was added dropwise to a solution of glucosone obtained in Example 1 in 0.1 N acetic acid (6 ml), and the resulting mixture was refluxed for about 1 hour. The reaction mixture was cooled with ice, and the precipitated crystals were collected by filtration and recrystallized from water to give glucosone-bis(thiosemicarbazone) (5 g).
M.P. 225C (decomp.). Elementary analysis for C8H16O4N6S2 (%): Calcd.: C, 29.62; H, 4O97; O, 19.73; N, 25.91; S, 19.77~ Found: C, 29.57; EI, 4.88; O, 19.46; N, 26.14; S, 19.70.
L~
s Example 3 Preparation of the non-radioactive carrier:-Glucosone-bis(thiosemicarbazone) obtained in Example 2 was dissolved in a 0.1 ~ acetate buffer (pH, 5.0) from which dissolved oxygen was previously elimin-ated, to produce a concentration o 10 3 M. This solution was filtered through a microfilter to eliminate bacteria and transferred to an ampoule. After the addition of benzyl alcohol as a preservative thereto to produce a 0.9 ~ concentration, the air above the solution in the ampoule was replaced by nitrogen gas, and the ampoule was sealed.
Example 4 Preparation of the non-radioactive carrier:-Glucosone-bis(thiosemicarbazone) obtained in Example 2 was dissolved in a 0.1 M acetate buffer (pH, 5.0) from which dissolved oxygen had been previously eliminated, to produce a concentration of 10 3 M. ~n aqueous solution of stannous chloride (4ug/ml; 10 ml) was added to the resulting solution (10 ml), and the resultant mixture was passed through a microfilter and transferred to an ampoule. Benzyl alcohol as a preservative was added thereto to produce a concentration of 0.9 %. After replacement of the air above the solution in the ampoule by nitrogen gas, the ampoule was sealed.
Example _ Preparation of the non-radioactive carrier:-Glucosone-bis(thiosemicarbazone) obtained in Example 2 was dissolved in a 0.1 M acetate buffer (pH, 5.0) to a concentration of 10 3 M. An ion-exchange resin containing adsorbed Sn++ ions (5.5 ~g of tin ion per mg of the resin; 4 mg) was added to the resulting solution (10 ml) and the resultant mixture was placed in an ampoule. After replacement of the air above the solution in the ampoule by nitrogen gas, the ampoule was sealed.
."i ,~
. , ~, , Example 6 Preparation of the radioactive diagnostic agent:-The non-radioactive carrier obtained in Example 3 (l ml) was admixed with an aqueous solution of gallium chloride-67Ga solution (l mCi/ml; pH, about 2) (l ml) under aseptic conditions and the resultant mixture was passed through a microfilter and placed in a vial. After replacement of the air above the solution in the vial by nitrogen gas, the vial was sealed.
The radioactive diagnostic agent as prepared above was subjected to paper chromatography (Toyo Filter Paper No. 51) using 80 ~ methanol as the developing sol-vent. After development, scanning was carried out with a radiochromato-scanner. In the radioactivity chart, a main peak was observed at an Rf value of about 0.6, and a small peak probably due to unlabeled gallium chloride-67 Ga was present near the original point. By the radiochroma-togram and the coloring method with a cuprous salt solution, it was con~irmed that nearly all of the radio-isotope formed a chelate compound with GBT.
Exam~
Preparation of the radioactive diagnostic agent:-The non-radioactive carrier obtained in Example 5 (l ml) was admixed with an aqueous solution of sodium per-technetate-99mTc solution tlO mCi/ml; pH, 5.5) (l ml) under aseptic conditions and the resultant mixture was passed through a microfilter and placed in a vial. After replacement of the ai~ above the solution in the vial by nitrogen gas, the vial was sealed.
The radioactive diagnostic agent as prepared above was subjected to thin layer chromatography using silica gel (Merck ~, 0.25 mm thick) as the adsorbent and 80 % acetone as the developing solvent~ After the development, scanning was carried out with a radiochroma-scanner. In the radioactivity chart, a main peak was -D~5~
_ g _ observed at an Rf value of about 0.9. Besides, a small peak probably due to 99mTc-labeled tin colloid was seen at the original point, and a small peak due to an unident-ified compound was present at an Rf value of about 0.7.
By the radiochromatogram and the coloring method with a cuprous salt so]ution, i-t was confirmed that nearly all of the radioisotope formed a chelate compound with GBT.
Example 8 Relationship between the amount o~ Sn++ ion in the non~radioactive carrier and the property of the 99m~c-labeled radioactive diagnostic agent prepared by the use of said non-radioactive carrier:-Non-radioactive carriers were prepared in the same manner as in Example 5 but using different amounts lS of the Sn++ ion~ Using those non-radioactive carriers, 99mTc-labeled radloactive diagnostic agents were prepared in the same manner as in Example 7. Chromatographic exam-ination was carried out in the same manner as in Example 7. On the thus prepared 99mTc~labeled radioactive diagnostic agents. The results are shown in Table 1 wherein the numerals indicate the relative radioactivity values (%)~
Table 1 . , __ \Amount of Sn ~ ~-ecl (~g) 1) 0.5 1.01.5 ~ 5.5 11 55 550 .__~ --r - ~ ~
Rf = 0.9 86.995.7 93.3 19.3 187.578.0 72.4 _ _ . - __ Rf = 0.7 1.91.9 2.3 3.4 ¦ 4.1 4.4 3.7 .. ~ . .
Original point11.2 2.34.4 6.3 ¦ 8.4 117.6 23.9 Note: *l) Amo~nt of Sn++ ion per ml of the non-radioactive carrier calculated from the amount of Sn++ ion adsorbed on the ion-exchange resin.
~,
Radioactive diagnostic agents for nuclear medical diagnosis of ailments of the brain, such as imaging of the brain and brain functional study, are required to have the following properties: (1) they must be able to pass through the blood-brain barrier to reach the brain;
and t2) they must accumulate in the brain at a high con-centration within a short time and skay there over the period of time required for clinical study. Various studies have been carried out in an attempt to dis-cover radioactive diagnostic agents satisfyiny these requirements. Of the materials studied, 18F-labeled deoxyglucose (Gallagher et al.: J. Nuclear Medicine, ~ol. 19, pages 1154-1161 (1978)) and 123I-labeled phenylalkylamines (Winchell et al.: J. Nuclear Medicine, Vol. 21, pages 940~946 (1980)) are notable from the practical viewpoint. These compounds can pass through the blood-brain barrier and accumulate in the brain and are evaluated as practically useful for the purpose of imaging of brain and brain functional study.
However, 18F is a positron emitting nuclide, and special apparatus, such as a positron camera, is needed for imaging. Thus, ordinary scintillation cameras, which are widely employed in the field of nuclear medicine, are not usable. Further, the half life of 18F is only 1.8 hours, and therefore there are severe limitations imposed on the time available for manufacture, transportation and supply of the radioactive element or the labeled diagnostic agent. These drawbacks exist inherently in 18F-labeled deoxyglucose.
On the other hand, 123~-labeled phenylalkylamines can not give a sufficiently clear image upon the use of a collimator for low energy gamma-rays, which is most frequently employed in scintillation cameras. Further, lS 1 3I is relatively expensive, and the use of 123I-labeled phenylalkylamines in amounts sufficient for diagnosis is uneconomical.
As a result of an extensive study seeking for any substance suitable as a carrier for radioactive elements in the field of nuclear medicine, it has now been found that glucosone bis(thiosemicarbazone) (hereinafter re-ferred to as "GBT") of the formula:
H-C=N-NH-CS-NH
C=N-NH-CS-NH
HO-C-H
H-C-OH
H-C-OH
can form stable chelate compounds with various radioactive elements and the resulting chelate compounds (i.e. the radioactive element-labeled compounds) can pass through the blood-brain barrier. ~t has also been found that the radioactive element-labeled GBT can be used as a radio-active diagnostic agent which malces possible highly reliable diagnosis, particularly in the brain.
According to one aspect of the present invention, there .. .
t~ 7 is provided a non-radioactive carrier, which comprises as the essential component glucosone-bis(thiosemicarbazone) of the formula:
~-C=N-N~-CS-NH2 C=N-NH CS-NH2 HO-C-H
H-C-OH
H-C-OH
CH20H, said carrier being of pharmaceutically acceptable purity.
There is also provided a radioactive diagnostic agent which comprises a radioactive element and the said non-radioactive carrier.
~GT can be produced, for example, by oxidizing ~-D-glucose with cupric acetate to form a carbonyl group at the 2-position and reacting the resultant glucosone with thiosemicarbazide to introduce thiosemicarbazone groups into the 1- and 2~positions.
GBT may be used as a carrier in two different ways depending upon the kind or state of the radioactive element to be carried. When the radioactive element is in a valency state which is not required to be reduced or oxidized for the formation of a stable chelate compound, GBT is contacted with the radioactive element in an aqueous medium to form a radioactive element-labeled BGT as a chelate compound. This labeling manner may be applied to Gallium-67, Indium-lll, etc. When the radioactive element is in a valency state which is required to be reduced or oxidized for the formation of a stable chelate compound, GBT is contacted with the radioactive element in an aqueous medium in the presence of a reducing agent or an oxidiz-ing agent to form a radioactive element-labeled G~T as a chelate compound. This labeling manner may be applied to Technetium-99m, etc.
Therefore, the non-radioactive carrier of the invention may comprise GBT optionally with a reducing agent or an oxidizing agent for the radioactive element to be used for labeling.
A stannous salt, i.e. a salt of the divalent tin ion (Sn++), may be employed, for example, as the reducing agent. Specific examples are stannous halides (eOg.
stannous chloride, stannous fluoride), stannous sulfate, stannous nitrate, stannous acetate, stannous citrate, etc. Sn ion-bearing resins, e.g. ion-exchange resins charged with the Sn++ ion, are also usable.
In addition to GBT as the essential component and a reducing agent or an oxidizing agent as the optional com-ponent, the carrier of the invention may comprise anyother additive(s) when desired. Bxamples of such additive(s) are a pH controlling agent e.g. an acid, a base or a buffering substance, a reductive stabilizer e.g.
ascorbic acid, erythorbic acid or gentisic acid or a salt thereof, an isotonizing agent e.g. sodium chloride, a preserving agent e.g. benzyl alcohol, etc.
When preparing the non-radioactive carrier of the invention, GBT and, if used, other additives including a reducing agent or an oxidizing agent, may be mixed in any optional order. The carrier may be formulated in the form of a powder, particularly a lyophilized powder, or in the form of liquid preparation, particularly an aqueous solution.
For preparation of a radioactive diagnostic agent of the invention, a radioactive element may be contacted with the non-radioactive carrier, usually in an aqueous medium, whereby the radioactive element-labeled radioactive diag-nostic agent is prepared in s1tu. The radioactive element is usually employed in the form of salt, preferably a water-soluble salt, and is normally used as an aqueous solution, which may additionally comprise any conventional additive(s) eOg. an isotonizing agent (e.g. sodium chloride) or a preserving agent (e.g. benzyl alcohol).
For instance, technetium-99m is usually available in the form of a pertechnetate (wherein 9gmTc is heptavalent) and may be employed as an aqueous solution. When such an p~
aqueous solution is combined with the non-radioactive carrier comprising a reducing agent, e.g. a stannous salt, 99mTc is reduced by the reducing agent to a lower valency (i.e. tetravalent) state, and a 99mTc-labeled radioactive diagnostic agent is obtained comprising a chelate compound between GBT and 99mTc in a stable stateO
When the reducing agent in a water-insoluble form, e.g. an ion-exchange resin charged with the Sn++ ion, is used, it is eliminated from the resulting radioactive diagnostic agent by an appropriate separation procedure, e.g.
filtration prior to its administration.
The radioactive element in the radioactive diagnostic agent should have sufficient radioactivity and radioactiv-ity concentration to insure reliable diagnosis, although there are no particular predetermined limitations. For instance, when the radioactive element is 99mTc, the amount of the radioactive diagnostic agent to be admin-istered to a human adult may be from about 0.5 to 5.0 ml, which usually displays a radioactivity of 0.1 to 50 mCi.
The radioactive diagnostic agent of this invention is useful for nuclear medical diagnosis, particularly for imaging of the brain and brain functional study.
Practical and presently preferred embodiments of the invention are illustratively shown in the following Examples wherein percentages are by weight, unless otherwise defined.
Exam~le 1 Preparation of glucosone:-A solution of cupric acetate (20 g) in methanol (250 ml) was added to a solution of ~-D-glucose (~.5 g) in water (10 ml) and the resultant mixture was heated on a water bath for 1 hour. The reaction mixture was cooled, and the precipitate cuprous oxide was eliminated by filtration. Hydrogen sulfide gas was introduced into the filtrate for about 1 minute to precipitate the unreacted cupric acetate in the form of cupric sulfide. After elimination of the precipitate b~ filtration, the filtrate was treated with a small amount of activated charcoal and concentrated under reduced pressure to give glucosone in a syrupy state.
Example 2 Preparation of glucosone-bis(thiosemicarbazone) (GBT):-~ solution of thiosemicarbazide (4.5 g) in water (50 ml) was added dropwise to a solution of glucosone obtained in Example 1 in 0.1 N acetic acid (6 ml), and the resulting mixture was refluxed for about 1 hour. The reaction mixture was cooled with ice, and the precipitated crystals were collected by filtration and recrystallized from water to give glucosone-bis(thiosemicarbazone) (5 g).
M.P. 225C (decomp.). Elementary analysis for C8H16O4N6S2 (%): Calcd.: C, 29.62; H, 4O97; O, 19.73; N, 25.91; S, 19.77~ Found: C, 29.57; EI, 4.88; O, 19.46; N, 26.14; S, 19.70.
L~
s Example 3 Preparation of the non-radioactive carrier:-Glucosone-bis(thiosemicarbazone) obtained in Example 2 was dissolved in a 0.1 ~ acetate buffer (pH, 5.0) from which dissolved oxygen was previously elimin-ated, to produce a concentration o 10 3 M. This solution was filtered through a microfilter to eliminate bacteria and transferred to an ampoule. After the addition of benzyl alcohol as a preservative thereto to produce a 0.9 ~ concentration, the air above the solution in the ampoule was replaced by nitrogen gas, and the ampoule was sealed.
Example 4 Preparation of the non-radioactive carrier:-Glucosone-bis(thiosemicarbazone) obtained in Example 2 was dissolved in a 0.1 M acetate buffer (pH, 5.0) from which dissolved oxygen had been previously eliminated, to produce a concentration of 10 3 M. ~n aqueous solution of stannous chloride (4ug/ml; 10 ml) was added to the resulting solution (10 ml), and the resultant mixture was passed through a microfilter and transferred to an ampoule. Benzyl alcohol as a preservative was added thereto to produce a concentration of 0.9 %. After replacement of the air above the solution in the ampoule by nitrogen gas, the ampoule was sealed.
Example _ Preparation of the non-radioactive carrier:-Glucosone-bis(thiosemicarbazone) obtained in Example 2 was dissolved in a 0.1 M acetate buffer (pH, 5.0) to a concentration of 10 3 M. An ion-exchange resin containing adsorbed Sn++ ions (5.5 ~g of tin ion per mg of the resin; 4 mg) was added to the resulting solution (10 ml) and the resultant mixture was placed in an ampoule. After replacement of the air above the solution in the ampoule by nitrogen gas, the ampoule was sealed.
."i ,~
. , ~, , Example 6 Preparation of the radioactive diagnostic agent:-The non-radioactive carrier obtained in Example 3 (l ml) was admixed with an aqueous solution of gallium chloride-67Ga solution (l mCi/ml; pH, about 2) (l ml) under aseptic conditions and the resultant mixture was passed through a microfilter and placed in a vial. After replacement of the air above the solution in the vial by nitrogen gas, the vial was sealed.
The radioactive diagnostic agent as prepared above was subjected to paper chromatography (Toyo Filter Paper No. 51) using 80 ~ methanol as the developing sol-vent. After development, scanning was carried out with a radiochromato-scanner. In the radioactivity chart, a main peak was observed at an Rf value of about 0.6, and a small peak probably due to unlabeled gallium chloride-67 Ga was present near the original point. By the radiochroma-togram and the coloring method with a cuprous salt solution, it was con~irmed that nearly all of the radio-isotope formed a chelate compound with GBT.
Exam~
Preparation of the radioactive diagnostic agent:-The non-radioactive carrier obtained in Example 5 (l ml) was admixed with an aqueous solution of sodium per-technetate-99mTc solution tlO mCi/ml; pH, 5.5) (l ml) under aseptic conditions and the resultant mixture was passed through a microfilter and placed in a vial. After replacement of the ai~ above the solution in the vial by nitrogen gas, the vial was sealed.
The radioactive diagnostic agent as prepared above was subjected to thin layer chromatography using silica gel (Merck ~, 0.25 mm thick) as the adsorbent and 80 % acetone as the developing solvent~ After the development, scanning was carried out with a radiochroma-scanner. In the radioactivity chart, a main peak was -D~5~
_ g _ observed at an Rf value of about 0.9. Besides, a small peak probably due to 99mTc-labeled tin colloid was seen at the original point, and a small peak due to an unident-ified compound was present at an Rf value of about 0.7.
By the radiochromatogram and the coloring method with a cuprous salt so]ution, i-t was confirmed that nearly all of the radioisotope formed a chelate compound with GBT.
Example 8 Relationship between the amount o~ Sn++ ion in the non~radioactive carrier and the property of the 99m~c-labeled radioactive diagnostic agent prepared by the use of said non-radioactive carrier:-Non-radioactive carriers were prepared in the same manner as in Example 5 but using different amounts lS of the Sn++ ion~ Using those non-radioactive carriers, 99mTc-labeled radloactive diagnostic agents were prepared in the same manner as in Example 7. Chromatographic exam-ination was carried out in the same manner as in Example 7. On the thus prepared 99mTc~labeled radioactive diagnostic agents. The results are shown in Table 1 wherein the numerals indicate the relative radioactivity values (%)~
Table 1 . , __ \Amount of Sn ~ ~-ecl (~g) 1) 0.5 1.01.5 ~ 5.5 11 55 550 .__~ --r - ~ ~
Rf = 0.9 86.995.7 93.3 19.3 187.578.0 72.4 _ _ . - __ Rf = 0.7 1.91.9 2.3 3.4 ¦ 4.1 4.4 3.7 .. ~ . .
Original point11.2 2.34.4 6.3 ¦ 8.4 117.6 23.9 Note: *l) Amo~nt of Sn++ ion per ml of the non-radioactive carrier calculated from the amount of Sn++ ion adsorbed on the ion-exchange resin.
~,
2~5 From the above results, it can be seen that when the amount of the Sn++ ion in the non-radioactive carrier is at least from 0.5 to 550 ~9 per ml of the lO 3 M GBT
solution, the 99mTc-labeled radioactive diagnostic agent can be produced with a good efficiency. Taking the produc-tion rate of the major component into consideration, the amount of Sn+~ ion is preferably from 1 to 5.5 ~g.
Exam~le 9 Distribution of the 99mTc-labeled radioactive diagnostic agent in rabbit:-The 99mTc-labeled radioactive diagnostic agent (containing the radioactivity of l mCi) (0.2 ml) was administered to each of several nembutal-anesthetized rabbits at the auricular vein, and continuous imaging with a scintillation camera was carried out. Regions of interest were provided in the brain, heart, left kidney and lung, and the relative values of the radioactivities in brain and in other organs were measured. The results are shown in Table 2.
Table 2 ..... _ _~ _ , \Time after admini- lO 20 30 60 120 240 \~ =,_~
Item _ _ Brain/Heart 5.3 3.1 l.9 1.0 0.6 0.5 Brain/Left kidney41.0 15.2 4.0 2.3 1.7 l~0 Brain/Lung 1.5 3.3 2.5 2.7 2.4 2.0 From the above results, it can be seen that the radioactive diagnostic agent of the invention can pass through the blood-brain barrier immediately after adminis-tration to accumulate in the brain, and the amount of accumulation in the brain is much higher than that in other organs. Thus, it is quite useful for imaging of the brain as well as dynamic study of the brain.
, ,~.~.'''~' Example 10 Toxicity of the 67Ga- or 99mTc~labeled radioactive diagnostic agent:-The 67Ga- and 99mTc-labeled radioactive diagnostic agent obtained in Examples 6 and 7 were attenuated radio-actively to an appropriate extent and then administered intravenously to groups of SD strain male and female rats, each group consisting of 10 rats, at a dose o~ 1 ml per 100 g of the bodyweight (which corresponds to 300 times the amount usually administered to human beings) or to groups of ICR strain male and female mice, each group consisting of 10 mice, at a dose of 0.5 ml per 10 g of the bodyweight (which corresponds to 1500 times the amount usually administered to human beings). For the control groups, the same volume of physiologically saline solution as above was intravenously administered. All the groups were bred for 10 days, and the variation of the bodywei~ht was recorded every day. No significant difference was observed between the medicated groups and the control groups. After the observation over 10 days, all the animals were sacrificed, and no abnormality was observed on any organ taken out from them. Thus, it is understood that the toxicity of the 67Ga- or 99mTc-labeled radioactive diagnostic agent is extremely low.
solution, the 99mTc-labeled radioactive diagnostic agent can be produced with a good efficiency. Taking the produc-tion rate of the major component into consideration, the amount of Sn+~ ion is preferably from 1 to 5.5 ~g.
Exam~le 9 Distribution of the 99mTc-labeled radioactive diagnostic agent in rabbit:-The 99mTc-labeled radioactive diagnostic agent (containing the radioactivity of l mCi) (0.2 ml) was administered to each of several nembutal-anesthetized rabbits at the auricular vein, and continuous imaging with a scintillation camera was carried out. Regions of interest were provided in the brain, heart, left kidney and lung, and the relative values of the radioactivities in brain and in other organs were measured. The results are shown in Table 2.
Table 2 ..... _ _~ _ , \Time after admini- lO 20 30 60 120 240 \~ =,_~
Item _ _ Brain/Heart 5.3 3.1 l.9 1.0 0.6 0.5 Brain/Left kidney41.0 15.2 4.0 2.3 1.7 l~0 Brain/Lung 1.5 3.3 2.5 2.7 2.4 2.0 From the above results, it can be seen that the radioactive diagnostic agent of the invention can pass through the blood-brain barrier immediately after adminis-tration to accumulate in the brain, and the amount of accumulation in the brain is much higher than that in other organs. Thus, it is quite useful for imaging of the brain as well as dynamic study of the brain.
, ,~.~.'''~' Example 10 Toxicity of the 67Ga- or 99mTc~labeled radioactive diagnostic agent:-The 67Ga- and 99mTc-labeled radioactive diagnostic agent obtained in Examples 6 and 7 were attenuated radio-actively to an appropriate extent and then administered intravenously to groups of SD strain male and female rats, each group consisting of 10 rats, at a dose o~ 1 ml per 100 g of the bodyweight (which corresponds to 300 times the amount usually administered to human beings) or to groups of ICR strain male and female mice, each group consisting of 10 mice, at a dose of 0.5 ml per 10 g of the bodyweight (which corresponds to 1500 times the amount usually administered to human beings). For the control groups, the same volume of physiologically saline solution as above was intravenously administered. All the groups were bred for 10 days, and the variation of the bodywei~ht was recorded every day. No significant difference was observed between the medicated groups and the control groups. After the observation over 10 days, all the animals were sacrificed, and no abnormality was observed on any organ taken out from them. Thus, it is understood that the toxicity of the 67Ga- or 99mTc-labeled radioactive diagnostic agent is extremely low.
Claims (8)
1. A non-radioactive carrier, which comprises as the essential component glucosone-bis(thiosemicarbazone) of the formula:
said carrier being of pharmaceutically acceptable purity.
said carrier being of pharmaceutically acceptable purity.
2. The non-radioactive carrier according to claim 1, which further comprises a reducing or an oxidizing agent.
3. The non-radioactive carrier according to claim 1, which is in the form of aqueous solution.
4. The non-radioactive carrier according to claim 1, which is in the form of lyophilized powder.
5. A radioactive diagnostic agent, which comprises a radioactive element and the non-radioactive carrier according to claim 1.
6. A radioactive diagnostic agent, which comprises a radioactive element and the non-radioactive carrier according to claim 2.
7. The radioactive diagnostic agent according to claim 5, prepared by contacting the radioactive element with the non-radioactive carrier according to claim 1 in an aqueous medium.
8. The radioactive diagnostic agent according to claim 6, prepared by contacting the radioactive element with the non-radioactive carrier according to claim 2 in an aqueous medium.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000386019A CA1186225A (en) | 1981-09-16 | 1981-09-16 | Radioactive diagnostic agent and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000386019A CA1186225A (en) | 1981-09-16 | 1981-09-16 | Radioactive diagnostic agent and its preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1186225A true CA1186225A (en) | 1985-04-30 |
Family
ID=4120968
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000386019A Expired CA1186225A (en) | 1981-09-16 | 1981-09-16 | Radioactive diagnostic agent and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1186225A (en) |
-
1981
- 1981-09-16 CA CA000386019A patent/CA1186225A/en not_active Expired
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