The present invention provides a radiation-protecting agent which protects the active ingredient of radiopharmaceuticals against the radiolysis caused by a reaction of the active ingredient with water radicals formed by radiolysis of water, without decomposing the reactive active ingredient such as readily reducible active ingredient. The radiation-protecting agent of the present invention is characterized by comprising an organic compound usable in medical drugs and having high physiological acceptability and protecting the radiolabeled active ingredient of radiopharmaceuticals against the action of radiation. The reaction rate constant of said organic compound with OH radical, H radical or hydrated electron must be in the range of from 1.times.10.sup.8 to 5.times.10.sup.10 M.sup.-1 s.sup.-1, and when added to radiopharmaceuticals, molar concentration of the organic compound must be at least 50 times as high as molar concentration of the active ingredient.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to radiation-protecting agents which protect 
the active ingredient of radiopharmaceuticals against radiolysis. 
2. Related Art Statement 
Radiopharmaceuticals are drugs to be administered into a living body for 
the purpose of nuclear medicine diagnosis or radiotherapy. In general, 
radiopharmaceuticals comprise a radioisotope ion itself or an organic 
compound stably bound with a radioisotope as an active ingredient, and 
further contain pharmaceutically necessary additives, and many of the 
radiopharmaceuticals are formulated as aqueous solution. When an organic 
compound is used as an active ingredient, the radioisotope is incorporated 
into the molecular structure of active ingredient through covalent bond or 
coordination bond. 
In radiopharmaceuticals, the radiation emitted from radioisotope decomposes 
the active ingredient by direct action or indirect action of radiation. 
The term "direct action" means decomposition caused by the direct 
collision of the radiation itself emitted from radioisotope against active 
ingredient molecule, while the term "indirect action" means decomposition 
of active ingredient molecule caused by the attack of water radicals such 
as OH radical, H radical and hydrated electron which are formed when the 
energy of the radiation emitted from radioisotope is absorbed by water 
molecule constituting the solvent. These actions of radiation are called 
radiolysis, and the radiolysis of an active ingredient is almost 
exclusively caused by the indirect action, in case of aqueous 
radiopharmaceuticals in which the concentration of active ingredient is 
generally low. The number of radicals generated per 100 eV of absorbed 
radiation energy is called radical yield, which is 2.5 for OH radical, 0.5 
for H radical, and 2.7 for hydrated electron. These values and the 
characteristic feature of the radical reaction suggest that the 
predominant water radical participating in radiolysis is OH radical in 
most cases. 
Further, water radicals form hydrogen peroxide in the process of the 
recombination reaction thereof. The hydrogen peroxide thus formed disturbs 
the active ingredient-forming reaction (complex formation) when 
technetium-99m (hereinafter abbreviated to Tc-99m), a typical radionuclide 
for radiopharmaceuticals, is linked to active ingredient through 
coordination bond. In addition, the hydrogen peroxide accelerates 
elimination of Tc-99m from active ingredient. In radiopharmaceuticals 
containing Tc-99m, a reductant (usually, a stannous salt) is added for the 
purpose of reducing pertechnetate (hereinafter abbreviated to .sup.99m 
TcO.sub.4.sup.-) and forming a complex with a chelating agent. Hydrogen 
peroxide oxidizes this reductant to disturb the complex-formation or 
re-oxidizes the coordinated Tc-99m to accelerate the elimination of 
Tc-99m. Since the above-mentioned attack of water radicals and the 
oxidative action of hydrogen peroxide cause decomposition of active 
ingredient and thereby markedly deteriorate the quality of 
radiopharmaceuticals, it has hitherto been conventional to add a 
stabilizer to radiopharmaceuticals in order to prevent the deterioration 
of drug quality. 
In Japanese Patent Publication JP-B-82036894, JP-B-82006409 and 
JP-B-90033019, there is disclosed a technique of adding ascorbic acid or 
erythorbic acid as a stabilizer for radiopharmaceuticals labeled with 
Tc-99m, one of the representative radionuclide used in 
radiopharmaceuticals. 
Ascorbic acid and erythorbic acid proposed as stabilizer in these patent 
gazettes have a general characteristic feature that they are both 
reductive substances, and their amount to be added is prescribed based on 
the amount of stannous salt which is a reductant for Tc-99m. The nature of 
their stabilizing action lies in decomposing hydrogen peroxide due to the 
reductivity of these stabilizers and thereby preventing the oxidation of 
the stannous salt used as reductant. However, these stabilizers, namely 
ascorbic acid and erythorbic acid, are unusable at all when a readily 
reducible active ingredient or additive is present in the drug formulation 
because these stabilizers reductively decompose such active ingredient or 
additive. For example, in a radiopharmaceutical comprising an active 
ingredient having porphyrin rings as fundamental chemical structure, the 
active ingredient is decomposed through a reaction with ascorbic acid as 
mentioned below, and thereby loses the original pharmaceutical activity. 
SUMMARY OF THE INVENTION 
In view of the above-mentioned situation, the objective of the present 
invention consists in providing radiation-protecting agents for use in 
radiopharmaceuticals which prevents an active ingredient from 
decomposition caused by the reaction between active ingredient and water 
radicals formed by radiolysis of water, without reductively decomposing 
the readily reducible active ingredient. 
The present invention provides a radiation-protecting agent comprising an 
organic compound having high physiological acceptability and, when added 
to a radiopharmaceutical, protecting the radiolabeled active ingredient of 
the drugs against the action of radiation. Said organic compound 
preferably has a high reaction ate constant with OH radical, H radical and 
hydrated electron, and the reaction rate constant is particularly in the 
range of from 1.times.10.sup.8 to 5.times.10.sup.10 M.sup.-1 s.sup.-1. 
When the radiation-protecting agent of the present invention is to be 
added to radiodiagnostic agents or radiotherapeutic drugs, molar 
concentration of the radiation-protecting agent is usually 50 times or 
more as high as the molar concentration of the active ingredient.

DETAILED DESCRIPTION OF THE INVENTION 
As used in the present invention, the term "organic compound having high 
physiological acceptability" means an organic compound exhibiting neither 
toxicity nor pharmacological action at the clinical dose when added to a 
radiopharmaceutical as an additive. Examples of such organic compound 
having high physiological acceptability include monosaccharides, 
disaccharides, organic acids, salts thereof and esters thereof. 
The active ingredient of the radiopharmaceuticals in the present invention 
comprises an organic compound capable of forming a stable linkage or a 
stable complex with a radioisotope ion or a radioisotope, and is used for 
medical diagnosis or therapy. Examples of the active ingredient of 
radiopharmaceuticals for diagnosis include technetium (.sup.99m Tc) 
hydroxymethylenediphosphonate, technetium (.sup.99m Tc) 
dimercaptosuccinate, N-pyridoxyl-5-methyltryptophane technetium (.sup.99m 
Tc), indium (.sup.111 In) diethylenetriaminepentaacetate, 
N-isopropyl-p-iodoamphetamine (.sup.123 I), 
15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid (.sup.123 I), 
7-[1-(2-hydroxyethyloxy)ethyl]-12-ethenyl-3,8,13,17-tetramethylporphine-2, 
18-dipropanoic acid manganese (III) complex diethylene-triaminepentaacetic 
acid monoester technetium (.sup.99m Tc), and the like. Examples of the 
active ingredient of radiotherapeutic drug include samarium (.sup.153 Sm) 
ethylenediaminetetra-methylenephosphonate, tin (.sup.117m Sn) 
diethylenetriamine-pentaacetate, rhenium (.sup.186 Re) 
hydroxyethylidenediphosphonate, and the like. 
The radiation-protecting agent of the present invention must capture most 
of the water radicals in competition with the active ingredient and water 
radicals. For this reason, the radiation-protecting agent must be selected 
from compounds having greater radical reaction rate constant than that of 
the active ingredient, or molar concentration of the radiation-protecting 
agent must be overwhelmingly higher than that of the active ingredient. In 
many cases, however, it is not always possible to add the additive in a 
large quantity, because of restriction in individual drug formulation, 
such as obstruction of labeling reaction by the presence of excess amount 
of additive. Accordingly, the radiation-protecting agent must have a high 
reaction rate constant with water radicals, namely OH radical, H radical 
and hydrated electron. In other words, the reaction rate constant between 
the radiation-protecting agent and water radicals must be higher than the 
so far known reaction rate constants between water radicals and common low 
molecular weight substances which are usually in the range of from 
10.sup.6 to 10.sup.9 M.sup.-1 s.sup.-1. It is preferably necessary that 
the reaction rate constant between the radiation-protecting agent and 
water radicals is in the range of from 1.times.10.sup.8 to 
5.times.10.sup.10 M.sup.-1 s.sup.-1, in order to exhibit a reliable effect 
as a radiation-protecting agent. 
Examples of the radiation-protecting agent of the present invention include 
monosaccharides such as glucose, fructose, mannose, galactose, arabinose 
and sorbitol; disaccharides such as sucrose, maltose and lactose; and 
organic acids such as sialic acid, lactic acid, benzoic acid and the like. 
The radiation-protecting agent of the present invention is reactive with 
the water radicals formed by radiolysis of water as has been mentioned 
above, however, it is equally important that the agent should be 
unreactive with the active ingredient of radiopharmaceutical. Based on 
this idea, the present inventors selected a compound containing porphyrin 
ring as a highly reactive active ingredient, and its reactivity with the 
radiation-protecting agent of the present invention was investigated. The 
compound selected herein could form a stable complex with radioisotope and 
was expected to be useful as an active ingredient of radiopharmaceutical 
used as a diagnostic or therapeutic agent, and at the same time the 
compound was highly reactive in reactions such as oxidation-reduction 
reaction, and the change of its state could readily be detected by 
spectral measurement after the reaction. 
In order to know whether or not the candidate radiation-protecting 
compounds selected above could actually protect an active ingredient of 
radiopharmaceutical from the indirect action of radiation, the reaction 
rate constant between the candidate compound and OH radical (hereinafter 
abbreviated to OH.), one of the water radicals, was determined in a 
bimolecular competitive reaction system. Since water radicals include the 
above-mentioned three species and the three species are usually comparable 
to one another in the reaction rate constant, OH. was selected in this 
experiment due to its highest radiolytic activity. In the measurement, a 
sample substance of unknown rate constant was added in various 
concentration to a solution of a standard substance of known rate constant 
with OH., and the sample substance and the standard substance were made to 
react with OH. competitively. The quantity of the standard substance 
having reacted with OH. and thereby having been decomposed was determined 
from the change in UV absorption spectrum thereof, based on which the 
reaction rate constant of the sample substance was calculated. (Henglein 
et al., translated by Junkichi Soma et al., Fundamental Radiation 
Chemistry, published by Tokyo Kagaku Dojin) Details of the theory are 
mentioned below. 
In the field of radiation chemistry, p-nitrosodimethylaniline (hereinafter 
abbreviated to NDA) is used as a standard OH. scavenger for measurement of 
reaction rate constant. When NDA reacts with OH., it decomposes to lose 
the light absorption peak at 440 nm. G value (a numerical value indicating 
the magnitude of various events taking place upon irradiation with 
radiation; the number of molecules of a substance undergoing a change at 
the time when the substance has absorbed 100 eV of radiation energy) of 
this reaction is 1.2, and its reaction rate constant is 
1.25.times.10.sup.10 M.sup.-1 s.sup.-1. When a sample substance X reacts 
with OH. in competition with standard substance NDA and the secondary 
reaction between X radical and NDA is negligible, the reaction rate 
constant between X and OH. can be determined from the reaction rate 
constant between the standard substance and OH., according to the reaction 
rate theory in homogeneous system. .sup.99m TcO.sub.4.sup.- is not 
regarded as a reaction element, because its concentration is extremely 
low. In order to simplify the reaction system, the solution is replaced 
with N.sub.2 O, and hydrated electron (e.sub.aq.sup.-) is converted to OH. 
: 
EQU N.sub.2 O+e.sub.eq.sup.- +H.sub.2 O.fwdarw.N.sub.2 +OH.+OH.sup.- 
EQU [N.sub.2 O]=ca. 24 mM (saturated with N.sub.2 O) 
EQU k=8.7.times.10.sup.9 M.sup.-1 s.sup.-1 
In a system in which only X and NDA exist, OH. disappears through the 
following reaction: 
##STR1## 
The disappearance velocity of OH. is expressed by the following Formulas 1 
and 2: 
EQU -d[OH.].sub.NDA /dt=k.sub.1 [NDA][OH.] Formula 1 
wherein k.sub.1 is reaction rate constant between OH. and NDA; 
EQU -d[OH.].sub.X /dt=k.sub.X [X][OH.] Formula 2 
wherein k.sub.X is reaction rate constant between OH. and X. 
The total disappearance velocity of OH. is the sum of Formulas 1 and 2, and 
expressed by the following Formula 3: 
EQU -d[OH.]/dt=(-d[OH.].sub.NDA /dt)+(-d[OH.].sub.X /dt) Formula 3 
The fraction of OH. reacting with NDA, namely F.sub.NDA, is expressed by 
Formula 4, and reciprocal of Formula 4 is Formula 5: 
EQU F.sub.NDA =(-d[OH.].sub.NDA /dt)/(-d[OH.]/dt)=k.sub.1 [NDA][OH.]/(k.sub.1 
[NDA][OH.]+k.sub.X [X][OH]) Formula 4 
EQU 1/F.sub.NDA =1+k.sub.X [X]/k.sub.1 [NDA] Formula 5 
Formula 5 indicates that 1/F.sub.NDA is a first order function with regard 
to [X]. Conversion of Formula 5 gives Formula 6: 
EQU 1/F.sub.NDA =1+k.sub.X.C.[X] Formula 6 
wherein C=1/k.sub.1 [NDA], k.sub.1 is 1.25.times.10.sup.10 M.sup.-1 
s.sup.-1, and [NDA] indicates an experimentally determined constant 
concentration. 
In Formula 6, k.sub.X can be determined by plotting 1/F.sub.NDA against 
various [X] and measuring the slope. 
1/F.sub.NDA can be determined in the following manner. NDA shows an intense 
absorption at 440 nm in aqueous solution, while its reaction product with 
OH., namely NDA*, shows no absorption at 440 nm. In an aqueous solution, 
the decrease of absorption at 440 nm observed in the absense of X 
indicates total quantity of OH. formed. In an aqueous solution of NDA 
containing X, the decrease of NDA absorption becomes smaller in proportion 
to progress of the reaction between X and OH.. If the decrease of light 
absorption in the absence of X is expressed by .DELTA.Abs.sub.0 and the 
decrease of light absorption in the presence of X is expressed by 
.DELTA.Abs.sub.X, the fraction of OH. having reacted with NDA is expressed 
by Formula 7. By inserting Formula 7 into Formula 5, Formula 8 is obtained 
: 
EQU F.sub.NDA =.DELTA.Abs.sub.X /.DELTA.Abs.sub.0 Formula 7 
EQU .DELTA.Abs.sub.0 /.DELTA.Abs.sub.X =1+k.sub.X [X]/k.sub.1 [NDA]Formula 8 
By optimizing the concentration of NDA and the quantity of .sup.99m Tc in a 
region making easy the measurement of .DELTA.Abs change in this reaction 
system and plotting the experimental data according to Formula 8, slope 
k.sub.X can be determined by the least square method. Experiments based on 
the above-mentioned theory revealed that candidate compounds belonging to 
monosaccharide, disaccharide and organic acid all have a sufficiently high 
reaction rate constant and therefore radiation-protecting effect can be 
expected therefrom. 
Subsequently, a saccharide or an organic acid having safety and 
physiological acceptability enough for use as a drug additive was blended 
with an active ingredient, and examined for radiation-protecting effect 
under an expected handling condition where the composition is put to 
practical use as radiopharmaceutical. As a result, glucose, fructose, 
sucrose, sorbitol, meglumine, lactic acid, benzoic acid, etc. exhibited a 
high radiation-protecting effect. Details are mentioned later in Examples. 
The purpose of the addition of a radiation-protecting agent to 
radiopharmaceutical consists in protecting the active ingredient molecule 
against the indirect action of radiation. The mechanism of indirect action 
of radiation is considered to be similar regardless of the kind of 
radiation, namely .alpha.-ray, .beta.-ray or .gamma.-ray, and thus 
regardless of the kind of isotopes. Accordingly, the radiation-protecting 
agent of the present invention and the use thereof are effective for all 
kind of radioisotopes used in radiopharmaceuticals. The radioisotopes 
generally used in radiopharmaceuticals are Tc-99m, I-123, I-131, Ga-67, 
In-111, Ru-97, Pb-203, C-11, N-13, O-15, F-18, Cu-62, Rb-87, Y-90, I-131, 
Sm-153, Dy-165, Ho-166, Lu-177, Re-186, Re-188, At-211, Cu-67, etc. 
The radiation-protecting agents of the present invention may be added to 
compositions for use in preparing radiopharmaceuticals either previously 
or afterwards. The form of the said composition may be any of freeze-dried 
composition, simple powder mixture, water-soluble liquid and freeze-dried 
product thereof. Further, a pH regulator such as an acid or a base, an 
isotonizing agent such as sodium chloride, a preserver such as benzyl 
alcohol, or a freeze-dry excipient such as lactose may be added to the 
composition, and addition of such additives makes no trouble on the 
practice of the present invention. 
When added to radiopharmaceuticals, the radiation-protecting agent of the 
present invention competitively protects the active ingredient against the 
attack of water radicals formed by radiolysis of water, and thereby 
prevents radiopharmaceuticals from deterioration of quality. This 
protecting effect can be expected when the reaction rate constant between 
the radiation-protecting agent and water radicals is in the range of from 
1.times.10.sup.8 M.sup.-1 s.sup.-1 to 5.times.10.sup.10 M.sup.-1 s.sup.-1 
and a chemical inertness of the radiation-protecting agent to active 
ingredient, namely unreactivity thereof, is secured. 
PREFERRED EMBODIMENTS OF THE INVENTION 
EXAMPLE 1 
In order to ascertain that porphyrin derivative is suitable model compound 
for searching and studying radiation-protecting agents, the radiolysis of 
7-[1-(2-hydroxyethyloxy)ethyl]-12-ethenyl-3,8,13,17-tetramethyl-porphine-2 
,18-dipropanoic acid manganese (III) complex diethylenetriaminepentaacetic 
acid monoester (HP-DTPA) which is one of the porphyrin derivatives was 
studied. 
A solution of .sup.99m TcO.sub.4.sup.- in an amount of 10-50 mCi as 
expressed in terms of quantity of radioactivity was added to a solution of 
HP-DTPA (0.25 or 0.20 mg/ml, solvent: purified water, pH 5). After tightly 
sealing the resulting mixture in a glass vial, the mixture was left to 
stand under either air-saturated or argon-saturated condition at room 
temperature for 24 hours. Then, UV absorption spectrum and fluorescence 
spectrum of the solution were measured. The changes in UV absorption 
spectrum and fluorescence spectrum were measured using a control sample 
containing no .sup.99m TcO.sub.4.sup.-. 
FIG. 1 illustrates UV absorption spectrum of the control sample, HP-DTPA 
solution containing no .sup.99m TcO.sub.4.sup.-. FIG. 2 and FIG. 3 
illustrate UV absorption spectra of samples prepared by adding 50 mCi of 
.sup.99m TcO.sub.4.sup.- solution to control HP-DTPA solution, and 
allowing the resulting mixture to stand under either air-saturated 
condition (FIG. 2) or argon-saturated condition (FIG. 3) for 24 hours at 
room temperature. It was shown from these results that the UV absorption 
peaks at 368 nm and 461 nm, characteristic of porphyrin derivatives, have 
been diminished by radiolysis. FIG. 4 is a graph obtained by plotting the 
decrease of UV absorption peak against radioactivity mixed in the range of 
10-50 mCi in samples allowed to stand for 24 hours under the same 
condition as above. Absorbance at 368 nm has decreased in proportion to 
the quantity of radioactivity added. At the same time, the addition of 
radioactivity produced a fluorescent substance, with fluorescence 
intensity also in proportion to the quantity of radioactivity added (FIG. 
5). The above-mentioned change was not observed when a .sup.99m 
TcO.sub.4.sup.- -free HP-DTPA solution was allowed to stand at room 
temperature, nor when an cooled-down .sup.99m TcO.sub.4.sup.- solution 
was added. An HPLC analysis of the HP-DTPA solution mixed with .sup.99m 
TcO.sub.4.sup.- has detected some peaks assignable to decomposed products 
by radiolysis. The above-mentioned experiments have proved that porphyrin 
derivatives are quite active to radiolysis. As mentioned below, the 
reaction rate constant of HP-DTPA with OH. is as great as 
2.8.times.10.sup.10 M.sup.-1 s.sup.-1. 
EXAMPLE 2 
The radiation-protecting agent of the present invention cannot be 
effective, unless the reaction rate constant thereof with water radicals 
is sufficiently high. In this experiment, the reaction rate constant 
between a radiation-protecting agent and OH. having the highest reactivity 
among water radicals was measured. The samples of radiation-protecting 
agent, namely compounds X, subjected to measurement in this example were 
saccharides (glucose and fructose), amino acid (glycine) an organic acids 
(lactic acid and benzoic acid). All these compounds had already been 
proved their safety and physiological acceptability as drug additives. 
A solution of X having a varied concentration (0, 2.times.10.sup.-5, 
5.times.10.sup.-5, 1.times.10.sup.-4, 2.times.10.sup.-4 and 
5.times.10.sup.-4 M) and a solution of .sup.99m TcO.sub.4.sup.- (20 
mCi/ml) were added to a diluted solution of NDA (2.times.10.sup.-5 M). 
After allowing the mixtures thus obtained to stand at room temperature for 
24 hours, the light absorption spectra thereof were measured. Since 
HP-DTPA could not directly be conformed a competitive reaction system with 
NDA due to the UV absorption of itself, the decrease of the absorption of 
HP-DTPA at 368 nm was measured by using glucose or fructose as a standard 
substance in the same manner as above, after the reaction rate constants 
of glucose and fructose were determined using NDA. The decrease of 
absorbance of NDA or HP-DTPA was plotted according to Formula 8, and 
k.sub.X was calculated from slope of the regression line. 
In the experiments using NDA, the decrease of absorbance of NDA at 440 nm 
became smaller as the quantity of compound X increased, as seen in FIG. 6. 
This indicates that the OH. formed by the .gamma.-ray of Tc-99m reacted 
with X. Plotting of 1/F.sub.NDA according to Formula 7 gave a nearly 
linear relationship in the low concentration region (FIG. 7). The values 
of k.sub.X calculated from the slopes are shown in Table 1. 
TABLE 1 
______________________________________ 
Reaction rate constants with OH radical 
Compound k (M.sup.-1 s.sup.-1) 
______________________________________ 
Glucose *) 8.52 .times. 10.sup.8 
Fructose 6.77 .times. 10.sup.8 
Lactic acid 6.74 .times. 10.sup.8 
Benzoic acid 14.6 .times. 10.sup.8 
HP-DTPA *) 282.00 .times. 10.sup.8 
______________________________________ 
*) Reaction rate constants of glucose and HPDTPA are average values of tw 
measurements. 
On the other hand, glycine did not inhibit the decrease of NDA absorbance, 
unlike the other compounds (FIG. 6). This is probably attributable to that 
a reaction between glycine and OH. formed glycine radical and the glycine 
radical further reacted with NDA, rather than that glycine did not react 
with OH.. Compounds with high reactivity are not suitable for use as a 
radiation-protecting agent, because such compounds may undergo further 
chain radical reaction and thereby eventually reacting with active 
ingredient. Amino acid is considered an example of such unsuitable 
compounds. 
All the compounds tested herein were found to have a sufficiently high 
reaction rate constant, and considered useful as radiation-protecting 
agents except for amino acid. 
EXAMPLE 3 
A radiation-protecting agent was added to a radiopharmaceutical comprising 
a porphyrin derivative as an active ingredient. After labeling, whether 
the radiolysis of the active ingredient was actually inhibited by the 
radiation-protecting agent or not was examined. 
Various concentration (2.5, 5, 10 and 20 mM) of glucose was added to 0.2 mM 
solution of HP-DTPA formulated for use as a radiopharmaceutical. Then, 10 
mCi of .sup.99m TcO.sub.4.sup.- was added, and the mixture thus obtained 
was allowed to stand at room temperature for 24 hours, after that UV 
absorption spectrum of each sample was measured. The results are shown in 
FIG. 8. The original HP-DTPA solution had a light absorbance of 0.88, 
which decreased to 0.76 when .sup.99m TcO.sub.4.sup.- was added. By 
adding glucose in an amount of 10 mM or more, the decrease in absorbance 
could be prevented completely. Since molar concentration of HP-DTPA was 
0.2 mM, the radiolysis of HP-DTPA could completely be prevented when molar 
concentration of glucose was 50 times higher than that of HP-DTPA. 
It was confirmed from the experimental result mentioned above that 
radiation-protecting agents of which reaction rate constant is around 
10.sup.8 M.sup.-1 s.sup.-1 can sufficiently exhibit the function thereof 
when molar quantity of such radiation-protecting agent present in the 
system is at least 50 times as high as molar quantity of active 
ingredient. 
EXAMPLE 4 
The radiation-protecting agent of the present invention is preferably 
unreactive with the active ingredient. In this experiment, whether or not 
a radiation-protecting agent reacts with active ingredient under an 
irradiated condition was examined. 
Under the practical conditions for the manufacture of radiopharmaceuticals 
with porphyrin derivatives, eight samples shown in Table 2 were prepared. 
Each sample contained a HP-DTPA solution (10 mM), calcium chloride (12 
mM), sodium chloride (80 mM), acetate buffer solution (pH 5.3, 20 mM), and 
.sup.99m TcO.sub.4.sup.- (100 mCi/ml) in addition to the ingredients 
shown in Table 2. After preparation, all the samples were allowed to stand 
in the dark at room temperature for 24 hours. Then, each sample was 
analyzed by reversed-phase HPLC for detecting the formation of fluorescent 
decomposition products in the HP-DTPA solution. The reversed-phase HPLC 
analysis was carried out an HPLC apparatus manufactured by Toso K. K. with 
a Puresil-Cl8 column (4.6 mm.phi..times.25 mmL) manufactured by Waters Co. 
As the eluent, a gradient system of 50 mM phosphate buffer (pH 3.5) and 
acetonitrile was used at a flow rate of 1 ml/minute, in which the 
concentration of acetonitrile was controlled so as to reach 15% in 0 
minute, 30% in 15 minutes, 31% in 28 minutes, and 95% in 40-45 minutes. 
For detection, an UV detector (368 nm), a .gamma.-ray detector and a 
fluorescence spectrometer (excitation: 378 nm; detection: 618 nm) were 
used. The results are shown in Table 2. It was demonstrated that the 
radiation-protecting agents other than ascorbic acid did not cause 
formation of fluorescent impurities and did not react with the active 
ingredient. 
TABLE 2 
______________________________________ 
Conditions of preparation and formation 
of fluorescent impurities 
Experi- [SnCl.sub.2 ] 
Fluorescent 
ment # Stabilizer* (.mu.g/ml) impurities 
______________________________________ 
1 -- -- Not detected 
2 -- 200 Not detected 
3 Asc.sup.a) -- Detected 
4 Asc.sup.a) 200 Detected 
5 Glu.sup.b) 200 Not detected 
6 Suc.sup.c) 200 Not detected 
7 Sol.sup.d) 200 Not detected 
8 MEG.sup.e) 200 Not detected 
______________________________________ 
Note) 
*Concentration of stabilizer is different from a run to another run. 
.sup.a) Asc: Ascorbic acid (2.5, 12.5, 25 mg/ml) 
.sup.b) Glu: Glucose (ca. 0.05, 0.5 M) 
.sup.c) Suc; Sucrose (ca. 0.05, 0.5 M) 
.sup.d) Sol: Sorbitol (ca. 0.05, 0.5 M) 
.sup.e) MEG: Meglumin (ca. 0.05, 0.5 M) 
In the test using ascorbic acid as a stabilizer, fluorescent impurities 
were formed. This result indicates that the use of ascorbic acid may not 
be appropriate when the active ingredient has a high reactivity. It can be 
concluded from these results that the radiation-protecting agents of the 
present invention can exhibit a high usefulness even in cases where 
ascorbic acid which is a conventional stabilizer frequently used hitherto 
cannot be used.