JPH04504263A - Radioactive iodine- or bromine-labeled piperidine compounds, and methods for producing the above-mentioned compounds and compositions containing the above-mentioned compounds - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Production of radioactive iodine or bromine labeled piperidine compounds and compositions containing the above compounds law The present invention relates to piperidine compounds labeled with radioactive iodine or bromine. Ru. Recent studies have shown that piperidine compounds consisting of e.g. kekunserin, ritanserin , pyrenverone, altanserin, etc. are serotonin-82 receptor antagonists. It has been proven that it behaves like During this time, serotonin-3 receptors are related to psychological and psychopathological processes, especially mood, such as aggression and depression. It is believed that this disorder plays an important role in headaches and related disorders. I've come to understand that.

In order to be able to treat the above abnormalities, their confirmation, i.e. correct diagnosis, is necessary. is essential. Therefore, in vivo, and therefore in the brain itself, We have developed a means that can selectively identify the serotonin-88 receptor binding site. The most important thing is to find it. This results in better identification of these anomalies and The possibility of achieving effective treatment has been achieved.

Janssen et al. (J, Label led Compound s and Radiopharmaceut [cals, @X X Volume V, No. 017.1988.783, page 788) for invltro research. For this purpose, ketanserin was radiolabeled with 3H and 14C. their radioactive isotopes Due to the elemental properties, such isotopes cannot be used for 1nvivi studies. I can't. Crouzel et al. radiolabeled with 11C and 1111'', respectively (J, 1abel le d　pounds　and　Radiophane+aceuticals, X Demonstrating the serotonin-5,- binding site in vivo by was completed. This technology makes it possible to create computerized tomography images of the brain. The resulting brain regions were visualized. PET is a very short film that emits positrons. It is an imaging method that uses long-lived radioactive isotopes.

■C and tap have very short half-lives of 20 minutes and 110 minutes, respectively. As a practical matter, compounds labeled with these isotopes must be labeled in situ. must be created: moreover, a cyclotron is needed for this purpose. be. All of this adds up to a relatively complex infrastructure in a hospital or clinic. This means a huge investment in char.

Another suitable technique, especially for confirming abnormal brain function, is photon ECT-(SPECT). This technique uses a sensitive detector to detect Utilize the emitted gamma rays. 5PECT is a cheaper technology than PET. So Additionally, this technique uses suitable gamma-ray emitters, e.g. radioactive materials with high specific activity. A compound labeled with iodine, for example +xsH, is used. As a result, relatively few Therefore, tissues with receptor binding sites can be studied with this method. 5PECT is a more or less "established" technique in nuclear medicine. The equipment is already available in well-equipped clinics and hospitals.

In 1986, Walters et al. (Bioehem, Pjan aacolOgL 1986.35 volume, No. 19.3199-3202 pages ) synthesized 7-amino-Bytsl-ketanserin. In principle, it is This is a compound that should be suitable for conducting functional brain research using the 5PECT method mentioned above. Ru.

The chemical structure of the above compound is shown in sub A' of the Table in the Appendix. As is clear from the official bulletin In addition, this compound was tested in in vitro experiments conducted in frontal cortex tissue of rats. In fact, it has a high affinity for serotonin-3 receptors. deer However, the specificity is not as pronounced for ketanserin because histamine-H, This is because considerable binding to receptors was also observed. As a result, specific seven A less clear image of the rotonin-S,-receptor binding site was obtained; Therefore, diagnosis of the abnormality involved is hindered. A much more serious drawback is the implementation As is clear from the above, the above compound synthesized by Wouter et al.

For practical purposes, no useful radioactivity is detected in the brain when used in . This compound therefore has only scientific significance. Apparently, at selected sites on the molecule By inserting a substituent, the properties of the molecule change and the compound is no longer It is no longer able to reach the serotonin-82 receptors in the brain.

In fact, from the aforementioned literature, ketanserin, when labeled with tritium, shows InVI It is known that VQ has a highly selective serotonin-8 receptor affinity. ing. Otherwise, the atom or group consisting of - certainly a bulky atom such as iodine Introducing children may have disastrous effects on pharmacokinetic behavior, resulting in compound can no longer reach its target or is no longer at the target receptor. cannot be combined with.

For functional brain research, especially related to brain serotonin-8,-receptor binding sites provides radiolabeled compounds for neurological and psychopathological processes that It is an object of the present invention to use the ECT (emission CT) method during this period. In the method of This method is performed using piperidine compounds, which are also used in vivo. Reached: Y is a radioactive iodine atom or a radioactive bromine atom: Q is N1 0, and at least two heteroatoms selected from the group consisting of S. two anel fated (to form a fused ring at the ortho position of the 61st ring) A group derived from a heterocyclic system having a ring, and the ring system has at least one ring. substituted with oxo and/or thioxo functional groups, C, -C, alkyl, C, -C, Alkoxy, halogen, Cr-Ca alkylamino and di(C,-C,)alkyl Optionally substituted with one or more substituents selected from the group consisting of Ruamino.

Radioactive iodine or bromine atoms are substituted at specific positions, i.e., on the phenyl group. As a result, radioactive iodine or bromine occupies a meta position relative to fluorine. Compounds are obtained that behave very little differently than their unconverted counterparts.

Radioactive halogen isotope, for example +131.7 @ B rl or ? ? Br is Particularly suitable for optical imaging.

Compound represented by the general formula below 7 has the above meaning.

Q- is a group derived from a heterocyclic system with two anellated rings; Of these rings, only a few rings are bonded to the ethyl group (and partially hydrated pyri). midine, which is substituted with a functional group selected from the group consisting of oxo and thioxo. may be substituted with a methyl group, and the other ring optionally contains a nitrogen atom and a third may be bonded to one ring and contain a petero atom selected from N, Ol and S .

Examples of the above-mentioned preferred compounds are recorded in the attached table under Nos. 011.2 and 3.

As a special aspect of the present invention, the method described in European Patent Application No. 165630 is used. If the new piperidine compounds labeled with radioactive iodine or bromine are It has been found that it can be prepared very conveniently from radiohalogen compounds. Those eyes For the purpose of water-soluble radioiodide or Reacts with bromides, such as radioactive sodium iodide, sodium bromide, potassium iodide, etc. make them respond. The reaction optionally includes one or more water-miscible solvents, such as ethanol. It is preferably carried out in an aqueous medium to which methanol, acetone, etc. are added. The reaction is It is preferably carried out at a slightly elevated temperature and then progresses quantitatively or almost quantitatively. nothing. To be used as a catalyst for the above reaction, dissolve it in the medium used for this reaction. As far as possible, various copper salts are suitable, such as nitrate steel, sulfate steel, etc. As a water-soluble acid Organic acids such as acetic acid, ascorbic acid, gentisic acid, etc. are preferably chosen. child The amount of reducing agent required for the reaction must be greater than the amount of catalyst. suitable reducing agent is Sn(■) salt, ascorbic acid, gentisic acid, citric acid, monosaccharide or sulfite. It is an acid salt. Several reducing agents may optionally be used in combination with each other. place If desired, antioxidants such as tin metal, ascorbic acid, citric acid, monosaccharides or antisic acid and the like can be used in this reaction.

In addition to pharmaceutically acceptable liquid carrier materials, such as physiological saline solution, the present invention provides Comprising the previously identified radioactive iodine or bromine labeled piperidine compounds. It also relates to radiopharmaceutical compositions. Performing radiodiagnostic examinations, especially as described above For the performance of radiodiagnostic examinations of brain function, the composition can be used, if desired, with pharmacological agents. The amount is administered to warm-blooded animals after dilution with a legally acceptable liquid, and the amount is per gram to 1000 MBq, more preferably 5 to 500 11 Bq. Yes, and the emitted radiation is then recorded. The ECT method described above is suitable for this test. used for.

As previously mentioned, this production reaction is carried out at a slightly elevated temperature, e.g. on a boiling water bath. done quantitatively or almost quantitatively. Therefore, this production reaction can be carried out in the clinic or is very suitable for performing in clinical laboratories. Labeled with radioactive iodine or bromine, The desired piperidine has a relatively short shelf life due to the natural decay of the radioisotope. The compound can be made on-site by the user and then used immediately. . pH suitable for physiological use in solutions containing all (or almost no) organic solvents Preferably, the desired product is formed quantitatively or almost quantitatively. It's convenient. The generated reaction mixture can be used immediately as a medicine without troublesome purification. and therefore can be injected intravenously or subcutaneously into living things. But non-isotopic intercourse A radioactive composition with the desired high specific activity is prepared by oxidation, and then a simple fractionation process is carried out. It may also be desirable to perform separations, such as column chromatographic separations.

Radiopharmaceutical compositions are very easy to make and are therefore very easy to make. This process starting from a pad is particularly suitable. This excludes radioactive iodine or bromine. A so-called “cold kit” containing all the components necessary for the production reaction is available. It means freedom for the user. Radioactive materials are provided separately to the user.

Here the user can carry out the above reaction himself: “Cold- The components of the kit° are mixed with radioactive iodine or bromine in the presence of a suitable solvent and the reaction mixture treat something as described above, for example by heating it on a boiling water bath for a certain period of time . If desired, after the reaction is complete, a simple separation may be carried out and the formulation liquid added. “Ko The components of the "Lold Kit" are in dry form, for example in lyophilized form.

This is preferred for stability.

From the foregoing, it is clear that the present invention provides a It is clear that this is also relevant to cold kits. Starting materials, i.e. corresponding In addition to non-radioactive halogen compounds, the above kit also contains water-soluble acids, copper salts, and acidic media. at least one reducing agent that is stable in the liquid and optionally a pharmaceutically acceptable formulation liquid and and/or adjuvants, such as stabilizers. The kit also includes instructions for performing the reactions described above. for use, including instructions for applying and optionally for simple separation. Also includes instructions.

The invention will be explained in more detail with reference to the following specific embodiments.

Example 1 3-[2-(4-(2-Radioiodine-4-fluorobenzoyl)piperidinyl )-ethyl]-2,4(IH13H)quinazolinedione (compound 1 in the table) SnSnSO41ffi gentisic acid 25 mg, citric acid 35 mg, 50 A solution of 500.1% acetic acid dissolved in 21% water is filtered, and this solution 500.1% is -[2-(4-(2bromo-4-fluorobenzoyl)piperidinyl)-ethyl ]-2,4(LH,3H)quinazolinedione and Cu” solution (Cu) Obtained by dissolving 5mg of S O4.5H,032.5mg in 10ml of water) Add to 30 μm. Shake the mixture in a sealed tube, then add I2m1-labeled sodium iodide with an active 370 MBQ was flushed with nitrogen for 15 minutes. Add #l to this solution.

The reaction mixture is placed in a sealed vial and heated in a boiling water bath for 60 minutes. radioactive iodine The labeling efficiency of the labeled product was determined by radio-HPLC and was >90%.

In order to obtain high specific activity, the generated radioactive products were further separated by HPLC. separated; in this case a semi-preparative ``reversed phase'' column is used [column filled RP18”; Eluent: methanol/acetonitrile/water/trimethylamine/ Acetic acid mixture, pH 4, 81 ° The labeled product is concentrated in a so-called “mini reverse phase ° column. [Column-filled Nijirica gel RP1B°, eluent; acidified with HCI] ethanol]. The radiopharmaceutical was finally diluted with isoerosive salt solution to 0.22% bacteria. Sterilized by filter. The composition is now ready for use.

The desired 2'-radioactive iodine compound can also be obtained starting from a non-radioactive 2'-iodine compound. Therefore, it is obtained.

The corresponding In(- and l!I It is made by using a solution of sodium iodide labeled with the element. Corresponding In this method, 7.Br- and 773r-labeled compounds are labeled vsBr and 77B, respectively. ``Produced by sodium bromide labeled with.

Compounds 2 and 3 listed in the table can be prepared using the corresponding non-radioactive 2'bromine by the corresponding method. - or from a 2' iodine compound.

1 day of poverty tn vitro binding lattice of the compound (■ book = l!J) prepared according to Example ■ In vitro binding was studied in the membrane composition of the frontal cortex of the human. This tissue flak The radiopharmaceutical composition 25 #l and lO obtained in Example ① were added to Sample 0 and F++1. Binding was tested using a mixture containing 25 μm% ethanol. pH 7.7 After incubation at 37°C in Lys-HCl buffer and filtration (plus washing) , the radioactivity on the filter was measured. Convert the results to Scatchard and Hill's method After further analysis, the dissociation constant was found to be =0.82, B11. -37 fmo per mg of tissue A linear saturation curve with i was created. The linearity of the curve is determined by the linearity of the test compound l. It has been shown that the cells bind to a similar single receptor population. From inhibition studies, this You can check what type of glue it is. For that purpose, it is well known selective serotonin-82-receptor antagonists ketanserin, licunserin and Inhibition of binding of compound 1 by methylsergide and antagonist 2 in the above experiments Measured by adding 5 μl. Binding is significantly inhibited by the above antagonists. Second, the values are 2.3×10−”11.0.53×, respectively. 10-'M and 0.64 XIG-''M, from the above inhibition experiments, compound 1 It appears to bind selectively to serotonin-$2- receptors. tritium In a comparative experiment using labeled ketanserin, there was a difference between this compound and compound l. No essential difference in bond placement was found.

The radiopharmaceutical composition obtained according to Example I was administered to male mice weighing 200-500 g. Talat was given an intravenous injection. Marked with bromine-76 and iodine-131 and iodine-125 The identified compound was used as a radioactive compound. After a certain period of time, the experimental animals are killed and The radioactivity of the posterior organs and relevant brain parts was measured using a multichannel spectrometer and Measured by automatic γ-scintillation counter. The obtained results show that the radiation It has been shown that large amounts of compounds labeled with radioactive iodine and radioactive bromine were taken into the rat brain. It is therefore clear that these compounds readily cross the blood-brain barrier. be. This is a known compound, namely 7-amino-812si-ketanserin ( Contrast with compound A) in the table. The latter compound had no or little effect on the brain in comparative experiments. It could not be detected. When using Compound 1, brain radioactivity is higher than plasma radioactivity and Increases linearly with the amount of compound injected. This is because brain radioactivity is directly related to blood flow. means that Radioactivity in the frontal cortex also increases until receptor saturation begins. increases linearly with injection volume. This indicates saturable and reversible binding. this Why is the frontal cortex the part of the brain most relevant to this problem? If so, this is because this is a brain region that contains a high concentration of heptarotonin-S,- receptors. (See also Example ■). Radioactivity ratio between frontal cortex and cerebellum at 3 hours and 15 hours after injection still increases between: this suggests strong binding.

A male baboon weighing 15 kg was first treated with 250 ff of ketamine and then with bendopacon. Anesthetize by injecting Rubital 15 mg/kg. Marked with l-123 The animal was injected intravenously with 200 MBq of a radiopharmaceutical composition of Compound 1. The specific radioactivity of the composition is 7.10' MBq/wool. 0 minutes and 60 minutes after injection View gamma camera placed over the head and body in large area for 1 minute. A sequence of 60 images is obtained.

At 1 and 2 hours after injection, a rotating gamma camera (40 bec/vlew, 64 A 5PECT study is performed using a rotation angle of 360°. -backrilt A total volume fi (total volume IIe) three-dimensional image is obtained by ering-. In this case, a Hummingburn (RainingIlann) filter is used. It will be done.

Reorient the three-dimensional volume to obtain a transverse image parallel to the orbital tract plane. 1st post-injection 5PECT images obtained at the first and second hours are shown in Figures 1 and 2, respectively. Crossing (top ) image plane is shown. Highly selective uptake of frontal cortex in both studies is recognized. Two hours after injection, the radioactivity ratio between frontal cortex and cerebellum was up to >10. increased. The frontal cortex is a region of the brain that has a high density of serotonin-52 receptors. It is an area. Therefore, selective uptake of the test compound into the frontal cortex Figure 2 shows that the compound selectively binds to serotonin-8,-receptors. this is real This was also confirmed by the experiment described in Example V.

Cold punishment-X In vivo studies in primates, substitution experiments on serotonin of compounds according to the invention -8! - Displacement experiments were performed to confirm selective binding to the receptor.

These experiments consisted of administering 5 mg of ketanserin 1 hour before injection of the radiopharmaceutical composition. The procedure is the same as in Example 2, except for intravenous injection. As mentioned above, ketane Serine is a well-known selective hepta-rotonin-S,-receptor antagonist, which is associated with the frontal cortex. attempts to occupy every serotonin-82-receptor binding site in the body. ! − 123 Labeled compound is administered in a very small amount, i.e. 203.5 MBq: specific radioactivity 7’IO’ MBq/wlIO1; This is a few nanometers equal to the amount used in Example It refers to the administration of no more than grams of active substance. 5PECT study described in Example ■ This is due to extremely small radioactivity uptake into the frontal cortex, that is, as found in Example ■. represents only about 1% of the radioactivity emitted. This indicates that the labeled compound according to the present invention and ketanseri selective binding to serotonin-8 receptors in the frontal cortex. In other words, the labeled compounds according to the invention It binds to the same type of receptor, the serotonin-82 receptor. It means to do something.

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Claims (9)

[Claims] 1. A piperidine compound labeled with radioactive iodine or bromine, represented by the formula below. ▲There are mathematical formulas, chemical formulas, tables, etc.▼In formula (I), Y* is a radioactive iodine atom or is a bromine atom; Q is a heteroatom selected from the group consisting of N, O, and S; derived from a heterocyclic system having two anellated rings together containing at least two derived: the ring system is substituted with at least one oxo and/or thioxo functional group, C 1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 alkylami one or more substituents selected from the group consisting of - and di(C1-C4) alkylamino A piperidine compound optionally substituted with a substituent. 2. It is expressed by the general formula below. ▲There are mathematical formulas, chemical formulas, tables, etc.▼In formula (II), Y* means the meaning described in claim 1 and Q' is a group derived from a heterocyclic ring system having two anellated rings. of which the ring bonded to the ethyl group is selected from the group consisting of oxo and thioxo an at least partially hydrated pyrimidine ring substituted with one or two functional groups , and the other ring optionally containing a nitrogen atom and bonded to the first ring can also be N. Wear A compound according to claim 1. 3. It is expressed by the general formula below. Contains a heteroatom selected from , O, and S ▲ Contains mathematical formulas, chemical formulas, tables, etc. In the formula (III), Q has the meaning described in claim 1, and X is a non-radioactive halogen. is an atom The compound is at least stable in a water-soluble acid, copper ions as a catalyst and an acid medium. also by reacting with water-soluble radioactive iodine or bromine in the presence of a reducing agent. , represented by the general formula I of claim 1, and the symbols in the formula have the meanings specified in claim 1. Compound manufacturing method. 4. It is expressed by the general formula below. ▲There are mathematical formulas, chemical formulas, tables, etc.▼In the formula (IV), Q' has the meaning described in claim 2. Mochi X has the meaning described in claim 3. Compounds can be prepared using water-soluble acids, copper ions as catalysts, and acidic medium to stabilize by reacting with water-soluble radioactive iodine or bromine in the presence of both reducing agents. is represented by the general formula II of claim 2, and the symbols in the formula have the meanings specified in claim 2. Method of manufacturing compounds. 5. Radioactive containing a radiolabeled compound in addition to a pharmaceutically acceptable liquid carrier material A pharmaceutical composition comprising radioiodine- or bromine-labeled piperidine according to claim 1. A composition comprising a compound. 6. Comprising a piperidine compound labeled with radioactive iodine or bromine according to claim 2. The composition according to claim 5, characterized in that: 7. The composition according to claim 5 or 6 is optionally diluted with a pharmaceutically acceptable liquid. 1 to 1000 NBq, preferably 5 to 500 NBq per 70 kg of body weight. The special method involves administering an amount of NBq to a warm-blooded animal and then recording the emitted radiation. A radiodiagnostic method of testing for symptoms, especially certain brain functions. 8. It is represented by the general formula III shown in claim 3, and the symbols in the formula have the meanings described in the preceding claim. A taste compound, a water-soluble acid, a copper salt, and at least one substance that is stable in an acidic medium. one reducing agent and optionally a pharmaceutically acceptable formulation liquid and/or adjuvant; containing a formulation for reacting aqueous solution of radioactive iodine or bromine with an aqueous solution of radioactive iodine or bromine according to claim 3. The kit for producing a radiopharmaceutical composition according to claim 5, comprising instructions for use. 9. It is represented by the general formula IV shown in claim 4, and the symbols in the formula have the meanings described in the preceding claim. a water-soluble acid, a copper salt, and at least one compound that is stable in an acidic medium. a reducing agent, optionally a pharmaceutically acceptable formulation liquid and/or adjuvant, and the above ingredients. A use comprising a formulation for reacting the radioactive iodine or bromine with the aqueous solution of radioactive iodine or bromine according to claim 4. 7. The kit for producing a radiopharmaceutical composition according to claim 6, comprising a disclaimer for use in the radiopharmaceutical composition.