CA1266662A - Radioactive iodospiroperidol and a process for the preparation thereof - Google Patents
Radioactive iodospiroperidol and a process for the preparation thereofInfo
- Publication number
- CA1266662A CA1266662A CA000459998A CA459998A CA1266662A CA 1266662 A CA1266662 A CA 1266662A CA 000459998 A CA000459998 A CA 000459998A CA 459998 A CA459998 A CA 459998A CA 1266662 A CA1266662 A CA 1266662A
- Authority
- CA
- Canada
- Prior art keywords
- radioactive
- iodine
- metal salt
- radioactive iodine
- iodospiroperidol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Abstract
ABSTRACT
A radioactive 2-iodospiroperidol represented by the formula:
A radioactive 2-iodospiroperidol represented by the formula:
Description
~26i666Z
TECHNICAL FIELD
This invention relates to a novel radioactive 2-iodospiroperidol and a process for preparing the same.
The compound of this invention is a novel compound not disclosed in any literature. This compound has a ; strong affinity for dopamine receptor and is very useful as a nuclear medical diagnostic agent of dopamine receptor and as a radioactive medicine~
~.
BACRGROUND ART
It has recently been found that in the pathological state of brain (such as Parkinson's disease or schizophrenia)~
the amount of dopamine receptor is different from that in~ the normal person, and attention has become directed to the relation between dopamine receptor and various : :
kinds of brain diseases in the fields of medicine and pharmacology. Under these circumstances, the advent of ,, a nuclear medical diagnostic agent and a radioactive mediclne targeting dopamine receptor has been strongly ` desired.
20 DlSCLOSllR3~ OF IN~ENTION ~
The present inventors~have made extenslve studies alml~ng at obtaLning~a~dopamine receptor-tropic diagnostic ;agent and ~a radioactive medicine having radloactive iodine : :: ,,: ,,, j ;;;.. :; : :,, ,. , :
, ",:
:~26~
1 in its molecule, and have found that the novel iodine compound represented by the formula (I) shown below has a strong affinity for dopamine receptor and can be specifical-ly combined therewith.
5According to this invention, there is provided a novel radioactive 2-iodospiroperidol represented by the formula (I):
F ~ COCH2CH2CH2N ~ ¦ (I) X
.~ ~
wherein X represents a radioactive iodine atom, and a process for preparing the same. The compound (I) of this invention has a much stronger affinity for dopamine receptor than p-iodospiroperidol which is a known iodine compound dis-closed in llterature [J. Nuelear Medieine, 23(5), 100 (1982~], and possesses very exeellent properties as a dopamine reeeptor-tropie radioactive diagnostic agent or radioactive ;15 medieine.
Therefore, proper application of the eompound (I~ -:
~ of th1s invention makes it possible not only to non-invasive-:
ly detect the presenee of dopamine receptor in the brain and other internal organs and tissues of human beings and animals but also to dynamically measure the change of amount ~ of the reeeptor, and thus, this compound is greatly useful ; _ 2 _ " , ., , , . . ,~ , :. : . : :. ,:
: ~ ~ .: ... :: , . ..
1~66~
1 for the nuclear medical diagnosis and treatment of brain troubles and other diseases. Also, in view of the relevancy of dopamine receptor to cancers such as breast cancer and the like, the compound is also useful in application to this field.
BEST MODE FOR CARRYING OUT THE INVENTION
The method for the preparation of the compound of this invention will be described below.
The compound of this invention represented by the above-mentioned formula (I) can be produced by a conven-tional method for the synthesis of radioactive iodine compounds. For instance, it can be produced according to either Process A or Process B shown below.
, ~
., , ~; [Process A]
:
~ 15 ~ An amino compound represented by the formula ~
O
F ~ COC~Cd2CI~ ~ (II) :,~, : : , , is~reacted with~an alkali metal salt of nitrous acid in a suitable~solvent~such~as tetrahydrofursn, dioxsne, sceton-itr~ile~or~;the like ln the presence of~an acld such as diluted sulfuric acid or~diluted hydrochloric acid to form a 20 ~dlazonium salt represented by the formula lIII):
:. , ~, :
~26~
~ H
F ~ -COCH2CH2CH2N ~ ~ (III) I
~-N
z 1 wherein Z represents an anion represented by a halogen ion or the formula HSO4 .
Then the compound (III~ is reacted with a radio-:~: active iodine metal salt to obtain the compound of the ; .5 formula (I). The above reactions are carried out at a temperature in a range~ of -5 to 30C.
, The compound (I) obtained can be purified by a : conventional method:such as thin layer chromatography ITLC) : or high-performance liquid chromatography ~HPLC).
10~ [Procesa B]
halogeno compound represented by the~formula
TECHNICAL FIELD
This invention relates to a novel radioactive 2-iodospiroperidol and a process for preparing the same.
The compound of this invention is a novel compound not disclosed in any literature. This compound has a ; strong affinity for dopamine receptor and is very useful as a nuclear medical diagnostic agent of dopamine receptor and as a radioactive medicine~
~.
BACRGROUND ART
It has recently been found that in the pathological state of brain (such as Parkinson's disease or schizophrenia)~
the amount of dopamine receptor is different from that in~ the normal person, and attention has become directed to the relation between dopamine receptor and various : :
kinds of brain diseases in the fields of medicine and pharmacology. Under these circumstances, the advent of ,, a nuclear medical diagnostic agent and a radioactive mediclne targeting dopamine receptor has been strongly ` desired.
20 DlSCLOSllR3~ OF IN~ENTION ~
The present inventors~have made extenslve studies alml~ng at obtaLning~a~dopamine receptor-tropic diagnostic ;agent and ~a radioactive medicine having radloactive iodine : :: ,,: ,,, j ;;;.. :; : :,, ,. , :
, ",:
:~26~
1 in its molecule, and have found that the novel iodine compound represented by the formula (I) shown below has a strong affinity for dopamine receptor and can be specifical-ly combined therewith.
5According to this invention, there is provided a novel radioactive 2-iodospiroperidol represented by the formula (I):
F ~ COCH2CH2CH2N ~ ¦ (I) X
.~ ~
wherein X represents a radioactive iodine atom, and a process for preparing the same. The compound (I) of this invention has a much stronger affinity for dopamine receptor than p-iodospiroperidol which is a known iodine compound dis-closed in llterature [J. Nuelear Medieine, 23(5), 100 (1982~], and possesses very exeellent properties as a dopamine reeeptor-tropie radioactive diagnostic agent or radioactive ;15 medieine.
Therefore, proper application of the eompound (I~ -:
~ of th1s invention makes it possible not only to non-invasive-:
ly detect the presenee of dopamine receptor in the brain and other internal organs and tissues of human beings and animals but also to dynamically measure the change of amount ~ of the reeeptor, and thus, this compound is greatly useful ; _ 2 _ " , ., , , . . ,~ , :. : . : :. ,:
: ~ ~ .: ... :: , . ..
1~66~
1 for the nuclear medical diagnosis and treatment of brain troubles and other diseases. Also, in view of the relevancy of dopamine receptor to cancers such as breast cancer and the like, the compound is also useful in application to this field.
BEST MODE FOR CARRYING OUT THE INVENTION
The method for the preparation of the compound of this invention will be described below.
The compound of this invention represented by the above-mentioned formula (I) can be produced by a conven-tional method for the synthesis of radioactive iodine compounds. For instance, it can be produced according to either Process A or Process B shown below.
, ~
., , ~; [Process A]
:
~ 15 ~ An amino compound represented by the formula ~
O
F ~ COC~Cd2CI~ ~ (II) :,~, : : , , is~reacted with~an alkali metal salt of nitrous acid in a suitable~solvent~such~as tetrahydrofursn, dioxsne, sceton-itr~ile~or~;the like ln the presence of~an acld such as diluted sulfuric acid or~diluted hydrochloric acid to form a 20 ~dlazonium salt represented by the formula lIII):
:. , ~, :
~26~
~ H
F ~ -COCH2CH2CH2N ~ ~ (III) I
~-N
z 1 wherein Z represents an anion represented by a halogen ion or the formula HSO4 .
Then the compound (III~ is reacted with a radio-:~: active iodine metal salt to obtain the compound of the ; .5 formula (I). The above reactions are carried out at a temperature in a range~ of -5 to 30C.
, The compound (I) obtained can be purified by a : conventional method:such as thin layer chromatography ITLC) : or high-performance liquid chromatography ~HPLC).
10~ [Procesa B]
halogeno compound represented by the~formula
2~cH2cH2 ~ ~ ~ (IV~
., ~ , , ;, ~,,, ~; ~; . , , - ~
wherein~Y:~:represents~a halogen atom is subjected~to~an ex hange~re~ct on with a~radio~c~l~e l-d.ne netal;salt ln -~Z6~
1 ~ suitable solvent such as acetonitrile, dimethylformamide, ethylene glycol, an ether derivative of ethylene glycol, an ether derivative of diethylene glycol, water or the like at a temperature of 50 to 180C. The compound (I) obtained can be purified by a conventional method such as TLC or HPLC.
In the process of this invention, for example, I-123, I-125, I-131, I-132, etc. are exemplified as the ra~ioactive iodine atom, and I-123, I-125 and I-131 are preferred. The radioactive iodine metal salt means a metal salt of the above radioactive iodine, and may be any of those capable of providing a radioactive I ion, though alkali metal salts such as, for example, sodium iodide, potassium - iodide and lithium iodide are preferred. As the halogen ion in the formula (III), anions of chlorine, bromine, iodine and the like are exemplified, and as the halogen atom in the formula (IV), there can be exemplified, for example, fluorine, ch1orine, bromine and iodine atoms.
By intravenously injecting the radioactive 2-iodo-spiroperidol (I) obtained by this invention into patients and taklng a sclntigram with the lapse of time, or by measur-lng the radioactivity b~ the probe~method and determining the intake o~ the~compound (I) in a speciflc organ, it is possible to simply and appropriately determine the site and 25~ scope of the~focus and the degree~of affection.
, The radioactive 2-iodospiroperidol according to thi~s invention is thus useful for the diagnosis of the brain dlseases, breast cancer and the like, but this compound is ~: : :
, ~ . , , - `
1 also useful for the diagnosls and treatment of other various diseases resulting from a change of dopamine receptor.
The present invention will further be specifically described below referring to Examples.
S REFERENTIAL EXAMPLE
Preparation of 8-[4-(4-fluoro-2-iodophenyl)-4-oxobutyl]-l-phenyl-1,3,8-triazaspiro[4,5]decane-4-one(2-iodo-spiroperidol~
2-Aminospiroperidol (410 mg) was suspended in 2 N
hydrochloric acid and acetonitrile, and to the resulting suspension was added dropwise an aqueous solution of sodium nitrite (95 mg) with ice-cooling. The resulting mixture was stirred at a temperature of 5C or less for 30 minutes and an aqueous solution of potassium iodide (166 mg) was added dropwise to the diazonium salt produced with ice-cooling, after which the mixture obtained was further stlrred at the same temperature for 1.5 hours. After the reaction, the react1on mixture was made alkaline and~subjected to a solvent extraction, and the solvent was then removed by distil1ation ; 0~ to~obtain~a;crude product. This was purified by silica gel column chromatography to obtaLn~2-iodospiroper1do1 ~427 mg).
Melting point: 170-175C.
IR (CHC13)~ om : 1710 (C=0~
H-NMR~(CDC1~3)~ ~(ppm):~1.40-3.18 ~/14H,~m,~ methylenej, 25~ 4.72 ~2H,~s,~-~HCH2N~), 6.31-7.79 (8H, m,~ benzene r~ing H).
Mass~spectrum~ 70 eV) m/e:~521 ~M 1, 244.
i6~;~
Preparation of [ I]-8-[4-(4-fluoro-2-iodophenyl) 4 oxobutyl]-l-phenyl-1,3,8-triazaspiro[4,5]decane-4-one([l25I]-2-iodospiroperidol) The diazonium salt prepared by using 2-aminospiro-peridol (40 ~gl, 2 N sulfuric acid and sodium nitrita was reacted with Na 125I (2 mCi) with ice-cooling in the same way as in the Referential Example, and the resulting crude product was purified by HPLC (column: Licrosorb RP-18) to obtain [125I]-2-iodospiroperidol (1.4 mCi). This product was identical with the specimen obtained in the Referential Example in Rf values of TLC and retention time of HPLC.
Preparation of [1 3I]-2-iodospiroperidol with Na 123I
In the same manner as in Example 1 using Na 12 I
(5 mCi), there was obtained [123I]-2-iodospiroperidol (1.4 mCi). This product was identical with the specimen obtained in the Referential~Example in Rf values of TLC and : retention time of HPLC.
Preparation of ~125I]-2-iodospiroperidol by exchange method :::
Dimeth~lformamide (10 ~1) and Na I (2.2 mCi) : were added to 2-iodospiroperidol (3 ~g) synthesized by the : 25 method of the Referential Example, and a slight amount of 0~1 N sulfuric acid was ~urther added thereto, and i:: :
': :
!
'. ~ ' , ,~ ' ' .
:, ~6~i66~
1 the resulting mixture was heated. After the reaction, the resulting crude product was purified by HPLC to obtain [125I]-2-iodospiroperidol (0.9 mCi). This product was identical with the specimen obtained in the Referential Example in Rf values of TLC and retention time of HPLC.
' ' .
.
, ~
: . :
~ 8 -,,, , ~
~: : : - :
~-: ~ .; . - . .
., ~ , , ;, ~,,, ~; ~; . , , - ~
wherein~Y:~:represents~a halogen atom is subjected~to~an ex hange~re~ct on with a~radio~c~l~e l-d.ne netal;salt ln -~Z6~
1 ~ suitable solvent such as acetonitrile, dimethylformamide, ethylene glycol, an ether derivative of ethylene glycol, an ether derivative of diethylene glycol, water or the like at a temperature of 50 to 180C. The compound (I) obtained can be purified by a conventional method such as TLC or HPLC.
In the process of this invention, for example, I-123, I-125, I-131, I-132, etc. are exemplified as the ra~ioactive iodine atom, and I-123, I-125 and I-131 are preferred. The radioactive iodine metal salt means a metal salt of the above radioactive iodine, and may be any of those capable of providing a radioactive I ion, though alkali metal salts such as, for example, sodium iodide, potassium - iodide and lithium iodide are preferred. As the halogen ion in the formula (III), anions of chlorine, bromine, iodine and the like are exemplified, and as the halogen atom in the formula (IV), there can be exemplified, for example, fluorine, ch1orine, bromine and iodine atoms.
By intravenously injecting the radioactive 2-iodo-spiroperidol (I) obtained by this invention into patients and taklng a sclntigram with the lapse of time, or by measur-lng the radioactivity b~ the probe~method and determining the intake o~ the~compound (I) in a speciflc organ, it is possible to simply and appropriately determine the site and 25~ scope of the~focus and the degree~of affection.
, The radioactive 2-iodospiroperidol according to thi~s invention is thus useful for the diagnosis of the brain dlseases, breast cancer and the like, but this compound is ~: : :
, ~ . , , - `
1 also useful for the diagnosls and treatment of other various diseases resulting from a change of dopamine receptor.
The present invention will further be specifically described below referring to Examples.
S REFERENTIAL EXAMPLE
Preparation of 8-[4-(4-fluoro-2-iodophenyl)-4-oxobutyl]-l-phenyl-1,3,8-triazaspiro[4,5]decane-4-one(2-iodo-spiroperidol~
2-Aminospiroperidol (410 mg) was suspended in 2 N
hydrochloric acid and acetonitrile, and to the resulting suspension was added dropwise an aqueous solution of sodium nitrite (95 mg) with ice-cooling. The resulting mixture was stirred at a temperature of 5C or less for 30 minutes and an aqueous solution of potassium iodide (166 mg) was added dropwise to the diazonium salt produced with ice-cooling, after which the mixture obtained was further stlrred at the same temperature for 1.5 hours. After the reaction, the react1on mixture was made alkaline and~subjected to a solvent extraction, and the solvent was then removed by distil1ation ; 0~ to~obtain~a;crude product. This was purified by silica gel column chromatography to obtaLn~2-iodospiroper1do1 ~427 mg).
Melting point: 170-175C.
IR (CHC13)~ om : 1710 (C=0~
H-NMR~(CDC1~3)~ ~(ppm):~1.40-3.18 ~/14H,~m,~ methylenej, 25~ 4.72 ~2H,~s,~-~HCH2N~), 6.31-7.79 (8H, m,~ benzene r~ing H).
Mass~spectrum~ 70 eV) m/e:~521 ~M 1, 244.
i6~;~
Preparation of [ I]-8-[4-(4-fluoro-2-iodophenyl) 4 oxobutyl]-l-phenyl-1,3,8-triazaspiro[4,5]decane-4-one([l25I]-2-iodospiroperidol) The diazonium salt prepared by using 2-aminospiro-peridol (40 ~gl, 2 N sulfuric acid and sodium nitrita was reacted with Na 125I (2 mCi) with ice-cooling in the same way as in the Referential Example, and the resulting crude product was purified by HPLC (column: Licrosorb RP-18) to obtain [125I]-2-iodospiroperidol (1.4 mCi). This product was identical with the specimen obtained in the Referential Example in Rf values of TLC and retention time of HPLC.
Preparation of [1 3I]-2-iodospiroperidol with Na 123I
In the same manner as in Example 1 using Na 12 I
(5 mCi), there was obtained [123I]-2-iodospiroperidol (1.4 mCi). This product was identical with the specimen obtained in the Referential~Example in Rf values of TLC and : retention time of HPLC.
Preparation of ~125I]-2-iodospiroperidol by exchange method :::
Dimeth~lformamide (10 ~1) and Na I (2.2 mCi) : were added to 2-iodospiroperidol (3 ~g) synthesized by the : 25 method of the Referential Example, and a slight amount of 0~1 N sulfuric acid was ~urther added thereto, and i:: :
': :
!
'. ~ ' , ,~ ' ' .
:, ~6~i66~
1 the resulting mixture was heated. After the reaction, the resulting crude product was purified by HPLC to obtain [125I]-2-iodospiroperidol (0.9 mCi). This product was identical with the specimen obtained in the Referential Example in Rf values of TLC and retention time of HPLC.
' ' .
.
, ~
: . :
~ 8 -,,, , ~
~: : : - :
~-: ~ .; . - . .
Claims (11)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A radioactive 2-iodospiroperidol represented by the formula:
(I) wherein X is a radioactive iodine atom.
(I) wherein X is a radioactive iodine atom.
2. A radioactive 2-iodospiroperidol according to claim 1, wherein X is an atom selected from the group of radioactive iodine isotopes consisting of I-123, I-125, I-131 and I-132.
3. A radioactive 2-iodospiroperidol according to claim 2, wherein X is I-123, I-125 or I-131.
4. A process for producing a radioactive 2-iodospiro-peridol of formula I as defined in claim 1, which process comprises:
(a) diazotizing a 2-aminospiroperidol represented by the formula and reacting a radioactive iodine metal salt with the thus obtained diazo compound represented by the formula:
wherein Z- represents an anion represented by a halogen ion or HSO4-, or (b) subjecting a 2-halogenospiroperidol represented by the formula wherein Y represents a halogen atom to an exchange reaction with a radioactive iodine metal salt.
(a) diazotizing a 2-aminospiroperidol represented by the formula and reacting a radioactive iodine metal salt with the thus obtained diazo compound represented by the formula:
wherein Z- represents an anion represented by a halogen ion or HSO4-, or (b) subjecting a 2-halogenospiroperidol represented by the formula wherein Y represents a halogen atom to an exchange reaction with a radioactive iodine metal salt.
5. A process according to claim 4(a), wherein the radio active iodine metal salt is a radioactive iodine alkali metal salt.
6. A process according to claim 5, wherein the radioactive iodine alkali metal salt is radioactive iodine sodium salt.
7. A process according to claim 4, wherein the radioactive iodine is I-123, I-125, I-131 or I-132.
8. A process according to claim 4, wherein the radioactive iodine is I-123, I-125 or I-131.
9. A process according to claim 4(b), wherein Y is an iodine atom.
10. A process according to claim 4(b), wherein the radio-active iodine metal salt is a radioactive iodine alkali metal salt.
11. A process according to claim 10, wherein the radioactive iodine alkali metal salt is radioactive iodine sodium salt.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA000459998A CA1266662A (en) | 1984-07-30 | 1984-07-30 | Radioactive iodospiroperidol and a process for the preparation thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA000459998A CA1266662A (en) | 1984-07-30 | 1984-07-30 | Radioactive iodospiroperidol and a process for the preparation thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1266662A true CA1266662A (en) | 1990-03-13 |
Family
ID=4128424
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000459998A Expired - Lifetime CA1266662A (en) | 1984-07-30 | 1984-07-30 | Radioactive iodospiroperidol and a process for the preparation thereof |
Country Status (1)
Country | Link |
---|---|
CA (1) | CA1266662A (en) |
-
1984
- 1984-07-30 CA CA000459998A patent/CA1266662A/en not_active Expired - Lifetime
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