JPH05310600A - Pancreatic imaging agent - Google Patents

Abstract

PURPOSE: To obtain a pancreatic imaging agent that comprises an iodine radioactive isotope and an N-containing heterocyclic ring-bearing N-substituted radioiodinated benzylamine derivative and can be used in conventional γ-ray camera and is useful for diagnosis of pancreatic diseases because it is easy to handle with a high discrimination level. CONSTITUTION: Properly substituted phenol is allowed to react with HCHO/SnCl4 anhydride to prepare a corresponding benzaldehyde, which is iodized with iodopyridinium nitrate to form a corresponding iodo-benzaldehyde. The product is subjected to the condensation reaction with an amine bearing desired substituents to form a corresponding imine. This imine is reduced with sodium borohydride, the product is reductively alkylated to prepare a desired N-alkyl derivative. Further, the iodine atom in the derivative is replaced with a radioactive iodine, I-121, I-125 or I-131 to give the objective pancreatic imaging agent comprising a compound represented by the formula ((n) is 1-10; R1 and R2 are each H, OH, a 1-6C alkyl; R3 is a 1-6C alkyl; and N' is an N atom as a part of a 4-8-membered heterocyclic ring).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a nuclear medicine technique for imaging body tissues and organs. In particular, the invention relates to compounds and methods useful for pancreatic imaging.

[0002]

2. Description of the Related Art The scintigraphic investigation of pancreatic diseases has been used in positron emission tomography (PET) studies until now, C-11-.
Amino acids labeled with radioisotopes such as L-tryptophan and planar gamma camera imaging
Amino acid analogs such as selenium methionine labeled with selenium-75, which have been used for imaging) have been mainly used. Due to the high patient radiation dose and pancreatic visualisation mismatch associated with selenium-75, and in part due to the relatively small amount of this substance that can be administered, the use of Se-75 selenium methionine has been extensive. Abandoned.

Baldwin et al ., US Pat. No. 4,360,511, discloses radioiodinated monoamine compounds that are primarily found in the brain and are useful as brain contrast agents.

Although these compounds are described as accumulating in the pancreas to some extent, no data are shown on the localization (localization) of these compounds in the pancreas and other abdominal organs, so that its suitability for pancreatic imaging should be predicted. I couldn't.

Kun and his collaborators used N, N, N'-trimethyl-N 'as an indicator of cerebral blood flow and as a brain contrast agent.
[2-hydroxy-3-methyl-5-iodobenzyl]
Developed certain radioactively iodinated diamines such as -1,3-propanediamine (HIPDM) [Kung et al., 1983, Nuclear Medicine Journal (J. Nucl. Med.)
24, 66; Blau et al., U.S. Pat.
430, 319].

[0006] Yamamoto's group uses HIP on the mouse pancreas
Although DM was found to localize somewhat, clinical studies in humans with this compound have shown that retention of this compound between the pancreas and liver is difficult to distinguish and the pancreas / liver ratio is relevant for clinical use. It was unsatisfactory in that it was not optimal [Yamamoto et al. (1985) Nuclear Medicine Journal (J. Nucl. Me
d.), 26, 764; (1986) Nuclear Medicine Journal (J. Nucl. Med.), 27, 1013; (199)
0) Nuclear Medicine Journal (J. Nucl. Med.), Vol. 31, p. 1015].

There is a need for an easy-to-use and discriminating pancreatic contrast agent suitable for routine diagnostic use.

[0008]

According to one aspect of the present invention,

[0009]

[Chemical 4] A compound effective for pancreatic imaging having n, where n is 1 to 10
R ₁ and R ₂ are the same or different and are hydrogen, hydroxyl or lower alkyl having 1 to 6 carbon atoms; R ₃ is lower alkyl having 1 to 6 carbon atoms; N'is a nitrogen atom forming part of a 4- to 8-membered heterocycle having 1 or 2 heteroatoms, one of the heteroatoms being this nitrogen and the heterocycle being unsubstituted Also provided are those substituted with one or more alkyl groups and pharmaceutically acceptable acid addition salts of these compounds. According to another aspect of the invention,
(A) Appropriately substituted phenol is HCHO / anhydrous SnC
to produce the corresponding benzaldehyde by reacting with l ₄ ,
(B) The obtained benzaldehyde is reacted with iodopyridinium nitrate to iodize to form a corresponding iodobenzaldehyde, and (c) the iodobenzaldehyde produced in step (b) is condensed with an amine having a desired substituent. A step of making the corresponding imine, (d) reducing the imine with sodium borohydride in ethanol, and (e) reductively alkylating the product of step (d) to give the desired N-alkyl derivative. Consists of

[0010]

[Chemical 5] A compound effective for pancreatic imaging, wherein n is 1 to 10
R ₁ and R ₂ are lower alkyl having 1 to 6 carbon atoms; N ′ is a nitrogen atom which is part of a 4 to 8 membered heterocycle having 1 or 2 heteroatoms. And one of the heteroatoms is this nitrogen and the heterocycle is unsubstituted or substituted with one or more alkyl groups. According to yet another aspect of the invention, an effective amount of a suitable carrier is present.

[0011]

[Chemical 6] A compound effective for pancreatic imaging having n, where n is 1 to 10
R ₁ and R ₂ are the same or different and are hydrogen, hydroxyl or lower alkyl having 1 to 6 carbon atoms; R ₃ is lower alkyl having 1 to 6 carbon atoms; N'is a nitrogen atom forming part of a 4- to 8-membered heterocycle having 1 or 2 heteroatoms, one of the heteroatoms being this nitrogen and the heterocycle being unsubstituted Alternatively, a compound substituted with one or more lower alkyl groups and a pharmaceutically acceptable acid addition salt of this compound is administered to a mammal to distribute the compound into the pancreas, and then the radiation emitted from the pancreas. Provided is a method of imaging a pancreas of a mammal which comprises detecting the ability.

According to yet another aspect of the invention, an effective amount of I-123N [3 (1-diethylamino) propyl] -N-methyl-2-hydroxy-3 in a suitable carrier.
-Methyl-5-iodobenzylamine or a pharmaceutically acceptable acid addition salt of this compound is administered to a mammal to distribute the compound into the pancreas and then detect the radioactivity released from the compound in the pancreas. A method of imaging a pancreas of a mammal is provided.

The invention illustrated by the preferred embodiments will be described with reference to the drawings. In the drawings, FIG. 1 shows a process chart of a method for producing a compound of the present invention. ^* R is - (CH _{2) 2}
Represents -N ', where N'is a suitable amino group. ⁺ Acetaldehyde is ethyl and acetone is isopropyl.

In FIG. 2, panel (a) shows a planar gamma camera image of the human pancreas and panel (b) shows the SPEC obtained using the compound of the present invention.
The T gamma camera image (SPECT gamma camera image) is shown.

FIG. 3 shows an image similar to that of FIG. 2 on a second human subject.

The present invention provides a group of novel radioisotope labeled diamines useful for imaging the human pancreas.

In order to be a useful reagent for pancreatic imaging, not only does the compound need to be ingested by the pancreas in sufficient quantity to obtain a satisfactory pancreatic image without interference from other organs, It must show sufficient differential localization in the pancreas as compared to localization in other abdominal organs such as the liver.

US Pat. No. 4,430,319 discloses reagents such as HIPDM which are useful as brain contrast agents because they accumulate in the brain. Kung gave no information about pancreatic uptake (absorption) of these compounds.

As used herein, the phrase "effective in pancreatic imaging" means that the compound exhibits a pancreatic uptake of at least about 4.5% of the radioactive dose administered at some point within 24 hours of administration and the pancreas. It means that the ratio of uptake of liver / liver should be at least about 1.5 at that time.

The novel diamine compounds of the present invention are superior to HIPDM in pancreas intake and pancreas / liver intake ratio, thereby providing an excellent diagnostic tool that allows the use of lower patient radiation doses. , Or provide an excellent diagnostic image at an equivalent dose rate.

The "lower alkyl" used in the present invention is 1
Represents a straight-chain or branched alkyl group having from 6 to 6 carbon atoms. Preferred lower alkyl groups are methyl and ethyl.

In the substituted benzene ring of formula I, R ₁ and R
₂ are the same or different and are hydrogen, hydroxyl or lower alkyl. The preferred arrangement of the benzene ring is 2-hydroxy, 3-lower alkyl, 5-iodo or 2-hydroxy, 3-iodo, 5-lower alkyl, the former being particularly preferred.

In formula I, N'is preferably a nitrogen which is part of a 5 or 6 membered ring having 1 or 2 heteroatoms, one of which is this nitrogen. If there is a second heteroatom it is preferably oxygen. The preferred value of n is 2, 3 or 4.

A preferred iodinated diamine according to the present invention is N [3 (4-morpholino) propyl] -N-methyl-2.
-Hydroxy-3-methyl-5-iodobenzylamine (ERC9); N [3 (1-pyrrolidino) propyl]-
N-methyl-2-hydroxy-3-methyl-5-iodobenzylamine (ERC46); and N [3 (1-piperidino) propyl] -N-methyl-2-hydroxy-
3-Methyl-5-iodobenzylamine (ERC90)
There is.

ERC9 is a particularly preferred embodiment of the present invention.

The compounds of the present invention have been tested in Tranpoche (Tr) as shown in the flow chart of FIG. 1 and illustrated in Examples 1-5.
amposch) and a modified method [1983,
J. Med. Chem., 26, 121].

For the iodination of phenol aldehydes 3,3, iodopyridinium nitrate was used in place of iodine monochloride in acetic acid. Iodopyridinium nitrate is the method of Lawn and Joshua [Can. J. C.
hem), 1977, 55, 122]] in chloroform-pyridine from iodine monochloride and silver nitrate.

Iodoaldehyde, 4, was condensed with the desired amine in refluxing benzene to form the imine, 5, which was reduced with sodium borohydride in ethanol. The product, 6, was converted to dihydrohydrochloride and crystallized from methanol-acetone for purification. N-alkyl derivative, 1,
Was prepared by reductive alkylation in methanol with the appropriate aldehyde or ketone (formaldehyde for methyl, acetaldehyde for ethyl, acetone for isopropyl, etc.) and purified as the dihydrohydrochloride salt.

The labeling of the compounds according to the invention with radioactive isotopes is exchanged by heating the compounds in the presence of acetic acid in a boiling water bath with radioactive iodine in the form of sodium iodide for 30 minutes followed by hydroxylation. Achieved by neutralizing with sodium. Radiochemical purity is 9 without further purification
It was 5% or more.

Although a particular method of making the compound of the present invention has been described, it is within the scope of the present invention to make this compound by any suitable method.

In the present invention, I-121, I-123, I-
Included are compounds labeled with iodine radioisotopes such as 125 and I-131. For humans, the preferred imaging isotope is I-123.

The compound of the present invention labeled with I-121 is P
It can be used in ET technology.

To confirm that the compound is effective for pancreatic imaging, its pancreas intake and pancreas / liver uptake ratio are measured in mice as described in Example 6.

For use in pancreatic imaging, the radioisotope-labeled compounds of the present invention are prepared as sterile, pyrogen-free products using conventional techniques known to those skilled in the art.
These compounds are administered intravenously and pancreatic uptake and pancreatic / liver uptake ratios are preferably assessed approximately 3 to 4 hours post administration.

[0035] The pancreas is imaged by single photon emission computed tomography (SPECT).
It can be performed with or without omography capability by conventional gamma camera imaging methods, which are well known to those skilled in the art.

If the compounds of the invention are labeled with I-121, they can be used for pancreatic imaging by positron emission tomography (PET).

The high quality pancreas images shown in FIGS. 2 and 3 were obtained on a human volunteer using the preferred embodiment of the present invention, ERC9, as described in Example 11.

According to another embodiment of the present invention, a diamine,
N [3 (1-diethylamino) propyl] -N-methyl-2-hydroxy-3-methyl-5-iodobenzylamine (ERC94) was found to be effective in pancreatic imaging. The corresponding dimethyl compound, HIPDM, was unsatisfactory for clinical use as described above, but unexpectedly it was found that ERC94, the diethyl compound, was effective in pancreatic imaging.

Compounds of the Invention, Particularly Preferred Examples ER
C9 provides a convenient radiodiagnostic agent for imaging the pancreas with a conventional, readily available gamma camera, and thus a routine clinical practice that improves diagnostic accuracy in pancreatic diseases such as pancreatitis and pancreatic cancer. Provide the law.

[0040]

EXAMPLES Example 1 N [3 (4-morpholino) propyl] -N-methyl-2
-Hydroxy-3-methyl-5-iodobenzylamine
Synthesis of dihydrohydrochloride (ERC9) a. Preparation of 2-hydroxy-3-methylbenzaldehyde
Ltd. nitrogen Fun'i care under in toluene (100ml) o- cresol [Fisher (Fisher), 21.6g, 20mmol]
And tributylamine [Eastman, 14.
8 g, 80 mmol] in a solution of anhydrous tin chloride (5.2 g, 20
mmol) was added dropwise for 5 minutes. The mixture was stirred at room temperature for 30 minutes. Paraformaldehyde [Aldrich (Aldr
ich), 13.2 g, 440 mmol] and the resulting suspension was heated at 95 ° C. for 20 hours. Cool the mixture and water (2 l)
Injected into. The mixture was acidified to pH 2 with concentrated hydrochloric acid and extracted with ether (2 x 200 ml). The combined extracts were washed with water (100 ml), dried (Na ₂ SO ₄ ) and evaporated. Residual oil was vacuum distilled to give the title compound containing about 30% starting material. Yield 20.6%; boiling point 64-69 ° C (3.5 torr). This material was used in the next step without further purification. b. 2-hydroxy-3-methyl-5-iodobenzyl
Preparation of aldehyde Silver nitrate (BDH, 39.42 g, 232 mmol) was dissolved in a mixture of chloroform (280 ml) and pyridine (120 ml). Chloroform (40 ml) was added to the stirred solution.
Iodine monochloride [Aldrich, 37.68
g, 232 mmol] was added dropwise for 30 minutes. The mixture was stirred for an additional 15-20 minutes. 2-Hydroxy-3-methylbenzaldehyde (20.6 g,
Containing about 30% o-cresol) was added dropwise (10 minutes). The mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ether (about 600 ml) to precipitate pyridinium nitrate and filtered. The precipitate was washed several times with ether. The filtrate was collected and subjected to vacuum evaporation. The residue was extracted several times with hexane, the extracts were combined and concentrated on a rotary evaporator to give a brown solid. The product was chromatographed on silica gel, eluting with hexane-dichloromethane (4: 1).
Crystallization from hexane gave the title compound as yellow crystals. Yield 27 g; melting point 85-86 ° C; NMR (CDC
l ₃ ): δ2.3 (s, 3H, —CH ₃ ), 7.8
(S, 2H, aromatic H), 9.93
(S, 1H, -CHO), 11.3 (s, 1H, -O)
H). c. N [3- (4-morpholino) propyl] -2-hydr
Roxy-3-methyl-5-iodobenzylamine dihydride
Preparation of Hydrochloride 2-Hydroxy-3-methyl-5-iodobenzaldehyde (5.24 g, 20 mmol), N- (3-aminopropyl) morpholine [Aldrich, 2.88
g, 20 mmol] and benzene (150 ml) was refluxed under a Dean-Stark head and water was separated (2 hours). The solvent was evaporated under reduced pressure to give a yellow oil. This oil was dissolved in ethanol (50 ml) and sodium borohydride (BDH, 0.76 g, 20 mmol) was added.
Was added and stirred at room temperature for 20 hours. Most of the ethanol was removed under vacuum, the residue was removed and deionized water (50 m
l) and extracted with dichloromethane (5 x 30 ml). The combined extracts were washed with deionized water (30 ml), dried (Na ₂ SO ₄ ) and the solvent removed in vacuo. The residual oil was dissolved in methanol (50 ml), acidified with concentrated hydrochloric acid (10 ml) and evaporated to dryness. The residue was crystallized from methanol-acetone to give 9.18 g (99%) of the title compound as colorless crystals. Melting point 194-195 ° C (d), NMR
(CDCl, free base): δ1.57-
_{1.87 (m, 2H, -CH 2} ), 2.2 (s, 3H,
_{-CH 3), 2.33-2.53 (m,} 6H, N-CH
_{2), 2.73 (t, 2H} , J = 6Hz, N-CH 2),
_{3.63-3.83 (m, 4H, CH 2} -O), 3.9
3 (s, 2H, benzyl _{CH 2 (benzylic CH 2))} ,
6.7 (bs, 2H, NH, OH), 7.16 (d, 1
H, J = 1 Hz, aromatic H (aromatic H), 7.36
(D, 1H, J = 1 Hz, aromatic H). I
R (KBr): 3420, 3180, 2940, 267
0, 2600, 1625, 1480, 1440, 139
0, 1270, 1210, 1105, 870 cm ^-1 . Analytical value: C 39.03; H 5.44; N
6.05 C ₁₅ H ₂₅ Cl ₂ IN ₂ O ₂ Theoretical value: C 38.90;
H 5.44, N 6.05. d. N [3- (4-morpholino) propyl] -N-methyl
Lu-2-hydroxy-3-methyl-5-iodobenzyl
Preparation of Amine Dihydro Hydrochloride To the above diamine dihydro hydrochloride (9.18 g, 19.8 mmol) and formaldehyde [Fisher, 37% solution, 10 ml] in methanol (100 ml) under stirring at 0 ° C. Sodium cyanoborohydride [Aldric
h), 1.89 g, 30 mmol] was added portionwise (5 min). The solution was gradually warmed to room temperature and stirred for 72 hours. Most of the methanol was evaporated under reduced pressure. The residual oil was removed, placed in deionized water (100 ml), treated with solid sodium bicarbonate (3 g) to neutralize excess hydrochloric acid and extracted with dichloromethane (5 x 30 ml). The combined extracts were washed with deionized water (30 ml), dried (Na ₂ SO ₄ ) and evaporated. Take off the residual oil and methanol (50 ml)
It was taken up, treated with concentrated hydrochloric acid (10 ml) and evaporated to dryness in vacuo. The product was recrystallized from methanol-acetone. Yield: 9.1 g (99%); melting point 194-195 ° C.
(D). NMR (CDCl, free base):
δ1.6-2.0 (m, 2H, —CH ₂ —), 2.2
_{(S, 3H, -CH 3)} , 2.33 (s, 3H, CH
_{3), 2.3-2.8 (m, 8H} , N-CH 2), 3.
_{6-3.9 (m, 6H, CH 2} -O, benzyl CH ₂
(Bezylic CH ₂ )), 7.17 (d, 1H, J = 1 Hz, aromatic H (aromatic H)), 7.4 (d, 1H, J = 1H)
z, aromatic H, 10.1 (bs, 1
H, -OH), IR (KBr): 3420, 2950,
2640, 1640, 1465, 1385, 1265,
1205, 1105 cm ^-1 . Analytical value: C 40.00; H 5.68; N
5.71 C ₁₆ H ₂₇ Cl ₂ IN ₂ O ₂ Theoretical value: C 40.27;
H 5.70, N 5.87. Example 2 Labeling of ERC9 with radioisotope 2 mg of the product prepared in Example 1, 100 μl glacial acetic acid, 400 μl distilled water and 1-15 MBq I-125, I-50.
MBq I-131 or 100-200 MBq I-12
Sodium iodide 3 was heated for 30 minutes in a sealed vial in a boiling water bath followed by 0.6 ml of 1
It was neutralized by adding N sodium hydroxide. This preparation is 0.
Dilute to the desired concentration with 9% aqueous sodium chloride.

Radiochemical purity was assessed by thin layer chromatography [Kodak Chromagram Silica Gel] using ethyl acetate-ethanol (1: 1) as a developing agent. In this system, the Rf of radioactively iodinated ERC9 is 0.1-0.
3, while the Rf of radioactive iodine sodium iodide is 0.8
It was -1.0. Radiochemical purity was always above 95%. Example 3 N [3 (1-pyrrolidino) propyl] -N-methyl-2
-Hydroxy-3-methyl-5-iodobenzylamine
Synthesis of dihydrohydrochloride (ERC46) a. Preparation of N- (3-aminopropyl) pyrrolidine Pyrrolidine [Aldrich, 7.1 g, 10
0 mmol], acrylonitrile (BDH, 7.96 g, 1
50 mmol) and ethanol (25 ml) at room temperature for 2
Stir for 0 hours. The solvent was removed by vacuum evaporation to give N-pyrrolidinopropionitrile quantitatively in most yields. This material was used in the next step without purification.

Lithium aluminum hydride [Alfa product, 4 g, 100 mmol] in anhydrous tetrahydrofuran (150 ml) under stirring under nitrogen atmosphere.
A solution of the above nitrile in THF (25 ml) was added dropwise to the above suspension (2 hours). The mixture was refluxed under a nitrogen atmosphere for 20 hours. Water (25 ml) in THF (30 ml) was added dropwise to remove excess lithium aluminum hydride, stirred for another 30 minutes and filtered. The filter cake was washed several times with THF-methanol (1: 1). The filtrates were combined and evaporated under reduced pressure, and the residue was vacuum distilled to obtain N (3-aminopropyl) pyrrolidine. Yield 4.5 g (35%); Boiling point 54-5
5 ° (5.5 torr), [boiling point in literature (lit. bp.) 85
-87 ° C (26 torr), J. J. Corse et al., J. Am. Chem. Soc., 68 , 1911 (1.
946)]]. b. N [3 (1-pyrrolidino) propyl] -2-hydro
Xy-3-methyl-5-iodobenzylamine dihydro
Preparation of the hydrochloride salt The procedure described in Example 1 was followed by 2-
Hydroxy-3-methyl-5-iodobenzaldehyde (1.048 g, 4 mmol) was reacted with N- (3-aminopropyl) pyrrolidine (0.512 g, 4 mmol),
The imine obtained was reduced in ethanol (20 ml) with sodium borohydride (0.160 g, 4 mmol),
Work-up, conversion to the dihydrohydrochloride salt (conc. Hydrochloric acid, 4 ml), evaporation to dryness and crystallization of the residue from methanol-acetone gave the title compound as off-white crystals. Yield: 1.685 g (94%); melting point 183.
-186 ° C. (d), NMR (CDCl ₃ , free base (fr
ee base)): δ1.5-2.0 (m, 6H, —CH ₂
-), 2.13 (s, 3H , -CH 3), 2.4-2.
8 (m, 8H, H- CH 2), 3.9 (s, 2H, benzyl _{CH 2 (benzylic CH 2))} , 6.7 (bs, 2H,
NH, OH), 7.1 (d, 1H, J = 1Hz, aromatic H
(Aromatic H)), 7.3 (d, 1H, J = 1 Hz, aromatic H (aromatic H)), IR (KBr): 3430, 2
960, 2700, 1625, 1475, 1390, 1
215 cm ^-1 , analytical value: C 40.06; H 5.86; N
6.05 C ₁₅ H ₂₅ Cl ₂ IN ₂ O theoretical value: C 40.29;
H 5.64; N 6.26. c. N [3- (1-pyrrolidino) propyl] -N-methyl
Lu-2-hydroxy-3-methyl-5-iodobenzyl
Preparation of Amine Dihydro Hydrochloride Using the method described in Example 1 in methanol (10 ml)
[3 (1-Pyrrolidino) propyl] -2-hydroxy-
3-Methyl-5-iodobenzylamine dihydrohydrochloride (0.894 g, 2 mmol) was added to formaldehyde (2 ml,
37% solution) and sodium cyanoborohydride (sodium c
yanoborohydride) (0.252 g, 4 mmol), reductively methylated, treated, converted to the dihydrohydrochloride salt (conc. hydrochloric acid, 2 ml) and crystallized from methanol-acetone,
The title compound was obtained as colorless crystals. Yield: 0.
911 g (99%), melting point 190-192 ° C. (d), N
MR (CDCl ₃ , free base): δ1.7
_{-2.2 (m, 6H, -CH 2} -); 2.23 (s, 3
_{H, -CH 3); 2.33 (} s, 3H, -CH 3);
2.43-2.8 (m, 8H, N- CH 2); 3.7
(S, 2H, benzyl _{CH 2 (benzylic CH 2))} ; 7.
2 (d, 1H, J = 1 Hz, aromatic H);
7.4 (d, 1H, J = 1Hz, aromatic H (aromatic
H)); 10.43 (s, 1H, -OH), IR (KB
r): 3420, 3220, 2960, 2670, 26
00, 2500, 1620, 1470, 1385, 12
00 cm ^-1 , analytical value: C 41.67; H 5.97; N
_{5.97 C 16 H 27 Cl 2 IN} 3 O theory: C 41.67;
H 5.90; N 6.07. Example 4 N [3 (1-piperidino) propyl] -N-methyl-2
-Hydroxy-3-methyl-5-iodobenzylamine
Synthesis of dihydrohydrochloride (ERC90) a. Preparation of N- (3-aminopropyl) piperidine Ethanol (25 ml) by the method described in Example 3.
In piperidine [Aldrich, 8.4 g,
100 mmol] to acrylonitrile (7.96 g, 150
mmol) and the resulting piperidinopropionitrile was reduced with lithium aluminum hydride (5 g, 125 mmol) in tetrahydrofuran (150 ml), treated and distilled under reduced pressure to give the title compound. yield:
3 g (21%); boiling point 65-66 ° (6 torr); [boiling point in literature (lit. bp.) 110-115 ° C. (31 torr),
J. J. Corse et al., American Chemical Journal (J. Amer. C
hem.Soc.), 68 , 1911 (1946)]. b. N [3 (1-piperidino) propyl] -2-hydro
Xy-3-methyl-5-iodobenzylamine dihydro
Preparation of the Hydrochloric Acid The procedure described in Example 1 was followed by 2-
Hydroxy-3-methyl-5-iodo-benzaldehyde (0.524 g, 2 mmol) was reacted with N- (3-aminopropyl) piperidine (0.284 g, 2 mmol),
The resulting imine was reduced and treated with sodium borohydride (0.16 g, 4 mmol) in ethanol (25 ml),
Conversion to the dihydrohydrochloride salt (conc. Hydrochloric acid, 2 ml), evaporation to dryness and crystallization from methanol-acetone gave the title compound as a colorless solid. Yield: 0.82g
(89%); melting point 201-203 ° C, NMR (CDCl
₃ , free base: δ1.2-1.9 (m,
_{8H, -CH 2 -); 2.2} (s, 3H, -CH 3);
2.27-2.53 (m, 6H, N- CH 2); 2.7
3 (t, 2H, J = 6Hz, NH- CH 2); 3.93
(S, 2H, benzyl _{CH 2 (benzylic CH 2))} ; 7.
17 (d, 1H, J = 1Hz, aromatic H (aromatic
H)); 7.4 (d, 1H, J = 1 Hz, aromatic H (aroma
tic H)); NH and OH appear on the baseline as broad bends between δ 5.7 and 7.9. IR (KB
r): 3430, 2950, 2720, 1605, 14
80, 1390, 1240, 1200, 1180, 87
0 cm ^-1 . Analytical value; C 41.49; H 5.94 N 5.
92 C ₁₆ H ₂₇ Cl ₂ IN ₂ O theoretical: C 41.47;
H 5.90; N 6.07. c. N [3- (1-piperidino) propyl] -N-methyl
Lu-2-hydroxy-3-methyl-5-iodobenzyl
Preparation of amine dihydrohydrochloride by the method described in Example 1 in N (10 ml) of methanol
[3 (1-Piperidino) propyl] -2-hydroxy-
3-Methyl-5-iodobenzylamine dihydrohydrochloride (0.463 g, 1 mmol) was added to formaldehyde (1 ml,
37% solution) and sodium cyanoborohydride (sodium c
yanoborohydride) (0.126 g, 2 mmol), reductively methylated, treated, converted to the dihydrohydrochloride salt (conc. hydrochloric acid, 1 ml) and crystallized from methanol-acetone to give the title compound as a colorless solid. Was obtained. yield:
0.467g (98%), melting point 200-203 ° C
(D), NMR (CDCl ₃ , free base (free bas
e)): δ1.2-1.9 (m, 8H, m, —CH ₂
-); 2.0-2.7 [2s on multiplet (2.15 and _{2.25), 14H, -CH 3;} N-CH 2]; 3.6
(S, 2H, benzyl _{CH 2 (benzylicCH 2));} 7.
13 (d, 1H, J = 1Hz, aromatic H (aromatic
H)); 7.37 (d, 1H, J = 1 Hz, aromatic H (aro
matic H)). IR (KBr): 3420, 2950,
2680, 1620, 1485, 1390, 1210 cm
^-1 , analytical value: C 42.96; H 6.22; N
_{5.98 C 17 H 29 Cl 2 IN} 2 O Theoretical value: C 42.96;
H 6.15; N 5.89. Example 5 N [3 (1-diethylamino) propyl] -N-methyl
-2-hydroxy-3-methyl-5-iodobenzylia
Synthesis of Mindihydro Hydrochloride (ERC94) a. N- (3-diethylamino) propyl] -2-hydr
Roxy-3-methyl-5-iodobenzylamine dihydride
Preparation of the hydrochloride salt 2-in benzene (80 ml) by the method described in Example 1.
Hydroxy-3-methyl-5-iodobenzaldehyde (1.31 g, 5 mmol) was added to 3- (diethylamino) propylamine [Aldrich, 0.65 g, 5
mmol], and the resulting imine is ethanol (25 m
l) sodium borohydride (0.4 g, 10 mmol) in
Reduction with, treated with, converted to the dihydrohydrochloride salt (conc. Hydrochloric acid, 5 ml) and evaporated to dryness in vacuo to give the title compound as a hygroscopic foam. This material was used in the next step without purification. NMR (CDCl ₃ , free base (fr
ee base)): δ1.05 (t, 6H, J = 6Hz, CH <sub>2
- CH 3); 1.53-1.9 (m</sub> , 2H, -CH 2
-); 2.23 (s, 3H , -CH 3); 2.4-2.
9 (m, 8H, -N- CH 2); 3.96 (s, 2H,
Benzylic CH ₂ (benzylicCH ₂ )); 7.2 (d, 1
H, J = 1 Hz, aromatic H (aromatic H)); 7.43
(D, 1H, J = 1 Hz, aromatic H (aromatic H)); N
H and OH appear as baselines on the baseline between δ 5.5 and 7.9. b. N [3 (diethylamino) propyl] -N-methyl
-2-hydroxy-3-methyl-5-iodobenzylia
Preparation of Mindihydrohydrochloride N 2 in methanol (25 ml) by the method described in Example 1.
[3 (diethylamino) propyl] -2-hydroxy-
3-Methyl-5-iodo-benzylamine dihydrohydrochloride (5 mmol, from previous step) was treated with formaldehyde (5 ml,
37% solution) and sodium cyanoborohydride (sodium c
yanoborohydride) (0.63 g, 10 mmol), reductively methylated, treated, converted to the dihydrohydrochloride salt (conc. hydrochloric acid, 5 ml) and evaporated to dryness in vacuo and the material obtained was crystallized from methanol-acetone. Upon elution, the title compound was obtained as colorless crystals. Yield (overall): 1.945 g
(84%); melting point 166-168 [deg.] C. (d), NMR (C
DCl ₃ , free base: δ 0.97 (t,
_{6H, J-6Hz, -CH 2} - CH 3); 1.5-1.9
_{(M, 2H, -CH 2 -} ); 2.13 (s, 3H, -C
_{H 3); 2.23 (s,} 3H, -CH 3); 2.3-
2.7 (m, 8H, N- CH 2); 3.6 (s, 2H,
Benzyl _{CH 2 (benzylic CH 2))} ; 7.1 (d, 1
H, J = 1 Hz, aromatic H (aromatic H)); 7.35
(D, 1H, J = 1 Hz, aromatic H (aromatic H)), I
R (KBr): 3420, 2940, 2640, 162
5, 1470, 1390, 1210 cm ^-1 , analytical value: C 41.47; H 6.24; N
_{5.93 C 16 H 29 Cl 3 IN} 2 O Theoretical value: C 41.49;
H 6.31; N 6.05. Example 6 Pancreatic uptake (absorption) of ERC-9 The pancreatic uptake and pancreas / liver ratio of I-125ERC9 and I-125-HIPDM (prepared in Examples 1 and 2) were compared for mice. Male Balb / c Mouse I-1
25 ERC9 or I-125-HIPDM (0.1 ml
20μg, 0.01MBq) in the tail vein
) Injected. Six mice from each group were sacrificed by CO ₂ asphyxiation at specified times from 5 minutes to 24 hours after administration. Blood samples were collected to remove various organs (including pancreas and liver). The intake of radioactive iodine in each organ was calculated by counting with a γ-ray spectrum detector. Injected dos based on the amount of radioactivity in each organ or tissue
e) compared to the radioactivity. Percentage uptake was calculated for each organ of individual animals. The pancreas-to-liver ratio was determined by dividing the pancreas intake percentage by the liver intake percentage. Mean organ intake and mean pancreas / liver ratio were calculated for these animals at each time point.

The results of pancreas intake and pancreas / liver ratio are shown in Table 1.

[0044]

[Table 1] Mean pancreatic / liver ratio of ERC9 was HI at all time intervals
Greater than the same ratio of PDM, and therefore I-123ERC9
Can be used as a contrast agent to clarify the distinction between pancreas and liver. Example 7 Pancreatic Uptake of ERC46 Pancreatic uptake and pancreas / liver ratios of I-125ERC46 and I-125HIPDM as described in Example 6
lb / c mice were compared. The results are shown in Table 2.

[0045]

[Table 2] The pancreatic intake of ERC46 was lower in the early stage, but the pancreatic intake of ERC46 was higher than that of HIPDM at 4 hours and 24 hours after administration. The pancreas / liver ratio was significantly higher for ERC46 at all times studied from 30 minutes to 24 hours. Example 8 Pancreatic Uptake of ERC90 The pancreatic uptake and pancreas / liver ratios of I-125ERC90 and I-125HIPDM were compared for Balb / c mice as described in Example 6. The results are shown in Table 3.

[0046]

[Table 3]Pancreatic intake was lower in ERC90 at the beginning, but
Pancreatic intake of ERC90 was 4 hours and 24 hours after feeding.
It was higher than IPDM. Survey from 30 minutes to 24 hours
Pancreas / liver ratio was higher in ERC90 for all
It was quite high. Example 9 Pancreatic intake of ERC94 Pancreatic intake of I-125ERC94 and I-125HIPDM
The amount taken and the pancreas / liver ratio were Balb / c as described in Example 6.
We compared each other. The results are shown in Table 4.

[0047]

[Table 4] Pancreatic intake of ERC94 was lower than HIPDM for all study periods except 24 hours. But from 30 minutes to 2
The pancreas / liver ratio was much higher for ERC94 than for HIPDM for all study periods up to 4 hours. Example 10 Toxicity and Radioactivity Measurement Toxicity Animal experiments show that ERC9 has low chemical toxicity. Maximum dose for an ERC9 person is 2 mg per 50 kg body weight
(0.04 μg per gram). The mouse experiment was performed at a ratio of 500 times the maximum dose for humans based on body weight. 1 male and 5 female Balb / c mice each
Once a day for 3 days, 0.005 ml of ERC9 aqueous solution (4 mg / ml) per gram of body weight was injected through the tail vein. These animals were reared for 30 days. No compound-induced toxicity was observed immediately or after a period of time. Histological examination of various organs and tissues did not reveal any changes that might be due to chemical toxicity. Radiation Dose Measurements Human radiation dose from I-123ERC9 was estimated from tissue distribution data in mice.

Male Balb / c mouse from tail vein to I-1
25 ERC9 (20 μg in 0.1 ml, 0.01 MBq) was injected. Six mice were killed by CO ₂ asphyxiation for a specified period of 5 minutes to 24 hours after administration. Blood samples were collected and various organs were taken out. Radioiodine uptake in various organs and tissues was calculated by counting with a γ-ray spectrum detector.
The amount of radioactivity in each organ or tissue was compared to the amount of radioactivity in the baseline infusion medication. Percentage uptake was calculated for each organ of each animal. Mean organ uptake percentages were calculated for groups of animals for each period.

The average intake of each organ and tissue was plotted against time on semi-log paper. From these plots, the intake and clearance half-life of each organ or tissue (clearance
halftime) was calculated.

Using these values and the MIRD method of radiation dose calculation [Society of Nuclear Medicine], the human radiation dose from I-123 was calculated. As a result, these pancreas showed 111 MBq of administered I-123ERC9.
It can be seen that this is a critical organ having a radiation dose of about 15.5 mGy per unit. Example 11 Pancreatic Imaging in 1 Subject Imaging studies were performed using I-123ERC9 on 2 volunteers.

I-123ERC9 prepared in Example 2
(185 MBq, 2 mg) was injected intravenously into two volunteers. Using a gamma camera with SPECT (single photon emission computed tomography) capability, 30 minutes after injection, 1.5
Planar image in hours, 3 hours and 24 hours
s) got. SPECT images were obtained 3-4 hours after injection.

Ingestion of this radioactive tracer was found as early as 30 minutes after administration. Optimal pancreas intake and pancreas / liver ratio appeared after 3-4 hours. By 24 hours, the amount of radioactivity in the pancreas had decreased to the extent that it was suboptimal, although there was fluoroscopy of the pancreas due to physical disruption and biological clearance.

FIG. 2a shows I-123 for the first subject.
3 shows a planar gamma camera image of the pancreas obtained 3 hours after the administration of ERC9.

FIG. 2b is a SPECT gamma camera image (SP of the pancreas) of the same subject at 3 to 4 hours after administration.
ECT gamma camera image) is shown.

3a and 3b show I for the second subject.
Similar images are obtained at the same time intervals after administration of -123 ERC9.

As can be seen from these figures, the plane image and S
Both PECT images show that there is a high degree of accumulation of radiolabel in the pancreas of normal humans and that the pancreas can be well distinguished from other abdominal organs, and the reduced intake of pancreas in the abnormal part of the pancreas in the disease state. It is possible to detect
Provide useful clinical tools and techniques.

While only preferred embodiments of the invention have been described, the invention is not limited to the features of these embodiments but includes all changes and modifications within the scope of the claims.

[0058]

The compounds of the present invention, especially ERC9, are useful for imaging the pancreas using conventional, readily available gamma cameras.

[Brief description of drawings]

FIG. 1 is a process chart of a method for producing a compound of the present invention. ^* R is - (CH ₂₎ 'in it represents the formula N' ₂ -N is a suitable amino groups. ⁺ Acetaldehyde is for ethyl, acetone is for isopropyl.

FIG. 2 Panel (a) shows a planar gamma camera image of a human pancreas, and panel (b) shows a SPECT gamma camera image obtained using the compound of the present invention. ) Is shown.

FIG. 3 shows an image similar to FIG. 2 for a second human subject.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] May 21, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Brief explanation of the drawing

[Correction method] Change

[Correction content]

[Brief description of drawings]

FIG. 1 is a process chart of a method for producing a compound of the present invention. ^* R is - (CH ₂₎ 'in it represents the formula N' ₂ -N is a suitable amino groups. ⁺ Acetaldehyde is for ethyl, acetone is for isopropyl.

FIG. 2 Panel (a) shows a copy of a planar gamma camera image of the human pancreas, panel (b) a SPECT obtained using the compound of the invention.
The following is a copy of a SPECT gamma camera image.

FIG. 3 shows a copy of the same image as in FIG. 2 for a second human subject.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor John Earl. Scott Canada Alberta Ardrossan Earl. R. 214 169-53050 Street (No house number)

Claims (17)

[Claims] Claims: A compound effective for pancreatic imaging having n, where n is 1 to 10
R ₁ and R ₂ are the same or different and are hydrogen, hydroxyl or lower alkyl having 1 to 6 carbon atoms; R ₃ is lower alkyl having 1 to 6 carbon atoms; N'is a nitrogen atom forming a part of a 4- to 8-membered heterocycle having 1 or 2 heteroatoms, one of the heteroatoms being the nitrogen, and the heterocycle being unsubstituted Or those substituted with one or more lower alkyl groups, and pharmaceutically acceptable acid addition salts thereof. 2. n is 2, 3 or 4; R ₁ is a hydroxyl attached at the 2-position of the benzene ring of the compound of claim 1; R ₂ has 1 to 6 carbon atoms. A lower alkyl is attached at position 3 of the benzene ring; I is attached at position 5 of the benzene ring,
N'is a nitrogen atom forming part of a 5- or 6-membered heterocycle having 1 or 2 heteroatoms, one of said heteroatoms being said nitrogen and said heterocycle being unsubstituted Or a compound of claim 1 substituted with one or more lower alkyl groups, and pharmaceutically acceptable acid addition salts thereof. 3. I is I-121, I-123, I-12.
The compound according to claim 1 or 2, which is a radioisotope of iodine selected from the group consisting of 5 and I-131. 4. The compound is I-123N [3 (4-morpholino) propyl] -N-methyl-2-hydroxy-3.
The compound of claim 2 which is -methyl-5-iodobenzylamine. 5. The compound is I-123N [3 (1-pyrrolidino) propyl] -N-methyl-2-hydroxy-3.
The compound of claim 2 which is -methyl-5-iodobenzylamine. 6. The compound is I-123N [3 (1-piperidino) propyl] -N-methyl-2-hydroxy-3.
The compound of claim 2 which is -methyl-5-iodobenzylamine. 7. (a) HCH prepared by appropriately substituting phenol
O / anhydrous SnCl ₄ is reacted to form the corresponding benzaldehyde, and (b) the obtained benzaldehyde is reacted with iodopyridinium nitrate to iodize to form the corresponding iodobenzaldehyde. Condensation of the iodobenzaldehyde with an amine having the desired substituent to form the corresponding imine, (d) reduction of the imine with sodium borohydride in ethanol, (e) formation of step (d) A reductive alkylation of the product to give the desired N-alkyl derivative. A compound effective for pancreatic imaging, wherein n is 1 to 10
R ₁ and R ₂ are lower alkyl having 1 to 6 carbon atoms; N ′ is a nitrogen atom which is part of a 4 to 8 membered heterocycle having 1 or 2 heteroatoms. Wherein one of the heteroatoms is the nitrogen and the heterocycle is unsubstituted or substituted with one or more alkyl groups. 8. The iodine atom in the compound is further converted to I-12.
The method according to claim 7, which comprises the step of labeling the compound with a radioactive isotope by substituting it with a radioactive iodine selected from the group consisting of 1, I-123, I-125 and I-131. 9. An effective amount of ## STR00003 ## in a suitable carrier. A compound effective for pancreatic imaging having n, where n is 1 to 10
R ₁ and R ₂ are the same or different and are hydrogen, hydroxyl or lower alkyl having 1 to 6 carbon atoms; R ₃ is lower alkyl having 1 to 6 carbon atoms; N'is a nitrogen atom forming part of a 4- to 8-membered heterocycle having 1 or 2 heteroatoms, one of said heteroatoms being said nitrogen and said heterocycle being unsubstituted Alternatively, one substituted with one or more lower alkyl groups and a pharmaceutically acceptable acid addition salt are administered to a mammal to distribute and infuse the compound into the pancreas, and then release from the compound in the pancreas. A method of imaging a pancreas of a mammal, the method comprising detecting radioactivity. 10. The method of claim 9, wherein the mammal is a human. 11. The method of claim 10, wherein the radiation detection is performed with planar gamma camera imaging. 12. The radiation detection is performed by SPECT gamma camera imaging.
Method 1. 13. The compound is I-123N [3 (4-morpholino) propyl] -N-methyl-2-hydroxy-.
10. It is 3-methyl-5-iodobenzylamine.
the method of. 14. The compound is I-123N [3 (1-pyrrolidino) propyl] -N-methyl-2-hydroxy-.
10. It is 3-methyl-5-iodobenzylamine.
the method of. 15. The compound is I-123N [3 (1-piperidino) propyl] -N-methyl-2-hydroxy-.
10. It is 3-methyl-5-iodobenzylamine.
the method of. 16. An effective amount of I-12 in a suitable carrier.
3N [3 (1-diethylamino) propyl] -N-methyl-2-hydroxy-3-methyl-5-iodobenzylamine or a pharmaceutically acceptable acid addition salt thereof is administered to a mammal to administer the compound to the pancreas. A method of imaging the pancreas of a mammal, which comprises: invading the pancreas and detecting the radioactivity released from the compound in the pancreas. 17. The method of claim 16, wherein the mammal is a human.