CN108997372B

CN108997372B - Compound for positron imaging, intermediate thereof, preparation method and imaging agent

Info

Publication number: CN108997372B
Application number: CN201810856154.9A
Authority: CN
Inventors: 兰晓莉; 盖永康; 包安瑞; 柳轻瑶; 韩娜
Original assignee: Union Hospital Tongji Medical College Huazhong University of Science and Technology
Current assignee: Union Hospital Tongji Medical College Huazhong University of Science and Technology
Priority date: 2018-07-31
Filing date: 2018-07-31
Publication date: 2020-07-28
Anticipated expiration: 2038-07-31
Also published as: CN108997372A

Abstract

The invention relates to a compound shown in formula I or formula II, wherein R is a compound with at least one¹⁸C of F substituent_1‑12Alkyl group of (i), (ii), (iii), (iv) and (iv)₂O)_x‑CH₃、‑(CH₂CH₂O)_y‑CH₂CH₃Or- (CH)₂CH₂CH₂O)_z‑CH₂CH₂CH₃Wherein x is an integer of 1 to 10, y is an integer of 1 to 5, and z is an integer of 1 to 3. The invention also relates to intermediates for the preparation of said compounds, to processes for the preparation of said compounds and to positron imaging agents comprising said compounds. The compound of the invention has simple preparation, good stability and high radiation amount, and can specifically target a tumor area with abnormal activation of a PI3K pathway.

Description

Compound for positron imaging, intermediate thereof, preparation method and imaging agent

Technical Field

The invention relates to the application field of Positron drugs and Positron Emission Tomography (PET), in particular to a novel PET molecular probe targeting a PI3K/Akt/mTOR signal pathway, and a preparation method and application thereof.

Background

The phosphatidylinositol-3-kinase (PI3K) signal transduction pathway plays an important role in the occurrence, development, treatment and prognosis of tumors, and abnormal activation of the pathway is found in many malignant tumors such as breast cancer, colorectal cancer, endometrial cancer, brain cancer, gastric cancer, lung cancer and the like (Bader,

A.G., et al, oncogeneic PI3K derivatives transformation and transformation, nat Rev Cancer,2005.5(12): p.921-9). PI3K may activate initiation Of a signal transduction cascade, the most prominent downstream kinases being the silk/threonine kinase (Protein kinase B, AKT) and the Mammalian Target Of Rapamycin (mTOR) (Huang, J.and B.D. Manning, Acomplex display between Akt, TSC2and the two mTOR complexes biochem SocTranss, 2009.37(Pt 1): p.217-22.).

In a retrospective study involving 19784 patients with Solid tumors, the pathologically confirmed mutation rate of PI3K/AKT/mTOR signaling Pathway was 38% (Millis, S.Z., et al, L and polypeptide of pathophysiologically linosomal-3-Kinase Pathway 19784 direct solutions, 2016.2(12): p.1565-1573. among Solid tumors, breast Cancer is the most common malignancy among women, with about 70% of breast Cancer patients presenting a mutation of this Pathway (Cancer Genome Atlas, N., comparative genes of human breast Cancer. natdy, 2012.490(7418) p.61-70) encoding PI3 58K catalytic subunit p 63110 p CA, and with the clinical trial of PI 3-chromosome 19, PI 3-20, PTE 3-20, PTE.7, PTE-5, PTE + 7, PTE + T + 5-1573. the gene was found to be a major tumor causing a tumor, and a major tumor, with a clinical phenotype of tumor, and a major tumor.

However, not all patients with solid tumors have mutations in PIK3CA gene, and to better utilize PI3K inhibitors for molecular targeted therapy, the patients must be screened as necessary to avoid the physical and economic burden on the patients from blind administration. In clinical work, the detection of the expression level of the PI3K protein often requires immunohistochemical detection of tumor tissues of patients, which is usually invasive, and the accuracy of the detection is closely related to the material selection.

With the development of non-invasive molecular imaging techniques, the use of radionuclide tagging techniques to track early functional metabolic changes in disease presents significant advantages that can reflect disease conditions earlier and more comprehensively than anatomical imaging.

The main imaging agent for PET-CT imaging at present is¹⁸F-FDG, i.e. positively charged electron species¹⁸F on glucose¹⁸F-deoxyglucose.¹⁸F-FDG can accurately reflect the glucose metabolism level of organs/tissues in vivo, and the glucose demand of malignant tumor cells is increased due to vigorous metabolism, so that¹⁸F-FDG is widely applied to the detection and diagnosis of tumors, can discover primary and metastatic lesions of the tumors at an early stage and accurately judge the benign and malignant tumors, thereby correctly guiding clinical treatment decisions. However, although¹⁸F-FDGPET has been successfully used in clinical tumor diagnosis, but¹⁸F-FDG PET imaging is difficult to play a role in further diagnosing and screening whether a patient has PIK3CA gene mutation to cause tumor, because the expression level of PI3K protein is not directly related to high glucose uptake.

Therefore, there is a need to develop an imaging agent targeting PI3K pathway, so as to provide an effective and noninvasive method for detecting the expression level of PI3K protein in tumor patients, and further screen patients with PIK3CA gene mutation for targeted therapy.

Disclosure of Invention

In order to solve the problems, the invention provides a molecular probe targeting a PI3K pathway, which is used for non-invasively evaluating the expression condition of a PI3K/Akt/mTOR signaling pathway of a patient. Therefore, the invention provides an effective screening tool for carrying out molecular targeted therapy on PI3K protein inhibitor sensitive patients on the one hand, and also provides an evaluation tool for the curative effect of PI3K/Akt/mTOR signaling pathway inhibitor drugs on the other hand.

According to a first aspect of the invention there is provided a compound of formula I or formula II:

wherein R is a group having at least one¹⁸C of F substituent_1-12Alkyl group of (i), (ii), (iii), (iv) and (iv)₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is an integer of 1 to 10, y is an integer of 1 to 5, and z is an integer of 1 to 3.

According to a preferred embodiment, in the above formulae I and II, R is a group having at least one¹⁸C of F substituent_1-6Alkyl group of (i), (ii), (iii), (iv) and (iv)₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is an integer of 1 to 5, y is an integer of 1 to 3, and z is 1. More preferably, said R has 1 to 3¹⁸And F is a substituent.

Further preferably, said has at least one¹⁸C of F substituent_1-6The alkyl group of (A) is selected from the group consisting of 1-3¹⁸F-substituted methyl, ethyl, propyl, butyl, pentyl and hexyl; and said has at least one¹⁸Of the F substituent- (CH)₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Selected from 1-3 terminal methyl groups¹⁸F-substituted- (CH)₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is an integer of 1 to 5, y is an integer of 1 to 3, and z is 1.

More preferably, R is a group having one on one terminal methyl group¹⁸Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, - (CH) of the F substituent₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is 1, 2 or 3, y is 1 or 2, and z is 1.

According to a particular embodiment, R may be selected from: -C¹⁸F₃、-CH¹⁸F₂、-CH₂ ¹⁸F、-CH₂C¹⁸F₃、-CH₂CH¹⁸F₂、-CH₂CH₂ ¹⁸F、-CH₂CH₂C¹⁸F₃、-CH₂CH₂CH¹⁸F₂、-CH₂CH₂CH₂ ¹⁸F、-CH(CH₃)C¹⁸F₃、-CH(CH₃)CH¹⁸F₂、-CH(CH₃)CH₂ ¹⁸F、-CH₂CH₂CH₂C¹⁸F₃、-CH₂CH₂CH₂CH¹⁸F₂、-CH₂CH₂CH₂CH₂ ¹⁸F、-C(CH₃)₂C¹⁸F₃、-C(CH₃)₂CH¹⁸F₂、-C(CH₃)₂CH₂ ¹⁸F、-CH₂OCH₂ ¹⁸F、-CH₂OCH₂OCH₂ ¹⁸F、-CH₂OCH₂OCH₂OCH₂ ¹⁸F、-CH₂CH₂OCH₂CH₂ ¹⁸F、-CH₂CH₂OCH₂CH₂OCH₂CH₂ ¹⁸F、-CH₂CH₂CH₂OCH₂CH₂CH₂ ¹⁸F, but is not limited thereto.

More preferably, R may be selected from: -CH₂OCH₂OCH₂ ¹⁸F、-CH₂OCH₂OCH₂OCH₂ ¹⁸F、-CH₂CH₂OCH₂CH₂ ¹⁸F、-CH₂CH₂OCH₂CH₂OCH₂CH₂ ¹⁸F、-CH₂CH₂CH₂OCH₂CH₂CH₂ ¹⁸F。

Most preferably, R may be selected from: -CH₂CH₂OCH₂CH₂OCH₂CH₂ ¹⁸F。

In the compound of the present invention, the introduction of the alkoxy unit improves water solubility, so that the metabolism in the liver is accelerated, and the retention time of the probe in blood is increased, which is advantageous for accumulation of the probe at a target site such as a tumor, and is more preferable than the alkyl group.

Preferred specific compounds of the invention are:

R＝-CH₂CH₂OCH₂CH₂OCH₂CH₂ ¹⁸a compound of F:

4- (2- (1- (2- (2- (2- (fluoro-18F) ethoxy) ethoxy) ethyl) -1H-indazol-4-yl) -6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) thiophen [3,2-d ] pyrimidin-4-yl) morpholine (4- (2- (1- (2- (2- (18F) ethoxy) ethoxy) ethyl) -1H-indazol-4-yl) -6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) thieno [3,2-d ] pyrimidin-4-yl) morpholinone), and

4- (2- (1- (2- (2- (fluoro-18F) ethoxy) ethoxy) ethoxy) ethyl) -2H-indazol-4-yl) -6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) thiophen [3,2-d ] pyrimidin-4-yl) morpholine (4- (2- (1- (2- (2- (18F) ethoxy) ethoxy) ethyl) -2H-indazol-4-yl) -6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) thieno [3,2-d ] pyrimidin-4-yl) morphine);

R＝-CH₂CH₂OCH₂CH₂ ¹⁸a compound of F:

4- (2- (1- (2- (2- (fluoro-18F) ethoxy) ethyl) -1H-indazol-4-yl) -6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) thiophen [3,2-d ] pyrimidin-4-yl) morpholine (4- (2- (1- (2- (2- (2- (fluoro-18F) ethoxy) ethoxy) ethyl) -1H-indazol-4-yl) -6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) thiophene [3,2-d ] pyrimidin-4-yl) morpholine), and

4- (2- (1- (2- (2- (fluoro-18F) ethoxy) ethyl) -2H-indazol-4-yl) -6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) thiophen [3,2-d ] pyrimidin-4-yl) morpholine (4- (2- (1- (2- (2- (fluoro-18F) ethoxy) ethoxy) ethyl) -2H-indazol-4-yl) -6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) thieno [3,2-d ] pyrimidin-4-yl) morpholine);

R＝-CH₂CH₂ ¹⁸a compound of F:

4- (2- (1- (2- (fluoro-18F) ethyl) -1H-indazol-4-yl) -6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) thieno [3,2-d ] pyrimidin-4-yl) morpholine (4- (2- (1- (2- (fluoro-18F) ethyl) -1H-indazol-4-yl) -6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) thio [3,2-d ] pyrimidin-4-yl) morphine), and

4- (2- (1- (2- (fluoro-18F) ethyl) -2H-indazol-4-yl) -6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) thiophene [3,2-d ] pyrimidin-4-yl) morpholine (4- (2- (1- (2- (fluoro-18F) ethyl) -2H-indazol-4-yl) -6- ((4- (methylsulfonyl) piperizin-1-yl) methyl) thio [3,2-d ] pyrimidin-4-yl) morpholine).

In a particularly preferred embodiment, the compound is compound 1 or compound 2 below:

in a second aspect the present invention provides an intermediate having the following structural formula I 'or II':

wherein, R' (Rm)_nDenotes C substituted by n Rm groups_1-12Alkyl group of (i), (ii), (iii), (iv) and (iv)₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is an integer of 1 to 10, y is an integer of 1 to 5, z is an integer of 1 to 3, n is an integer of 1 or more, Rm is selected from the group consisting of-OTs (p-toluenesulfonate), -OMs (methylsulfonate), -OTf (trifluoromethanesulfonate), -BF₃-phenyl- (R1) q, -I, -Br and-ClA leaving group, wherein R1 is NO₂、N(CH₃)₃Or Sn (CH)₃)₂And q is an integer of 1 to 5.

According to a preferred embodiment, R '(Rm) of said intermediate of formula I' or II_nDenotes C substituted by n Rm groups_1-6Alkyl group of (i), (ii), (iii), (iv) and (iv)₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is an integer of 1 to 5, y is an integer of 1 to 3, z is 1, n is an integer of 1 or more, Rm is selected from the group consisting of-OTs, -OMs, -BF₃、-p-N(CH₃)₃-Ph-，-p-NO₂-Ph-、-Sn(CH₃)₃A leaving group of-Ph-, -I, -Br and-Cl. Preferably, n is an integer from 1 to 3.

Further preferably, said C substituted with n Rm groups_1-6The alkyl group of (a) is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl substituted with 1-3 Rm groups; and said- (CH) substituted by n Rm groups₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Selected from- (CH) in which the terminal methyl group is substituted by 1-3 Rm groups₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is an integer from 1 to 5, y is an integer from 1 to 3, z is 1, Rm is selected from the group consisting of-OTs, -OMs, -BF₃、-p-N(CH₃)₃-Ph-，-p-NO₂-Ph-、-Sn(CH₃)₃A leaving group of-Ph-, -I, -Br and-Cl,

more preferably, R' (Rm)_nRepresents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, - (CH) substituted on one of the terminal methyl groups by a Rm group₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is 1, 2 or 3, y is 1 or 2, z is 1, Rm is selected from the group consisting of-OTs, -OMs, -OTf, -Br and-Cl.

According to a specific embodiment, R' (Rm)_nCan be selected from: -C (Rm)₃、-CH(Rm)₂、-CH₂Rm、-CH₂C(Rm)₃、-CH₂CH(Rm)₂、-CH₂CH₂Rm、-CH₂CH₂C(Rm)₃、-CH₂CH₂CH(Rm)₂、-CH₂CH₂CH₂Rm、-CH(CH₃)C(Rm)₃、-CH(CH₃)CH(Rm)₂、-CH(CH₃)CH₂Rm、-CH₂CH₂CH₂C(Rm)₃、-CH₂CH₂CH₂CH(Rm)₂、-CH₂CH₂CH₂CH₂Rm、-C(CH₃)₂C(Rm)₃、-C(CH₃)₂CH(Rm)₂、-C(CH₃)₂CH₂Rm、-CH₂OCH₂Rm、-CH₂OCH₂OCH₂Rm、-CH₂OCH₂OCH₂OCH₂Rm、-CH₂CH₂OCH₂CH₂Rm、-CH₂CH₂OCH₂CH₂OCH₂CH₂Rm、-CH₂CH₂CH₂OCH₂CH₂CH₂Rm, but is not limited thereto.

Rm is most preferably OTs.

According to a particular embodiment, preferred specific intermediates of the invention are:

R’(Rm)_n＝-CH₂CH₂OCH₂CH₂OCH₂CH₂intermediate compounds of OTs:

(2- (2- (2- (4- (6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -4-morpholinothiazol [3,2-d ] pyrimidin-2-yl) -1H-indazol-1-yl) ethoxy) ethoxy) ethyl-4-methylbenzenesulfonic acid (2- (2- (2- (4- (6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -4-morpholino no [3,2-d ] pyrimidin-2-yl) -1H-indazol-1-yl) ethoxy) ethoxy) ethyl-4-methylbenzenesulfonic acid (4-methylidenzenesulfonate), and

(2- (2- (2- (4- (6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -4-morpholinothiazole [3,2-d ] pyrimidin-2-yl) -2H-indazol-1-yl) ethoxy) ethoxy) ethyl-4-methylbenzenesulfonic acid) (2- (2- (2- (4- (6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -4-morpholino no [3,2-d ] pyrimidin-2-yl) -2H-indazol-2-yl) ethoxy) ethoxy) ethyl 4-methylbenezenesulfonate);

R’(Rm)_n＝-CH₂CH₂OCH₂CH₂intermediate compounds of OTs:

2- (2- (4- (6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -4-morpholinothiazole [3,2-d ] pyrimidin-2-yl) -1H-indazol-1-yl) ethoxy) ethyl-4-methylbenzenesulfonate (2- (2- (4- (6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -4-morpholinothiono [3,2-d ] pyrimidin-2-yl) -1H-indazol-1-yl) ethoxy) ethyl-4-methylbenzenesulfonate), and

2- (2- (4- (6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -4-morpholinothiazole [3,2-d ] pyrimidin-2-yl) -2H-indazol-1-yl) ethoxy) ethyl-4-methylbenzenesulfonate (2- (2- (4- (6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -4-morpholinothiono [3,2-d ] pyrimidin-2-yl) -2H-indazol-1-yl) ethoxy) ethyl-4-methylbenezenesulfonate);

R’(Rm)_n＝-CH₂CH₂intermediate compounds of OTs:

2- (4- (6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -4-morpholinothiazole [3,2-d ] pyrimidine-2-and) -1H-indazol-1-yl) ethyl-4-methylbenzenesulfonate (2- (4- (6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -4-morpholino no [3,2-d ] pyrimidin-2-yl) -1H-indazol-1-yl) ethyl-4-methyl-benzyl sulfonate), and

2- (4- (6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -4-morpholinothiazole [3,2-d ] pyrimidine-2-and) -2H-indazol-1-yl) ethyl-4-methylbenzenesulfonate (2- (4- (6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -4-morpholino no [3,2-d ] pyrimidin-2-yl) -2H-indazol-1-yl) ethyl-4-methyl-benzyl sulfonate).

In a particularly preferred embodiment, the intermediate compound is compound 1 'or compound 2' below:

in a third aspect, the present invention provides a process for the preparation of a compound of formula I or formula II as defined above, which process comprises reacting an intermediate as defined above with K¹⁸F or Na¹⁸F, carrying out a one-step reaction to obtain the compound.

According to one embodiment, the reaction is carried out at 40-150 ℃ for 5-60 minutes. After the reaction was complete, it was cooled to about 30 ℃.

The intermediate may be dissolved in a polar organic solvent in advance, specifically, for example, DMF, DMSO, or the like.

The method according to the preferred embodiment, further comprising a step of purification by high performance liquid chromatography or flash column chromatography (e.g., using C18 separation column from Sep-Pak). The eluent can be 10% -100% acetonitrile or ethanol, and the radioactive component is collected.

The preparation method of the compound of formula I or formula II is directly prepared by one-step substitution by adopting the intermediate, and can be automatically synthesized by using full-automatic synthesis equipment (such as TRACE L AB FXC Pro, FAST L AB 2and the like of GE company in America), thereby reducing or avoiding the contact of production personnel with radioactive substances.

The method has high synthesis efficiency, the marking rate reaches 50-70% (attenuation correction is not carried out), the specific activity is more than or equal to 37 Gbq/mu mol, the radiochemical purity is more than 95%, and the method meets the requirements of clinical application.

According to a preferred embodiment of the present invention, the preparation method further comprises, prior to the substitution reaction, preparing K by¹⁸F or Na¹⁸F：

Step 1, bombardment of 18 oxygen-water generation by a cyclotron¹⁸F-HF。

Step 2, adding¹⁸Target water of F-HF via anion exchangeExchange resin column (e.g., QMA small column (Waters, USA)) to exchange resin column¹⁸F^-The ions are retained on the resin column and then the salt solution is used to remove the ions from the resin column¹⁸F^-Eluted and then introduced into the reaction flask.

Step 3, adding a phase transfer catalyst and a certain amount of organic solvent into a reaction bottle, introducing nitrogen, heating, and evaporating the solvent in the reaction bottle to dryness to obtain dry anhydrous¹⁸And (F) a hydrofluoride salt of F.

In a preferred embodiment according to the invention, the salt solution used in step 2 may be those conventionally used in the art, for example one or more selected from sodium chloride, potassium carbonate and potassium bicarbonate, giving K accordingly¹⁸F or Na¹⁸F。

In another preferred embodiment of the present invention, the phase transfer catalyst used in step 3 may be any commonly used catalyst, such as an aminopolyether (K2.2.2, available from Sigma-Aldrich, carbofuran, Aladdin, TCI, etc.).

The organic solvent used is not particularly limited, and may be, for example, one or more of acetonitrile, acetone, and ethanol.

In another embodiment, step 3 may be performed by heating with an electric oven, or by microwave heating.

According to one embodiment, the intermediates of the invention can be synthesized starting from GDC-0941(2- (1H-indazol-4-yl) -6- (4-methylsulfonyl-piperazin-1-ylmethyl) -4-morpholin-4-yl-thieno [3,2-d ] pyrimidine), an inhibitor of type 1 phosphatidylinositol 3kinase (PI 3K).

Starting materials GDC-0941 (commercially available) and Rf-R' - (Rm) are shown in the following reaction scheme_nIn an organic solvent in the presence of a base to form a monosubstituted intermediate mixture of formula I '/II'. Wherein the organic solvent may be, for example, DMF, acetonitrile, DMSO, acetone, or the like, but is not limited thereto. The base may be an inorganic base such as an alkali metal hydroxide (e.g., sodium hydroxide), an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, cesium carbonate), an alkali metal hydride (e.g., sodium hydride, potassium hydride); an organic base, such as an alkyl amine (e.g.,triethylamine, diisopropylethylamine), and the like. Wherein R', Rm, n are as defined above; rf is a leaving group selected from the group consisting of-OTs, -OMs, -OTf, -I, -Br and-Cl; rm and Rf may be the same or different.

The synthesis is carried out starting from GDC-0941 as in the above reaction scheme, usually obtaining a mixture of two N-substitutions on the indazolyl group.

Thus, the method of the invention comprises obtaining a composition comprising the same-R' (Rm)_nThe two intermediate mixtures of formula I 'and formula II' for the substituents are directly prepared without isolation by the one-step process described above to give the final mixture of compounds of formula I and formula II having the same-R groups.

The resulting final mixture containing compounds of formula I and formula II having the same-R group can be used directly as a mixture without separation into individual compounds and without affecting the quality of the image, thus simplifying the preparation process and steps.

In a fourth aspect, the invention provides a positron imaging agent comprising at least one compound of formula I and formula II as described above.

According to a particular embodiment, the positron imaging agent comprises as active substance a mixture of compounds of formula I and formula II of the same-R group.

The imaging agent may further include necessary solvents and medical additives such as physiological saline, a small amount of ethanol, and the like.

The compounds of the present invention are derivatives of GDC-0941. GDC-0941 (or Pictilisib) is known as a novel selective class I phosphatidylinositol 3-kinase (PI3K) inhibitor. GDC-0941 competitively binds with the ATP-binding pocket of PI3K and prevents the formation of the second messenger phosphatidylinositol 3, 4, 5-triphosphate (PIP 3) that conveys signals downstream of PI3K (FolkesaJ, Ahmadi K, Alderton WK, et al. the identification of 2- (1H-Indazol-4-yl) -6- (4-methylsulfonyl-piperazine-1-yl) -4-morpholino-4-yl-tho [3,2-d ] pyridine (GDC-0941) as a potential, selective, organic biological available inorganic I PI3kinase for the treatment of cancer center J2008. 51:5522 5532; and K + K K.35. Biochemical K. Biochemical K.32. Soktay et al K.32. K.2007).

GDC-0941 is highly selective for PI3K α and PI3K subtypes and moderately selective for PI3K β and PI 3K. gamma. in a number of tumor cell lines, including A2780, MDA-MB-361, PC3 and U87MG, GDC-0941 causes growth inhibition (Folkes AJ, Ahmadi K, Alderton WK, et al. the identification of 2- (1H-Indazol-4-yl) -6- (4-methyl-piperonyl-piperzin-1-yl methyl) -4-morpholino-4-yl-thieno [3,2-D ] pyridine (GDC-0941) as a potential, selection, organic biological activity of said receptor for PI3kinase for expression of said I3kinase of said PI3, and for expressing said receptor, PI 0941, Western kinase for inhibiting growth of PI3, Western kinase, and tumor growth inhibition (also decrease of tumors of the growth inhibition of PI3, 11. 19. beta. K, 5. K, Pti.5. the growth inhibition of tumors, P, E. A, P-5. A, E. 7. A, E. K-095. A. 7. A. 7. A. and K, E. 7. A. K, E. 3. 9. A. 9. K, K).

GDC-0941 belongs to the thieno [3,2-d ] pyrimidine class of compounds. It relies on specific binding of a morpholinyl-thiophene [3,2-d ] pyrimidine structure, in particular a morpholinyl structure, to PI3K (Folkes AJ, Ahmadi K, Alderton WK, et al. the identification of 2- (1H-Indazol-4-yl) -6- (4-methylsulfonyl-piperazine-1-yl) -4-morpholino-4-yl-tho [3,2-d ] pyridine (GDC-0941) a potential, selective, organic biological activity of class I PI3 enzyme for the molecular analysis of cancer. J Med. chem. 2008; 51: 5522-.

As is clear from the above definitions, the alkyl or alkoxy/polyether chains carrying the radionuclide in the compounds of formula I and formula II of the present invention are far from the effective binding site (i.e., morpholino-thiophene [3,2-d ] pyrimidine structure), have no particular effect on specific binding, and thus have similar binding properties to GDC-0941. Therefore, it is assumed that the compounds of the present invention are also capable of specifically binding to the ATP-binding pocket of PI 3K.

It was demonstrated that when the PI3K/Akt/mTOR signaling pathway is aberrantly activated, the compounds of the invention are able to enrich at the lesion, thereby generating a radiographic image, effectively indicating high expression of the PI3KPI3K/Akt/mTOR signaling pathway.

Thus, the compounds and imaging agents herein may be used for the diagnosis of diseases with high expression of the PI3KPI3K/Akt/mTOR signaling pathway, in particular tumors, such as carcinomas, e.g. of the primary tumors (SAmuels Y, Wang Z, Bardelli A, et al: high frequency of tumors of the PIK3CA genes in human carcinomas scientific, 2004.304: 554; Yuan T L, cancer tl L C: PI3K pathway tumors in carcinomas in tumors of the group of carcinomas of the cervical carcinomas, the human on cancer 2008.27:5497, Ikeue T, Kanai F, Hitho gene, et al: functional tumors of the human colon cancer 2005, 4565: 4562; cancer of the prostate tumors, colon cancer of the group of carcinomas of the prostate cancer, colon cancer of the colon cancer.

The compound molecular probe targeting the PI3K pathway can evaluate the expression level of PI3K of a subject in real time by high-sensitivity noninvasive PET imaging, and effectively perform differential diagnosis, molecular typing, curative effect evaluation, prognosis evaluation and the like on PI3K high-expression tumors.

Has the advantages of¹⁸The compounds of formula I and formula II of the present invention of F may have a half-life of about 110 minutes. And those commonly used¹¹C-labeled radionuclides (with half-lives of about 20 minutes) enable longer visualization monitoring, longer imaging, better target to non-target ratios, and better imaging quality and contrast.

The compounds of formula I and formula II are prepared by one-step synthesis, and can be automatically synthesized by using a full-automatic synthesizer, so that the ray radiation of operators can be reduced, the reaction is rapid, the repeatability of the reaction process is high, and the stability of the product is good. The product has a radioactive yield, a non-corrected radioactive yield of up to 70% or more of the compound according to the preferred embodiment. The mixtures obtained according to the preferred embodiment have a labelling ratio of 50% to 70%, a specific activity of greater than 37 GBq/. mu.mol and an radiochemical purity of greater than 95%.

Drawings

FIG. 1 is a HP L C spectrum of precursor BAR-2 of example 1, wherein the presence of two compounds in precursor BAR-2 as isomers of each other is confirmed by two peaks in 19-20 min.

FIG. 2 is a drawing of the precursor BAR-2 of example 1¹H-NMR spectrum.

FIG. 3 shows a schematic view of a liquid crystal display device of example 1¹⁹HP L C spectrum of F-BAR-3 standard, in which two peaks at 10.5min and 12.5min confirm¹⁹Two compounds exist in F-BAR-3 as isomers of each other.

FIG. 4 shows the structure of example 2¹⁸Radioactive HP L C spectrum of F-BAR-3, wherein the peak at 15min is¹⁸F-BAR-3, no free¹⁸F is present.

Figure 5 is a schematic view of a process according to example 3,¹⁸F-BAR-3 and¹¹PET imaging and Metabolic analysis studies of C-BAR-1 in healthy Kunming mice, wherein A shows¹¹PET imaging of C-BAR-1; b shows¹⁸PET imaging of F-BAR-3; c shows a comparison of liver uptake values for both.

Figure 6 is a schematic view of a process according to example 4,¹⁸the result of PET imaging of F-BAR-3 in MCF-7 tumor-bearing mice highly expressing PI3K (A) and the study of biodistribution metabolism (B).

Figure 7 is a schematic view of a process according to example 4,¹¹C-BAR-1 and¹⁸results of static imaging of F-BAR-3 in MCF7 and MDA-MB-231 tumor-bearing mice, respectively, wherein the two left panels are¹⁸F-BAR-3, right two panels¹¹C-BAR-1, and A are static imaging results of MCF-7 tumor-bearing mice; b is the static imaging result of MDA-MB-231 tumor-bearing mice.

Detailed Description

The invention is further described below with reference to examples and figures. It is to be understood that the following specific examples are merely illustrative of and explanatory of the invention and are not to be construed as limiting the scope of the invention.

Unless otherwise specifically indicated, the starting materials and reagents used in the following examples are all commercially available or may be prepared by methods well known in the art.

Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings¹⁸F-BAR-3 specifically illustrates the present invention.

Example 1:¹⁹preparation of F-BAR-3

To facilitate the study of the preparation method, the non-radioactive compound was prepared according to the following reaction scheme.

0.5 grams of BAR-1 (i.e., GDC-0941, Selleck, USA) was combined with 1.5 grams of TsO-PEG₃-OTs (carbofuran) dissolved in 50m L acetonitrile, 0.5 g potassium carbonate added, reaction at 70 ℃ for 1-3 days, after the reaction was completed, concentration to remove the solvent, purification of the residue by silica gel column chromatography to give 0.4 g product as a pale yellow oil in 82% yield, mass spectrometry (m/z (ESI +), calculated 799.25, found 800.25, mass Spectrometer Expression CMS, Advion), 1H-NMR (400 MHzNMR DRX Spectrometer, Bruker Corporation, see FIG. 2) and HP L C (Shimadzu L C-20A, column Philonom L una C18(2),250mm 4.6mm, see FIG. 1, where the two peaks from 19 to 20min are isomers to each other) were confirmed as BAR-2 isomer mixture (2- (2- (2- (4- (6- (methylsulfonyl) piperazine-1-morpholino) methyl) -thiazole [ 3-d ] shown in the following figure]Pyrimidine-2-and) -1H-indazol-1-yl) ethoxy) ethyl-4-methylbenzenesulfonate (2- (2- (2- (4- (6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -4-morpholino) no [3,2-d]pyrimidin-2-yl) -1H-indazol-1-yl) ethoxy) ethoxy) ethyl 4-methyllbenzenesufonate and 2- (2- (4- (6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -4-morpholinothiazole [3,2-d]Pyrimidine-2-and) -2H-indazol-2-yl) ethoxy) ethyl-4-methylbenzenesulfonate (2- (2- (2- (4- (6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -4-morpholino) no [3,2-d]pyrimidin-2-yl)-2H-indazol-2-yl)ethoxy)ethoxy)ethyl-methylbenzenesulfonate)。

Subsequently, 2mg of the synthesized BAR-2 was directly dissolved without isolation of both isomers in 10mg of tetrabutylammonium fluoride (TBAF) (molar ratio of two is more than 1:1) in 5M L THF, stirred at room temperature overnight, then the solvent was removed by rotary evaporation, the residue was purified by silica gel column chromatography to give 0.5mg of the product as a pale yellow oil, yield 30%, and the obtained product was subjected to mass spectrometry (M/z (ESI +)]+ calculated 647.2, found 648.2), HP L C (see fig. 3, where the 10.5min and 12.5min peaks are isomers of each other) were confirmed as¹⁹F-BAR-3(4- (2- (2- (2- (2- (2-fluoroethoxy) ethoxy) ethyl) -2H-indazol-4-yl) -6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) thiophene [3,2-d]Pyrimidin-4-yl) morpholine and 4- (2- (1- (2- (2- (2-fluoroethoxy) ethoxy) ethyl) -1H-indazol-4-yl) -6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) thiophene [3,2-d]Pyrimidin-4-yl) morpholine).

Example 2:¹⁸synthesis of F-BAR-3

This example was carried out by a full-automatic one-step rapid synthesis method using an automated synthesis apparatus (TRACE L AB FXFn) from GE, USA.

Bombardment of 3m L18 oxygen-water (H) by a cyclotron (GE)₂ ¹⁸O) generation¹⁸F-HF500 mCi. Make it contain¹⁸The target water of F-HF was passed through a QMA column (Waters, Accell Plus QMA) to remove the water¹⁸F^-The ions remained on the QMA cartridge, then treated with 1.5m L aqueous acetonitrile (acetonitrile to water volume ratio 2:1) containing 3mg potassium carbonate and 15mg phase transfer catalyst K2.2.2(Sigma-Aldrich)¹⁸F^-Eluting from QMA column, introducing into reaction flask, heating and introducing nitrogen gas until the solvent in the reaction flask is evaporated to dryness to obtain dry anhydrous K¹⁸F(～450mCi)。

A1.0 m L anhydrous DMSO solution containing 2mg of BAR-2 prepared in example 1 was charged in a reaction flask, reacted at 80 ℃ for 30 minutes, then cooled to 30 ℃ before separation and purification with HP L C (Shimadzu L C-20A, column: Philomena L una C18(2),250mm × 10mm) and collected by a manual methodCollecting the peak components of the emission. Filtration through a 0.22 μm sterile filter (Millipore, Millex-FG) afforded the product¹⁸F-BAR-3 mixture.

Get¹⁸F-BAR-310. mu. Ci/20. mu.l, radiochemical purity determined by radioactive high performance liquid chromatography (HP L C: Shimadzu L C-20A, column: Philomena L una C18(2)250mm × 4.6.6 mm.) starting at 500mCi18F, final product activity 300mCi + -50 mCi (n ═ 3), marker compound¹⁸Labeling Rate of F-BAR-3: 60% ± 10% (n ═ 3), radioactive chemical purity greater than 95%. The results of the radiochemical purity test are shown in FIG. 4.

Example 3:¹⁸F-BAR-3 and¹¹comparison of biodistribution and metabolism of C-BAR-1

Examination of the inventive products prepared in example 2 by PET imaging¹⁸F-BAR-3 biodistribution and metabolism in Normal Kunming mice (female, 4 weeks old, purchased from Beijing Huafukang Biotech GmbH, Inc.) combined with use of¹¹C-BAR-1 served as a control.

¹¹Preparation of C-BAR-1:

the following reaction scheme was used with an automated synthesis apparatus (TRACE L AB FX, GE, USA)_CPro) is subjected to full-automatic one-step rapid synthesis¹¹C-BAR-1。

Generation of 500mCi externally by a cyclotron (GE MINitrace)¹¹CO₂. Will 500mCi¹¹CO₂Conveyed into a reactor and mixed with 100m L/min H₂Mixing, on-line generation¹¹CH₄500 mCi. Then reacts with sublimed iodine (the temperature of the iodine furnace is 100 ℃, the iodine particle is about 20g) at the high temperature of 720 ℃ to generate methyl iodide (¹¹CH₃I，160mCi)。

Make 300mCi¹¹CH₃I into the reaction flask of an automated Synthesis apparatus (room temperature, 2mg of Compound BAR-1 solutionIn 5N NaOH/400. mu.l DMSO). The mixture was reacted at 65 ℃ for 5min and then cooled to 30 ℃.

Separating and purifying the mixture in HP L C, collecting radioactive peak components by manual method "peak-cut", filtering with 0.22 μm sterile filter membrane to obtain product¹¹C-BAR-1 (starting 500mCi carbon-11, final product about 12.5mCi ± 2.5mCi (n ═ 3), decay corrected yield: 10.5% ± 2.5%, (n ═ 3)).

Get¹¹C-BAR-110. mu. Ci/20. mu.l, radiochemical purity determined by radioactive high performance liquid chromatography (HP L C, Shimadzu L C-20A, column: Philomo L una C18(2),250mm × 4.6.6 mm.) radiochemical purity is greater than 95%.

Dynamic imaging

Dynamic imaging was performed using the BioCaliburn L H small animal imaging system of Raycan Technology, inc.

Normal Kunming mice (3 mice per group) were first anesthetized intraperitoneally with Ketamine/Xylazine (carbofuran, 110/10mg/Kg), their prone positions were fixed on a MicroPET examination couch, and 3.7MBq of toluene was injected via the bedside tail vein¹⁸F-BAR-3 or¹¹Immediately after the C-BAR-1 probe is placed in the scan center field, data acquisition begins (23 frames for 6 × 10s, 4 × 30s, 4 × 60s, 4 × 2min, 5 × 5 min) for a total of about 40 min.

Region of interest (ROI, Regions of interest): the organ of interest is manually delineated on the attenuation corrected whole-body coronal image. The uptake of radioactivity into each organ (ROI) was quantitatively analyzed to obtain the percentage% ID/g injected dose per gram of tissue at the corresponding site.

Better observation and comparison can be achieved by MicroPET dynamic imaging of mice¹⁸F-BAR-3 and¹¹distribution and metabolic characteristics of C-BAR-1 probes in vivo. Referring to FIG. 5, wherein A shows¹¹PET imaging of C-BAR-1 as a function of time; figure B shows¹⁸PET imaging of F-BAR-3 as a function of time; c comparison shows twoThe liver uptake value of the subject was plotted against time.

As can be seen from the A, B diagram of FIG. 5, over time¹⁸F-BAR-3 and¹¹the radioactive concentration of C-BAR-1 in liver is gradually reduced with time, while the radioactive concentration in gallbladder and intestinal tract is gradually increased, which indicates that the two are mainly excreted and metabolized through liver, gallbladder and intestinal tract.

Additional comparison¹⁸F-BAR-3 (FIG. 5B) and¹¹imaging results of C-BAR-1 (FIG. 5A) revealed that¹¹C-BAR-1 comparison, starting from 5min,¹⁸the contrast to background in F-BAR-3 imaged liver was significantly lower (see FIG. 5B) because of¹⁸The introduction of PEG3 as a linking group into F-BAR-3 improves water solubility, resulting in accelerated metabolism in the liver. From the quantitative results in figure 5C,¹⁸the total clearance rate of F-BAR-3 in the liver is significantly higher¹¹C-BAR-1 is fast, with liver uptake higher initially but from 5 to 35 minutes¹⁸F-BAR-3 uptake in liver was significantly lower than¹¹C-BAR-1。

In addition, the introduction of PEG3 linking group also increased the retention time of the probe in blood, at 30min,¹⁸F-BAR-3 intake was significantly higher in blood¹¹C-BAR-1 (3.19. + -. 1.05% ID/g vs 1.34. + -. 0.66% ID/g) is advantageous for accumulation of the probe at the target site such as tumor.

As can be seen from FIG. 5, the half-life of the present invention is 110min¹⁸F-labeled probes, which allow longer imaging and better in vivo imaging results and comparative example 2 to the preparation of the compounds of the invention and this example to¹¹Preparation of C-BAR-1, Compounds of the invention¹⁸The yield of F-labeled probe was high (50-70%).¹¹C marking step (C)¹⁸F-mark is more complex and requires multiple steps to prepare from accelerator¹¹C-CO₂Is converted into¹¹C-BAR-1 labelling of the desired Radioactive precursors¹¹C-CH₃I, and¹⁸f-labelling only requiring preparation of the accelerator¹⁸F is available by simple ion-exchange resin treatment, and thus¹⁸Overall ratio of F-BAR-3 preparation process¹¹C-BAR-1 is less and simpler, label controllable and stable.¹⁸The F-BAR-3 can be used by more than 10 patients (calculated according to 0.1mCi/kg per person) in one production, and is beneficial to the clinical wide use of the probe; in contrast to this, the present invention is,¹¹the yield of the C-labeled probe is limited (8-13%), and the C-labeled probe can be used by only 1-3 people in one production.

Example 4:¹⁸biological Properties of F-BAR-3 in tumor-bearing mice

Examination of the inventive products prepared in example 2 by PET imaging¹⁸The in vivo biological properties of F-BAR-3 in a tumor-bearing mouse model.

Animal tumor model construction Balb/c-nu nude mice (female, 4 weeks old) were provided by Beijing Huafukang Biotech Co., Ltd, and were bred in animal testing center of Huazhong university of science and technology without special pathogen barrier system, all animals used in the experiment were examined by Committee for animal use and management of the college of Hospital of medicine of Huazhong university of science and technology, and PI3K low-expression MDA-MB-231 cells (cell bank of the Committee for type culture Collection of China academy of sciences), PI3K high-expression MCF-7 cells (cell bank of the Committee for type culture Collection of China academy of sciences) were each 5 × 10⁶The two were suspended in 100. mu.l PBS respectively, and mixed with an artificial basement membrane (Matrigel, BD) of the same volume, subcutaneously planted on the shoulder and back of the right upper limb of a Balb/c-nu nude mouse, and animal experimental studies were performed when the tumor diameter was 0.7cm to 1.0 cm.

Dynamic imaging: firstly, using ketamine/xylazine (carbofuran, 110/10mg/Kg) abdominal cavity anesthesia model to construct successful MDA-MB-231 and MCF-7 tumor-bearing mice, fixing the prone position on a MicroPET examination bed, and then adopting the tail vein at the bedside to construct the mice with about 3.7-5.55MBq (100-¹⁸F-BAR-3 was injected into the body and immediately placed in the scan center field to begin data acquisition (24 frames total acquisition 6 × 10s, 4 × 30s, 4 × 60s, 4 × 2min, 3 × 5min, 3 × 10 min), 60min total acquisition static imaging data acquisition 1h after imaging agent injection using the small animal PET imaging system of example 3 for 10min experimental use for abdominal anesthesia.

Region of interest (ROI): the organ or tumor of interest is delineated manually on the attenuation corrected whole-body coronal image. The uptake of radioactivity at the tumor site and other organs was quantitatively analyzed to obtain the% ID/g injected dose per gram of tissue at the corresponding site. For tumor/muscle ratio counts, the ROI first delineates the region of interest in the tumor site, and then delineates the contralateral muscle as background.

FIG. 6 shows¹⁸Imaging results of F-BAR-3 as a molecular probe in MCF-7 tumor-bearing mice (A) and biodistribution metabolism studies (B). As can be seen from FIG. 6A, the radioactive concentration in the liver, which is the most important excretion pathway, gradually decreases with time as in normal mice, whereas the MCF-7 tumor is clearly visible after 10s injection of the probe, and the MCF-7 tumor has good contrast in the tested 30min-2h time interval. The radioactive concentration of the probe in the MCF-7 tumor increased gradually with time, was highest at 1h, and decreased slowly during the following 1h, and still maintained a high uptake. As can be seen from the quantitative results in figure 6B,¹⁸the uptake of F-BAR-3 in MCF-7 tumors reached a maximum around ten minutes and remained at a higher level of 6-7% ID/g for the 2h tested. At the same time, the uptake in muscle was low, only 1% ID/g. The ratio of tumor to muscle uptake was 6-7.

FIG. 7 shows MCF-7 and MDA-MB-231 tumor-bearing mice injected separately¹⁸F-BAR-3 and¹¹PET imaging results 1h after C-BAR-1. The two figures on the left side are¹⁸The result of the development of F-BAR-3, the two right panels¹¹Imaging results of C-BAR-1. A is the static development result of MCF-7 model mouse at 60min, and B is the static development result of MDA-MB-231 model mouse at 60 min.

As can be seen from the view in figure 7,¹⁸F-BAR-3 and¹¹the accumulation of C-BAR-1 in PI3K high-expression tumor MCF-7 was significantly higher than that in PI3K low-expression tumor MDA-MB-231. Display device¹⁸F-BAR-3 and¹¹the uptake of C-BAR-1 in the tumor has a certain correlation with the expression level of PI3K, thus confirming that¹⁸F-BAR-3 and¹¹C-BAR-1 is capable of specifically suggesting abnormally high expression of PI3K and is further used for screeningPatients sensitive to PI3K protein inhibitors are selected or an assessment is provided for the efficacy of PI3K/Akt/mTOR signaling pathway inhibitor drugs.

As can be further seen in FIG. 7, the method includes¹¹Compared with the C-BAR-1,¹⁸the overall uptake of F-BAR-3 in mice was increased, which correlates with the increased PEG3 linker contributing to a decreased blood clearance rate.

After 1h of injection of two probes, MCF-7 tumors were clearly visible with good contrast, but¹⁸F-BAR-3 has an absolute value of uptake significantly higher than that of the sample¹¹C-BAR-1, and¹⁸the radioactive concentration of F-BAR-3 in abdominal organs such as liver is significantly lower than that of F-BAR-3¹¹C-BAR-1. And also¹⁸F-BAR-3 tumor uptake value and tumor to background ratio¹¹C-BAR-1 is high. For MDA-MB-231 tumor-bearing mouse model with relatively low PI3K expression, the injection is carried out¹¹After the C-BAR-1 probe, no specific uptake is observed at the tumor part, but the radioactive concentration is higher in abdominal organs such as liver, which may be combined with the above¹¹C-BAR-1 is associated with a faster clearance in blood. To inject¹⁸1h after F-BAR-3, MDA-MB-231 tumors were clearly visible, and no significant radioactive concentrations were seen in the liver, with higher radioactive concentrations only in the gallbladder, bladder and small intestine. This indicates PEG 3-modified¹⁸F-BAR-3 Probe had a ratio¹¹The better pharmacokinetic profile of C-BAR-1, while maintaining or even increasing affinity to PI3K high expressing tumors.

Claims

1. A compound of formula I or formula II:

wherein R is a group having at least one¹⁸Of the F substituent- (CH)₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is an integer of 1 to 10, y is an integer of 1 to 5,z is an integer of 1 to 3.

2. The compound of claim 1, wherein R is a cyclic alkyl having at least one¹⁸Of the F substituent- (CH)₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is an integer of 1 to 5, y is an integer of 1 to 3, and z is 1.

3. The compound of claim 2, wherein said R has 1-3¹⁸And F is a substituent.

4. The compound of claim 2, wherein said has at least one¹⁸Of the F substituent- (CH)₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Selected from 1-3 terminal methyl groups¹⁸F-substituted- (CH)₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is an integer of 1 to 5, y is an integer of 1 to 3, and z is 1.

5. The compound of claim 4, wherein R is one having one on one terminal methyl group¹⁸Of the F substituent- (CH)₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is 1, 2 or 3, y is 1 or 2, and z is 1.

6. An intermediate having the following structural formula I 'or II':

wherein, R' (Rm)_nRepresents- (CH) substituted by n Rm groups₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is an integer of 1 to 10, y is an integer of 1 to 5, z is an integer of 1 to 3, n is an integer of 1 or more, Rm is selected from the group consisting of-OTs, -OMs, -BF₃, -phenyl- (R1)_qA leaving group of the group consisting of-I, -Br and-Cl, wherein R1 is NO₂、N(CH₃)₃Or Sn (CH)₃)₂And q is an integer of 1 to 5.

7. The intermediate of claim 6, wherein R' (Rm)_nRepresents- (CH) substituted by n Rm groups₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is an integer of 1 to 5, y is an integer of 1 to 3, z is 1, n is an integer of 1 or more, Rm is selected from the group consisting of-OTs, -OMs, -BF₃、-p-N(CH₃)₃-Ph-，-p-NO₂-Ph-、-Sn(CH₃)₃A leaving group of-Ph-, -I, -Br and-Cl.

8. The intermediate of claim 7, wherein n is an integer from 1 to 3.

9. An intermediate according to claim 7, wherein the- (CH) substituted with n Rm groups₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Selected from the group consisting of- ((R) C) in which the terminal methyl group is substituted by 1-3 Rm groupsCH₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is an integer of 1 to 5, y is an integer of 1 to 3, z is 1, Rm is selected from the group consisting of-OTs, -OMs, -OTf, -BF₃、-p-N(CH₃)₃-Ph-，-p-NO₂-Ph-、-Sn(CH₃)₃A leaving group of-Ph-, -I, -Br and-Cl.

10. Intermediate according to claim 9, wherein R' (Rm)_nRepresents- (CH) substituted on one terminal methyl group by an Rm group₂O)_x-CH₃、-(CH₂CH₂O)_y-CH₂CH₃Or- (CH)₂CH₂CH₂O)_z-CH₂CH₂CH₃Wherein x is 1, 2 or 3, y is 1 or 2, z is 1, Rm is selected from the group consisting of-OTs, -OMs, -OTf, -Br and-Cl.

11. A process for the preparation of a compound as claimed in any one of claims 1 to 5, wherein the process comprises reacting an intermediate as claimed in any one of claims 6 to 10 with K¹⁸F or Na¹⁸F, carrying out a one-step reaction to obtain the compound.

12. The method of claim 11, wherein the reaction is carried out at 40-150 ℃ for 5-60 minutes.

13. The method of claim 11, wherein the method further comprises the step of purification by high performance liquid chromatography or column chromatography.

14. A positron imaging agent comprising at least one compound according to any one of claims 1 to 5.