WO2021175338A1 - 一种psma结合剂及其用途 - Google Patents

一种psma结合剂及其用途 Download PDF

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WO2021175338A1
WO2021175338A1 PCT/CN2021/086783 CN2021086783W WO2021175338A1 WO 2021175338 A1 WO2021175338 A1 WO 2021175338A1 CN 2021086783 W CN2021086783 W CN 2021086783W WO 2021175338 A1 WO2021175338 A1 WO 2021175338A1
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cooh
compound
psma
formula
hynic
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宋少莉
许晓平
刘畅
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Fudan University Shanghai Cancer Center
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Fudan University Shanghai Cancer Center
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Priority to US17/642,179 priority Critical patent/US12612343B2/en
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Priority to CA3179523A priority patent/CA3179523A1/en
Priority to NZ792994A priority patent/NZ792994B2/en
Priority to EP21765279.1A priority patent/EP4011903A4/en
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Definitions

  • the present invention relates to a radioisotope-labeled prostate specific membrane antigen (PSMA) binding compound and its precursor compound.
  • PSMA prostate specific membrane antigen
  • the compounds are used as tracers and imaging agents for various disease states of prostate cancer in nuclear medicine.
  • the present invention is a subsequent invention patent application whose application number is 202010140466.7 and the application date is March 03, 2020 as the priority text.
  • Prostate cancer is the second most common cancer among men worldwide, and its mortality rate ranks fifth among male cancers. In 2018, the number of deaths due to PCa worldwide was close to 400,000. Metastasis, recurrence, and androgen treatment resistance are the main causes of death in prostate cancer patients. At present, there is no effective diagnosis method and treatment plan for metastasis, recurrence and androgen therapy-resistant prostate cancer.
  • Traditional anatomical imaging methods such as computed tomography (CT), magnetic resonance (MR) imaging and ultrasound have obvious defects. Molecular imaging can understand tumor physiology at the molecular level, so as to achieve more accurate prognosis judgment and efficacy monitoring.
  • 18 F-labeled deoxyglucose is the most commonly used molecular imaging probe in clinical practice.
  • 18 F-FDG PET/CT has limited diagnostic value for PCa.
  • radioactive molecular imaging tracers are being explored clinically to detect PCa, including radiolabeled choline drugs ( 11 C-choline), radiolabeled acetate ( 11 C-acetate), and radiolabeled testosterone ( 18 F-FDHT), anti-1-amino-3-[ 18 F]fluorocyclobutyl-1-carboxylic acid ( 18 F-FACBC) and 1-(2-deoxy-2-[18F]-fluoro-L -Arabinofuranosyl)-5-methyluracil ( 18 F-FMAU) and the like. They each reflect the status of prostate cancer through different mechanisms, but none of them is ideal (ie, easy to synthesize, minimally metabolized by the urinary system, and tumor-specific uptake).
  • PSMA Prostate-specific membrane antigen
  • the present invention satisfies new tissue-specific compounds for prostate cancer, and their use as imaging agents and tracers for PCa in nuclear medicine.
  • the present invention provides an imaging agent that is different from the prior art in terms of modification.
  • the imaging agent has not been known or suggested before, and aims to solve the urinary system excretion of the imaging agent, and the high uptake of the bladder can easily cover the tumor lesions. The problem.
  • the present invention relates to a compound represented by the following general formula (I):
  • n is an integer from 0 to 5;
  • n is an integer from 0 to 5;
  • f, g are 0 or 1;
  • R and R' are each independently selected from H, alkyl, halogen, -CN, -OH, -NH 2 , alkoxy or cycloalkyl;
  • Q is -COOH, -SOOH, -SO 3 H, -SO 4 H, -POOH, -PO 3 H or -PO 4 H 2 ;
  • X is an optionally substituted aryl group or heteroaryl group, and the substitution is substituted by at least one R group;
  • Y is an optionally substituted aryl group, an optionally substituted heterocyclic aryl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocycloalkyl group, and the substitution is by at least one R group replace;
  • AA 1 is a natural or unnatural amino acid, or -CH 2 CH 2 -.
  • R and R' are each independently selected from H, C 1 -C 10 alkyl
  • the X is optionally substituted phenyl, naphthyl, biphenyl, indolyl, benzothiazolyl or quinolinyl;
  • the optionally substituted heterocycloalkyl is selected from N-piperidinyl or N-methylated piperidinyl salts.
  • the present invention also provides a radionuclide complex, which can be used for SPECT/CT imaging of target tissues.
  • the radionuclide complex comprises a radionuclide and the PSMA small molecule inhibitor of the present invention, which has the structure shown in the general formula (II):
  • L is N-tris(hydroxymethyl)methylglycine, ethylenediamine-N,N'-diacetic acid, triphenylphosphine trimetasulfonate, 3,3'-(phenylphosphine diyl) bis( Benzene-1-sulfonic acid) disodium, sodium diphenylphosphine benzene-3-sulfonate, niacin, glucoheptonate, glucosamine, mannitol, or diphenylphosphine benzoic acid.
  • alkyl by itself or as part of another molecule refers to a linear or branched or cyclic hydrocarbon group, or a combination thereof, which can be fully saturated, single or Polyunsaturated, and can include divalent and multivalent groups.
  • Alkyl residues are preferably C 1 to C 10 and may be unsubstituted or substituted (e.g. with halogen).
  • Preferred alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl or n-octyl and the like.
  • the same also applies to the corresponding cycloalkyl compounds preferably having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • An unsaturated alkyl group is an alkyl group having one or more double bonds or triple bonds.
  • alkyl groups include, but are not limited to, vinyl, 2-propenyl, 2-butenyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3 -(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers.
  • alkyl is also used to include those derivatives of alkyl, such as “heteroalkyl", “haloalkyl” and "high alkyl".
  • aryl refers to a closed ring structure that has at least one ring with a conjugated ⁇ -electron system and includes carbocyclic aryl and heterocyclic aryl (or “heteroaryl” or " Heteroaromatic ”) group.
  • the carbocyclic or heterocyclic aromatic group may contain 5 to 20 ring atoms.
  • the aforementioned terms include covalently linked monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.
  • the aromatic group can be unsubstituted or substituted.
  • Non-limiting examples of "aromatic” or “aryl” groups include phenyl, 1-naphthyl, 2-naphthyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, anthracenyl And Fiki.
  • the substituents for each of the aforementioned aryl and heteroaryl ring systems are selected from the acceptable substituents described herein (e.g., alkyl, carbonyl, carboxy, or halogen).
  • aryl includes aryl and heteroaryl rings.
  • aralkyl or “alkaryl” is used to include those groups in which the aryl group is attached to an alkyl group (including but not limited to benzyl, phenethyl, pyridylmethyl, etc.), which includes those Alkyl groups, in which carbon atoms (including but not limited to methylene groups) have been replaced by heteroatoms, are for example only, replaced by oxygen atoms.
  • alkyl group including but not limited to benzyl, phenethyl, pyridylmethyl, etc.
  • Alkyl groups in which carbon atoms (including but not limited to methylene groups) have been replaced by heteroatoms, are for example only, replaced by oxygen atoms.
  • Examples of such aryl groups include, but are not limited to, phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like.
  • Heteroaryl refers to an aryl group containing at least one heteroatom selected from N, O, and S; wherein nitrogen and sulfur atoms can be optionally oxidized, and nitrogen atoms can be optionally quaternized . Heteroaryl groups can be substituted or unsubstituted. The heteroaryl group can be attached to the rest of the molecule through a heteroatom.
  • Non-limiting examples of suitable groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl , 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl, purinyl, 2-benzimidazolyl, 4-indolyl, 5 -Indolyl, 6-indolyl
  • amino acid refers to naturally occurring and unnatural amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to naturally occurring amino acids.
  • Natural amino acids are 20 common amino acids in their D- or L-forms (alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine) , Histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine) and pyrrolysine Amino acids and selenocysteine.
  • Amino acid analogs refer to compounds that have the same basic chemical structure as naturally-occurring amino acids, just as an example, ex-carbon, which binds to hydrogen, carboxyl, amino, and R groups. Such analogs may have a modified R group (by way of example, norleucine) or may have a modified peptide backbone while still retaining the same basic chemical structure as a naturally occurring amino acid.
  • Non-limiting examples of amino acid analogs include homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium.
  • Amino acids can be referred to herein by their names, their commonly known three-letter symbols, or by single-letter symbols (recommended by the IUPAC-IUB Biochemical Nomenclature Committee).
  • “Unnatural amino acid” refers to an amino acid that is not one of the 20 common amino acids or pyrrolysine or selenocysteine.
  • Other terms that can be used synonymously with the term “non-natural amino acid” are “non-naturally encoded amino acid”, “non-natural amino acid”, “non-naturally occurring amino acid” or “man-made amino acid”.
  • the term “non-natural amino acid” includes, but is not limited to, amino acids that occur through modification of naturally-encoded amino acids in their backbone or side chains.
  • the unnatural amino acid comprises a carbonyl group, an acetyl group, an aminooxy group, a hydrazine group, a hydrazide group, a semicarbazide group, an azide group, or an alkyne group.
  • AA 1 has the following chemical formula:
  • R' H, COOH, CH 2 COOH, C 2 H 4 COOH, CH(COOH) 2 , CH(CH2COOH) 2 , CH(COOH)(CH 2 COOH), CH 2 CH(COOH) 2 , or SO 3 H;
  • AA 1 can be bound within the molecule via peptide or amide bonds, that is, natural amino acids and/or non-naturally occurring amino acids.
  • acidic amino acids e.g., glutamic acid, aspartic acid
  • the binding may alternatively be via the ⁇ -, ⁇ , or ⁇ -position.
  • the Z group is -COOH
  • it can be easily replaced by biosteric substitutes such as -SO 2 H, -SO 3 H, -SO 4 H, -PO 2 H, -PO 3 H,- For PO 4 H 2 replacement, see, for example, "The Practice of Medicinal Chemistry” (Academic Press New York, 1996), page 203.
  • the compound of formula (I) provided by the present invention can be preferably selected from, but not limited to, compounds having the following structure:
  • complexes of formula (II) provided by the present invention can be preferably selected from, but not limited to, complexes with the following structures:
  • L is N-tris(hydroxymethyl)methylglycine, ethylenediamine-N,N'-diacetic acid, triphenylphosphine trimetasulfonate, 3,3'-(phenylphosphine diyl) bis( Benzene-1-sulfonic acid) disodium, sodium diphenylphosphine benzene-3-sulfonate, niacin, glucoheptonate, glucosamine, mannitol, or diphenylphosphine benzoic acid.
  • the above-mentioned compound or complex provided by the present invention can be used in a method of imaging in a patient, in a method of diagnosing prostate cancer and/or its metastases, or in a method of treating prostate cancer and/or its metastases .
  • the present invention also provides a pharmaceutical composition, which comprises the aforementioned compound or complex, or a pharmaceutical prodrug, salt or ester thereof, and a pharmaceutical carrier.
  • a pharmaceutical composition which comprises the aforementioned compound or complex, or a pharmaceutical prodrug, salt or ester thereof, and a pharmaceutical carrier.
  • Such pharmaceutical compositions can be used in methods of imaging in patients, in methods of diagnosing prostate cancer and/or its metastases, or in methods of treating prostate cancer and/or its metastases.
  • the 99m Tc complex of the general formula (II) of the present invention can be used for SPECT/CT imaging of prostate cancer and/or its metastases, providing a new method for the diagnosis of prostate cancer.
  • the present invention adjusts the lipophilicity of the overall compound by modifying the intermediate linker of the PSMA pharmacophore and the radioactive coordination group, increases the proportion of the compound metabolized by the liver and gallbladder, and reduces the excretion of the urinary system, thereby avoiding physiological ingestion and imaging The undesirable effect of the result.
  • the compounds of the present invention especially 99m Tc-HYNIC-PSMA-XL-3, have outstanding low urine clearance, which enables excellent evaluation of prostate cancer. Therefore, the tracer according to the present invention is completely suitable for the preliminary diagnosis of the primary and recurrence of prostate cancer.
  • Figure 1 shows the HPLC UV spectrum of HYNIC-PSMA-XL-2.
  • Figure 2 shows the mass spectrum of HYNIC-PSMA-XL-2.
  • Figure 3 shows the HPLC UV spectrum of HYNIC-PSMA-XL-3.
  • Figure 4 shows the mass spectrum of HYNIC-PSMA-XL-3.
  • Figure 5 shows the Radio-HPLC spectrum of 99m Tc-HYNIC/EDDA-PSMA-XL-2.
  • Figure 6 shows the Radio-HPLC spectrum of 99m Tc-HYNIC/EDDA-PSMA-XL-3.
  • Figure 7 shows the Radio-HPLC spectrum of 99m Tc-HYNIC/TPPTS-PSMA-XL-2.
  • Figure 8 is the Radio-HPLC spectrum of 99m Tc-HYNIC/TPPTS-PSMA-XL-3.
  • Figure 9 shows the in vitro stability of 99m Tc-HYNIC/EDDA-PSMA-XL-2 and 99m Tc-HYNIC/EDDA-PSMA-XL-3.
  • Figure 10 is a SPECT/CT image of 99m Tc-HYNIC/EDDA-PSMA-XL-2 on the LNCaP tumor model.
  • Figure 11 is the SPECT/CT image of 99m Tc-HYNIC/EDDA-PSMA-XL-3 on the LNCaP tumor model.
  • Figure 12 is a SPECT/CT image of 99m Tc-HYNIC/EDDA-PSMA-XL-2 on the PC-3 tumor model.
  • Figure 13 is a SPECT/CT image of 99m Tc-HYNIC/EDDA-PSMA-XL-3 on the PC-3 tumor model.
  • Figure 14 shows the in vivo distribution of 99m Tc-HYNIC/EDDA-PSMA-XL-3 in the LNCaP tumor model.
  • Figure 15 is a graph of target book ratio (TBR) of SPECT/CT imaging of different tissues in prostate cancer patients after injection of 99m Tc-HYNIC-PSMA-XL-3.
  • TBR target book ratio
  • Figure 16 Typical images of SPECT/CT imaging in patients with primary prostate cancer after injection of 99m Tc-HYNIC-PSMA-XL-3.
  • Figure 17 Typical images of SPECT/CT imaging in patients with multiple prostate cancer metastases all over the body after injection of 99m Tc-HYNIC-PSMA-XL-3.
  • Figure 18 is an immunohistochemical map of 99m Tc-HYNIC-PSMA-XL-3 SPECT/CT imaging of prostate cancer patients and corresponding surgical specimens. It showed that 99m Tc-HYNIC-PSMA-XL-3 SPECT/CT imaging lesions of prostate cancer patients were highly consistent with the immunohistochemical PSMA expression of the corresponding surgical specimens.
  • FIG. 19 The primary lesions of prostate cancer patients, the commonly used clinical PSMA molecular probes 99m Tc-HYNIC-ALUG and 68 Ga-PSMA11 have high physiological distribution in the bladder (A/B in Figure 19), affecting prostate tumors and bladder Physiological area discrimination.
  • the 99m Tc-HYNIC-PSMA-XL-3 of this patent has less radioactive distribution in the bladder (C in Figure 19), which can clearly distinguish prostate cancer lesions from normal tissue structures, and lays a foundation for further clinical puncture, surgery and other applications. Base.
  • SPR Surface Plasmon Resonance
  • Human prostate cancer LNCaP cells (PSMA positive) were cultured in RPMI1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin double antibody in a 5% CO 2 incubator at 37°C, maintaining saturated humidity, and cultured .
  • the cells are collected by 0.25% trypsinization, washed twice with PBS solution, and cultured as a cell suspension.
  • a cell line with a fixed number of cells was placed in each well of a 24-well cell culture dish, and the experiment was carried out after the logarithmic growth phase.
  • the intake experiment is divided into experimental group and blocking group. 0.5 ⁇ Ci complex 99m Tc-HYNIC/EDDA-PSMA-XL-2 or 99m Tc-HYNIC/EDDA-PSMA-XL-3 is added to each well, and the blocking group is half an hour earlier Excessive PSMA inhibitor 2-PMPA (1000 times molar equivalent) was added, and 6 groups of experiments were paralleled. After 1h, the culture solution was aspirated, placed in a gamma counter, washed 3 times with PBS, and the washing solution and culture solution were combined and stored. Then trypsinize the cells, collect the cells in another counting tube, measure the count with a gamma counter, and calculate the percentage of cell uptake. The results are shown in Table 2:
  • SCID mice male, weighing 18-20g, were provided by Shanghai Slack Laboratory Animal Co., Ltd. and raised in the SPF animal laboratory of the Laboratory Animal Department of Fudan University. After two days of adaptive feeding in the animal room, nude mice were injected with LNCaP human prostate cancer cells under the armpit.
  • the injection method was subcutaneous injection with a volume of 0.2ml (1 ⁇ 10 7 cells/ml dispersed in 50% Matrigel). After the injection, continue to culture for 4-6 weeks, and when the solid tumor mass grows to 500-600mm 3 , it will be used for imaging experiments.
  • mice Male, weighing 18-20g, were provided by Shanghai Slack Experimental Animal Co., Ltd. and raised in the SPF animal laboratory of the Experimental Animal Department of Fudan University. After two days of adaptive breeding in the animal room, the nude mice were injected with PC-3 human prostate cancer cells under the armpit.
  • the injection method was subcutaneous injection, and the injection volume was 0.2ml. After the injection, continue to culture for 4-6 weeks, and when the solid tumor mass grows to 500-600mm 3 , it will be used for imaging experiments.
  • Example 11 Study on the in vivo distribution of prostate tumor model mice
  • SCID mice male, weighing 18-20g, were provided by Shanghai Slack Laboratory Animal Co., Ltd. and raised in the SPF animal laboratory of the Laboratory Animal Department of Fudan University. After two days of adaptive feeding in the animal room, nude mice were injected with LNCaP human prostate cancer cells under the armpit.
  • the injection method was subcutaneous injection with a volume of 0.2ml (1 ⁇ 10 7 cells/ml dispersed in 50% Matrigel). After the injection, continue to culture for 4-6 weeks, and when the solid tumor mass grows to 500-600mm 3 , it will be used for the in vivo distribution experiment.
  • the 99m Tc-HYNIC/EDDA-PSMA-XL-3 complex of 20 ⁇ Ci/0.2ml was injected into the tumor mice through the tail vein. 0.5, 1 and 2 hours after the injection, the mice were anesthetized and killed. The organs and tissues were dissected and weighed, the radioactivity counts were measured, and the drug intake of each tissue was calculated. The results are shown in Figure 14.
  • SPECT/CT imaging was performed on 10 prostate cancer patients. These 10 patients included 5 newly diagnosed prostate cancer, 3 biochemical recurrence, and 2 hormone-resistant prostate cancer. The specific clinical information is shown in Table 3. The patients were injected with approximately 740MBq of 99m Tc-HYNIC-PSMA-XL-3 respectively, and checked on the computer with a Discovery 670 (GE, USA) scanner 2 hours later. The right obturator internal muscle was used as the background to calculate the target-to-cost ratio (TBR). The results are shown in Figure 15. It can be seen that the radioactivity distribution in the bladder is low, which is significantly lower than the tumor uptake, and the diagnostic efficiency for the primary tumor is excellent. A typical example is shown in Figure 16. In addition, tumor targeting is strong, and the detection value of lymph node/bone metastasis is very high. A typical example is shown in Figure 17.
  • a mouse monoclonal antibody against PSMA (clone 3E6, Dako) was used at a dilution of 1:100 and incubated overnight at 4°C, followed by immunoassay using Histostain-Plus detection kit (Invitrogen).
  • a Nanozoomer 2.0-HT Scansystem (Hamamatsu Photonics) was used to scan the stained section to generate a digital overall image. Pathological PSMA expression is consistent with SPECT/CT high uptake lesions. Typical cases are shown in Figure 18.

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Abstract

一种前列腺特异性膜抗原(PSMA)结合化合物，以及其放射性同位素络合物，以及它们在核医学中作为用于前列腺癌的各种疾病状态的示踪剂和成像剂的应用。

Description

一种PSMA结合剂及其用途 技术领域
本发明涉及一种放射性同位素标记的前列腺特异性膜抗原(PSMA)结合化合物，以及其前体化合物。所述化合物在核医学中作为用于前列腺癌的各种疾病状态的示踪剂和成像剂的应用的领域。本发明是以申请号为：202010140466.7、申请日为2020年03月03日的申请文件作为优先权文本的在后发明专利申请。
背景技术
前列腺癌(PCa)是全球范围内男性第二位最常见的癌症，其死亡率在男性癌症中排名第五，2018年全球因PCa死亡人数接近40万。转移、复发以及雄激素治疗抵抗是导致前列腺癌患者死亡的主要原因。目前临床上对于转移、复发和雄激素治疗抵抗性前列腺癌尚缺乏有效的诊断方法和治疗方案。传统解剖影像方法如计算机断层扫描(CT)、磁共振(MR)成像和超声均存在明显缺陷。分子成像可以从分子水平上理解肿瘤生理学，从而实现更精确的预后判断和疗效监测。 18F标记的脱氧葡萄糖(FDG)是临床最常用的分子影像探针，但由于PCa相对低代谢，所以 18F-FDG PET/CT对于PCa诊断价值有限。目前临床上正在探索其它放射性分子影像示踪剂对PCa进行检测，包括放射性标记的胆碱类药物( 11C-choline)、放射性标记的乙酸盐( 11C-acetate)、放射性标记的睾酮( 18F-FDHT)，抗-1-氨基-3-[ 18F]氟环丁基-1-羧酸( 18F-FACBC)和1-(2-脱氧-2-[18F]-氟-L-阿糖基呋喃糖基)-5-甲基尿嘧啶( 18F-FMAU)等。它们各自通过不同的机制来反映前列腺癌状态，但其中没有一种药物是理想的(即易于合成、极少泌尿系统代谢且具有肿瘤特异性摄取)。
前列腺特异性膜抗原(PSMA)是一种在前列腺癌细胞表面高度特异性表达的蛋白，在转移性激素抵抗型PCa中表达会进一步升高。由于转移性激素抵抗型PCa恶性程度高，预后差，且是PCa发展的必经阶段，，因此PSMA是非常优秀的一个PCa诊断和治疗的靶标。已经成功市场化的
Figure PCTCN2021086783-appb-000001
就是一款针对PSMA的单抗类核素显像剂，它早于上世纪90年代就被美国食品药品监督管理局(U.S.Food and Drug Administration，FDA)批准用于前列腺癌显像。然而
Figure PCTCN2021086783-appb-000002
和PSMA结合位点位于细胞膜内，主要结合肿瘤的坏死部分而不是活的肿瘤细胞，因此
Figure PCTCN2021086783-appb-000003
并未得到推广。
最近研究表明，基于谷氨酸-脲-谷氨酸(GUG)或谷氨酸-脲-赖氨酸(GUL)构建的一类小分子化合物呈现出PSMA的高亲和力，借助于各种放射性核素可用于前列腺癌的诊断和治疗。目前临床上进行实验性研究的一些化合物如 68Ga-PSMA11， 18F-DCFPyL， 18F-FDCBC， 99mTc-MIP-1404， 99mTc-HYNIC-ALUG等。然而这些化合物全部或部分从泌 尿系统排泄，会影响PCa原发灶及术后前列腺床局部复发的诊断。
发明内容
本发明满足了针对前列腺癌的新的组织特异性的化合物，以及它们在核医学中作为PCa的显像剂和示踪剂。特别地，本发明提供了与现有技术在修饰方面不同的成像剂，所述的成像剂在之前未知晓或者未被建议，旨在解决显像剂泌尿系统排泄，膀胱高摄取易掩盖肿瘤病灶的问题。
为解决上述问题，本发明涉及由以下通式(Ⅰ)表示的化合物：
Figure PCTCN2021086783-appb-000004
其中：
m是0至5的整数；
n是0至5的整数；
f，g为0或者1；
R和R'各自独立选自H、烷基、卤素、-CN、-OH、-NH 2、烷氧基或者环烷基；
Q为-COOH、-SOOH、-SO 3H、-SO 4H、-POOH、-PO 3H或-PO 4H 2；
X为任选被取代的芳基、杂芳基，所述取代为被至少一个R基团取代；
Y为任选被取代的芳基、任选被取代的杂环芳基、任选被取代的环烷基、或任选被取代的杂环烷基，所述取代为被至少一个R基团取代；
AA 1为天然或非天然氨基酸、或-CH 2CH 2-。
进一步地，所述式(I)为式(I-1)所示化合物：
Figure PCTCN2021086783-appb-000005
进一步地，所述R和R'各自独立选自H、C 1-C 10烷基；
所述X为任选被取代的苯基、奈基、联苯基、吲哚基、苯并噻唑基或喹啉基；
所述任选被取代的杂环烷基选自N-哌啶基或N-甲基化的哌啶基盐。
在此基础上，本发明还提供一种放射性核素配合物，所述的配合物可用于靶组织SPECT/CT显像。
具体地说，所述的放射性核素配合物包含放射性核素和本发明所述的PSMA小分子抑制剂，其具有通式(Ⅱ)所示的结构：
Figure PCTCN2021086783-appb-000006
其中：Q、R、X、f、Y、g、m、R’、AA 1、n如上所定义，
L为N-三(羟甲基)甲基甘氨酸、乙二胺-N,N'-二乙酸、三苯基膦三间磺酸盐、3,3'-(苯基膦二基)二(苯-1-磺酸)二钠，二苯基膦苯-3-磺酸钠、烟酸、葡庚糖酸盐，葡糖胺、甘露糖醇、或二苯基膦苯甲酸。
进一步地，所述配合物为式(II-1)所示化合物：
Figure PCTCN2021086783-appb-000007
如果没有另行说明，在本发明中，术语“烷基”本身或作为另一分子的一部分，是指直链或支链或环状烃基、或它们的组合，其可以是完全饱和的、单或多不饱和的，以及可以包括二价和多价基团。“烷基”残基优选是C 1至C 10并且可以是未取代或取代的(例如用卤素)。优选的烷基残基是甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、正己基、正庚基或正辛基等。这同样也适用于优选具有3至10个碳原子的相应的环烷基化合物，例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。不饱和烷基是具有一个或多个双键或三键的烷基。不饱和烷基的实例包括但不限于乙烯基、2-丙烯基、2-丁烯基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基、3-丁炔基、以及高级同系物和异构体。除非另有说明，否则术语"烷基"还用来包括烷基的那些衍生物，如"杂烷基"、"卤代烷基"和"高烷基"。
如在本文中所使用的，术语"芳基"是指闭环结构，其具有至少一个具有共轭π电子系统的环并且包括碳环芳基和杂环芳基(或"杂芳基"或"杂芳族的")基团。碳环或杂环芳族基团可以含有5至20个环原子。上述术语包括共价连接的单环或稠环多环(即，共享相邻对的碳原子的环)基团。芳族基团可以是未取代或取代的。"芳族"或"芳基"基团的非限制性实例包括苯基、1-萘基、2-萘基、2-联苯基、3-联苯基、4-联苯基、蒽基和菲基。用于每种上述芳基和杂芳基环系统的取代基选自本文中所描述的可接受的取代基(例如烷基、羰基、羧基或卤素)。当连同其他术语(包括但不限于芳氧基、芳硫氧基、芳烷基)一起使用时，术语"芳基"包括芳基和杂芳基环。因此，术语"芳烷基"或"烷芳基"用来包括那些基团，其中芳基连接于烷基(包括但不限于苄基、苯乙基、吡啶基甲基等)，其包括那些烷基，其中碳原子(包括但不限于亚甲基)已被杂原子取代，仅作为示例，被氧原子取代。这样的芳基的实例包括但不限于苯氧基甲基、2-吡啶氧基甲基、3-(1-萘氧基)丙基等。
“杂芳基"是指这样的芳基，其含有至少一个选自N、O和S的杂原子；其中氮和硫原子可以被可选地氧化，而氮原子可以被可选地季铵化。杂芳基可以是取代或未取代的。可以通过杂原子将杂芳基连接于分子的剩余部分。适宜的基团的非限制性实例包括1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-噁唑基、4-噁唑基、2-苯基-4-噁唑基、5-噁唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、4-苯并噻唑基、5-苯并噻唑基、6-苯并噻唑基、7-苯并噻唑基、嘌呤基、2-苯并咪唑基、4-吲哚基、5-吲哚基、6-吲哚基、7-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、2-喹啉基、3-喹啉基、4-喹啉基、5-喹啉基、6-喹啉基、7-喹啉基或8-喹啉基。
术语"氨基酸"是指天然存在和非天然氨基酸，以及以类似于天然存在的氨基酸的方式起作用的氨基酸类似物和氨基酸模拟物。天然氨基酸是20种常见的处于它们的D-或L-形式的氨基酸(丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、 甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、蛋氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸)以及吡咯赖氨酸和硒代半胱氨酸。氨基酸类似物是指这样的化合物，其具有和天然存在的氨基酸相同的基本化学结构，仅作为示例，离碳(ex-carbon)，其结合于氢、羧基、氨基和R基团。这样的类似物可以具有经修饰的R基团(通过举例的方式，正亮氨酸)或可以具有经修饰的肽主链，同时仍保留和天然存在的氨基酸相同的基本化学结构。氨基酸类似物的非限制性实例包括高丝氨酸、正亮氨酸、蛋氨酸亚砜、甲硫氨酸甲基锍。在本文中可以通过它们的名称、它们的通常已知的三字母符号或通过单字母符号(由IUPAC-IUB生化命名委员会推荐的)来提及氨基酸。"非天然氨基酸"是指这样的氨基酸，其不是20种常见氨基酸或吡咯赖氨酸或硒代半胱氨酸的之一。可以与术语"非天然氨基酸"同义使用的其他术语是"非天然编码的氨基酸"、"非天然氨基酸"、"非天然存在的氨基酸"或“人造氨基酸"。术语"非天然氨基酸"包括但不限于这样的氨基酸，其是通过对天然编码氨基酸在它们的主链或侧链中的修饰而发生。在一些实施方式中，非天然氨基酸包含羰基、乙酰基、氨氧基、肼基团、酰肼基团、氨基脲基、叠氮基或炔基。在一种优选实施方式中，AA 1具有以下化学式：
Figure PCTCN2021086783-appb-000008
其中
Figure PCTCN2021086783-appb-000009
并且R'＝H、COOH、CH 2COOH、C 2H 4COOH、CH(COOH) 2、CH(CH2COOH) 2、CH(COOH)(CH 2COOH)、CH 2CH(COOH) 2、或SO 3H；
i＝1-3；R＝H、CH 3。
优选的是将亲水元素带入通式I的化合物的那些氨基酸。
本文中的一些残基(包括但不限于非天然氨基酸)可以以若干互变异构形式而存在。所有这样的互变异构形式被视为本文中所描述的化合物的一部分。另外，本文中任何化合物的所有烯醇酮形式被视为本文中所描述的组合物的一部分。
可以在分子内通过肽或酰胺键结合AA 1，即，天然氨基酸和/或非天然存在的氨基酸。然而，在酸性氨基酸(例如谷氨酸、天冬氨酸)的情况下，结合可替代地经由α-、β或γ-位置。
尽管优选的是Z基团是–COOH，但它可以容易被生物空(biosteric)替代物如-SO 2H、-SO 3H、-SO 4H、-PO 2H、-PO 3H、-PO 4H 2所替换，见例如“The Practice of Medicinal Chemistry”(Academic Press New York,1996),page 203。
在本发明的含义内，除非在残基的定义中另有说明，否则所有残基被认为是可组合的。认为披露了它们的所有可以想象的亚组。
根据本发明，所有手性C原子应具有D-和/或L-构型；此外在一种化合物内的组合应 该是可能的，即一些手性C原子可以是D-构型而其他手性C原子可以是L-构型。
本发明提供的式(I)化合物，可优选自，但不限于具下述结构的化合物：
Figure PCTCN2021086783-appb-000010
Figure PCTCN2021086783-appb-000011
Figure PCTCN2021086783-appb-000012
Figure PCTCN2021086783-appb-000013
Figure PCTCN2021086783-appb-000014
Figure PCTCN2021086783-appb-000015
Figure PCTCN2021086783-appb-000016
Figure PCTCN2021086783-appb-000017
Figure PCTCN2021086783-appb-000018
Figure PCTCN2021086783-appb-000019
Figure PCTCN2021086783-appb-000020
Figure PCTCN2021086783-appb-000021
本发明提供的式(II)的配合物，可优选自，但不限于下述结构的配合物：
Figure PCTCN2021086783-appb-000022
Figure PCTCN2021086783-appb-000023
Figure PCTCN2021086783-appb-000024
Figure PCTCN2021086783-appb-000025
Figure PCTCN2021086783-appb-000026
Figure PCTCN2021086783-appb-000027
Figure PCTCN2021086783-appb-000028
Figure PCTCN2021086783-appb-000029
Figure PCTCN2021086783-appb-000030
Figure PCTCN2021086783-appb-000031
Figure PCTCN2021086783-appb-000032
Figure PCTCN2021086783-appb-000033
其中：
L为N-三(羟甲基)甲基甘氨酸、乙二胺-N,N'-二乙酸、三苯基膦三间磺酸盐、3,3'-(苯基膦二基)二(苯-1-磺酸)二钠，二苯基膦苯-3-磺酸钠、烟酸、葡庚糖酸盐，葡糖胺、甘露糖醇、或二苯基膦苯甲酸。
本发明提供的上述化合物或配合物，可在患者中成像的方法中使用，在诊断前列腺癌和/或其转移灶的方法中使用，或在治疗前列腺癌和/或其转移灶的方法中使用。
本发明还提供一种药物组合，所述药物组合物包括前述的化合物或配合物，或其药用前药、盐或酯，以及药用载体。此类药物组合物可在患者中成像的方法中使用，在诊断前列腺癌和/或其转移灶的方法中使用，或在治疗前列腺癌和/或其转移灶的方法中使用。
本发明的通式(Ⅱ)的 99mTc配合物可用于前列腺癌和/或其转移灶的SPECT/CT显像，为前列腺癌的诊断提供新方法。本发明通过对PSMA药效基团和放射性配位基团中间连接体的修饰，调节整体化合物的亲脂性，提高化合物通过肝胆代谢的比例，减低泌尿系统的排泄，从而避免生理性摄取对显像结果的不良影响。相比于其他重要的PSMA SPECT示踪剂，本发明的化合物，特别是 99mTc-HYNIC-PSMA-XL-3突出的低尿清除使得能极好地评估前列腺癌。因此，根据本发明的示踪剂完全适合于前列腺癌原发和复发的初步诊断。
附图说明
图1为HYNIC-PSMA-XL-2的HPLC紫外谱图。
图2为HYNIC-PSMA-XL-2的质谱谱图。
图3为HYNIC-PSMA-XL-3的HPLC紫外谱图。
图4为HYNIC-PSMA-XL-3的质谱谱图。
图5为 99mTc-HYNIC/EDDA-PSMA-XL-2的Radio-HPLC谱图。
图6为 99mTc-HYNIC/EDDA-PSMA-XL-3的Radio-HPLC谱图。
图7为 99mTc-HYNIC/TPPTS-PSMA-XL-2的Radio-HPLC谱图。
图8为 99mTc-HYNIC/TPPTS-PSMA-XL-3的Radio-HPLC谱图。
图9为 99mTc-HYNIC/EDDA-PSMA-XL-2和 99mTc-HYNIC/EDDA-PSMA-XL-3体外稳定性。
图10为 99mTc-HYNIC/EDDA-PSMA-XL-2对LNCaP肿瘤模型的SPECT/CT显像图。
图11为 99mTc-HYNIC/EDDA-PSMA-XL-3对LNCaP肿瘤模型的SPECT/CT显像图。
图12为 99mTc-HYNIC/EDDA-PSMA-XL-2对PC-3肿瘤模型的SPECT/CT显像图。
图13为 99mTc-HYNIC/EDDA-PSMA-XL-3对PC-3肿瘤模型的SPECT/CT显像图。
图14为 99mTc-HYNIC/EDDA-PSMA-XL-3在LNCaP肿瘤模型中的体内分布图。
图15为前列腺癌患者注射 99mTc-HYNIC-PSMA-XL-3后SPECT/CT显像不同组织的靶本比值(TBR)图。
图16原发前列腺癌患者注射 99mTc-HYNIC-PSMA-XL-3后SPECT/CT显像典型图像。
图17全身多处转移前列腺癌患者注射 99mTc-HYNIC-PSMA-XL-3后SPECT/CT显像典型图像。
图18为前列腺癌患者 99mTc-HYNIC-PSMA-XL-3 SPECT/CT显像病灶和相应手术标本免疫组化图。显示前列腺癌患者 99mTc-HYNIC-PSMA-XL-3 SPECT/CT显像病灶与对应手术标本免疫组化PSMA表达高度一致。
图19前列腺癌患者原发病灶，临床常用PSMA分子探针 99mTc-HYNIC-ALUG和 68Ga-PSMA11均在膀胱内有较高生理性分布(图19中的A/B)，影响前列腺肿瘤与膀胱生理性区域分辨。而本专利的 99mTc-HYNIC-PSMA-XL-3，膀胱内放射性分布较少(图19中的C)，可以明显区分前列腺癌病灶和正常组织结构，为进一步的临床穿刺、手术等应用打下基础。
实施例
下面的实施例更纤细地解释了本发明，但是不以任何方式解释为本发明仅限制于举例说明的实施方式。
实施例1
Glu-Urea-Lys-2NaI-AMB-Glu-Glu-HYNIC(HYNIC-PSMA-XL-2)的合成
采用固相合成法合成，以2-CTC树脂固定的2mmol叔丁酯保护的谷氨酸为起始原料，加入2mol N,N'-羰基二咪唑，室温下反应过夜，DMF洗去未反应的N,N'-羰基二咪唑，然后加入三氟甲(烷)磺酸甲酯和三乙胺反应1h，然后在加入Fmoc-Lys(OtBu)-NH 2反应2h。之后在DMF中，以1.96mmol的HOBt和2mmol的DIC作为酰胺化催化剂，依次加入2mmol的Fmoc-2NaI-OH，Fmoc-4-氨甲基-苯甲酸，Fmoc-Glu(OtBu)-OH，Fmoc-Glu(OtBu)-OH和Boc-HYNIC。最后用三氟乙酸、三异丙基硅烷和水(95/2.5/2.5)组成的混合物去除保护 和2-CTC树脂，得到粗产品。
所得粗产品用制备型RP-HPLC分离纯化，并通过分析型RP-HPLC和LC-MS来分析纯化后产品。其HPLC谱图见图1所示，质谱图见图2所示。
Figure PCTCN2021086783-appb-000034
HYNIC-PSMA-XL-2合成反应式
实施例2
Glu-Urea-Lys-2NaI-AMB-Glu-HYNIC(HYNIC-PSMA-XL-3)的合成
采用固相合成法合成，以2-CTC树脂固定的2mmol叔丁酯保护的谷氨酸为起始原料，加入2mol N,N'-羰基二咪唑，室温下反应过夜，DMF洗去未反应的N,N'-羰基二咪唑，然后加入三氟甲(烷)磺酸甲酯和三乙胺反应1h，然后在加入Fmoc-Lys(OtBu)-NH 2反应2h。之后在DMF中，以1.96mmol的HOBt和2mmol的DIC作为酰胺化催化剂，依次加入2mmol的Fmoc-2NaI-OH，Fmoc-4-氨甲基-苯甲酸，Fmoc-Glu(OtBu)-OH和Boc-HYNIC。最后用三氟乙酸、三异丙基硅烷和水(95/2.5/2.5)组成的混合物去除保护和2-CTC树脂，得到粗产品。
所得粗产品用制备型RP-HPLC分离纯化，并通过分析型RP-HPLC和LC-MS来分析纯化后产品。其HPLC谱图见图3所示，质谱图见图4所示。
Figure PCTCN2021086783-appb-000035
HYNIC-PSMA-XL-3合成反应式
实施例3
HYNIC-PSMA-XL-2和HYNIC-PSMA-XL-3亲和力测定
采用表明等离子共振(Surface Plasmon Resonance,SPR)测定HYNIC-PSMA-XL-2和HYNIC-PSMA-XL-3与PSMA蛋白的结合力。因HYNIC-PSMA-XL-2和HYNIC-PSMA-XL-3解离均非常慢，kd均超出仪器检测限(1E-6)，根据ka结果计算得出最终HYNIC-PSMA-XL-2结合PSMA蛋白的KD值应小于6.43pM，HYNIC-PSMA-XL-3结合PSMA蛋白的KD值应小于4.857pM。为与已报道PSMA抑制剂对比，同时以相同方法测定了PSMA11，19F-PSMA1007，2-PMPA以及本课题组公开报道的HYNIC-ALUG化合物。具体KD值见表1。
表1不同PSMA抑制剂与PSMA亲和KD值
化合物 KD值(SPR方法)
HYNIC-PSMA-XL-2 <6.43pM
HYNIC-PSMA-XL-3 <4.897pM
2-PMPA 9.868nM
PSMA11 1.255nM
19F-PSMA1007 64.92nM
HYNIC-ALUG 299.4nM
结果证实HYNIC-PSMA-XL-2和HYNIC-PSMA-XL-3与PSMA的亲和力要远远大于已报道化合物。
实施例4
99mTc-HYNIC/EDDA-PSMA-XL-2配合物的制备：
取1μg HYNIC-PSMA-XL-2，5mg乙二胺-N,N'-二乙酸，50mg琥珀酸二钠，30mg琥珀酸，20mg Tricine，100mg甘露醇和30μg氯化亚锡加入1ml无菌注射水溶解，然后加入0.5ml Na 99mTcO 4淋洗液(1100MBq)，沸水浴反应20min，即得目标化合物 99mTc-HYNIC/EDDA-PSMA-XL-2，采用Radio-HPLC测定其放射化学纯度大于99％，相关分析谱图见图5所示。
Figure PCTCN2021086783-appb-000036
99mTc-HYNIC/EDDA-PSMA-XL-2合成反应式
实施例5
99mTc-HYNIC/EDDA-PSMA-XL-3配合物的制备：
取10μg HYNIC-PSMA-XL-3，50mg乙二胺-N,N'-二乙酸，20mg琥珀酸二钠，10mg琥珀酸，1mg Tricine，40mg甘露醇和500μg氯化亚锡加入0.5ml无菌注射水溶解，然后加入2ml Na 99mTcO 4淋洗液(1100MBq)，沸水浴反应20min，即得目标化合物 99mTc-HYNIC/EDDA-PSMA-XL-3，采用Radio-HPLC测定其放射化学纯度大于99％，，相关分析谱图见图6所示。
Figure PCTCN2021086783-appb-000037
99mTc-HYNIC/EDDA-PSMA-XL-3合成反应式
实施例6： 99mTc-HYNIC/TPPTS-PSMA-XL-2配合物的制备
取50μg HYNIC-PSMA-XL-2，1mg三苯基膦三间磺酸盐，35mg琥珀酸二钠，5mg琥珀酸，15mg Tricine和10μg氯化亚锡加入0.8ml无菌注射水溶解，然后加入1ml  Na 99mTcO 4淋洗液(1100MBq)，沸水浴反应20min，即得目标化合物 99mTc-HYNIC/TPPMS-PSMA-XL-2，采用Radio-HPLC测定其放射化学纯度大于99％，相关分析谱图见图7所示。
Figure PCTCN2021086783-appb-000038
99mTc-HYNIC/TPPTS-PSMA-XL-2合成反应式
实施例7： 99mTc-HYNIC/TPPTS-PSMA-XL-3配合物的制备
取100μg HYNIC-PSMA-XL-3，25mg三苯基膦三间磺酸盐，45mg琥珀酸二钠，20mg琥珀酸和50mg Tricine和60mg甘露醇加入2ml无菌注射水溶解，然后加入1ml Na 99mTcO 4淋洗液(1100MBq)，沸水浴反应20min，即得目标化合物 99mTc-HYNIC/TPPMS-PSMA-XL-3，采用Radio-HPLC测定其放射化学纯度大于99％，相关分析谱图见图8所示。
Figure PCTCN2021086783-appb-000039
99mTc-HYNIC/TPPTS-PSMA-XL-3合成反应式
实施例8
配合物体外稳定性实验：
取一定量 99mTc-HYNIC/EDDA-PSMA-XL-2和 99mTc-HYNIC/EDDA-PSMA-XL-3分别加入到PBS以及新鲜小鼠血清中，于不同时间点测定放射化学纯度，检测两个配合物的稳定性。结果见图9,6h后两个配合物放射化学纯度均大于90％，保持较高稳定性。
实施例9
细胞摄取实验：
人前列腺癌LNCaP细胞(PSMA阳性)在含10％胎牛血清、1％青霉素－链霉素双抗的RPMI1640培养液中，于37℃的5％CO 2培养箱中培养，保持饱和湿度，培养。细胞于对数期时，用0.25％胰酶消化收集细胞，经PBS液洗涤2次，制成细胞悬液培养。在24孔细胞培养皿每个孔置入固定细胞数的细胞株(1.0×10 6cell/1ml)，经对数生长期后进行实验。
摄取实验分实验组和阻断组，每孔加入0.5μCi配合物 99mTc-HYNIC/EDDA-PSMA-XL-2或者 99mTc-HYNIC/EDDA-PSMA-XL-3，其中阻断组提前半小时加入过量的PSMA抑制剂2-PMPA(1000倍摩尔当量)，平行6组实验。1h后将培液吸出，置于γ计数管中，PBS洗涤3次，洗涤液和培液合并保存。然后胰酶消化细胞，将细胞收集于另一计数管中，采用γ计数器测定计数，计算细胞摄取百分比，结果见表2：
表2 LNCaP细胞摄取实验结果
化合物 实验组 阻断组
HYNIX-PSMA-XL-2 16.54±1.33％ 3.07±0.80％
HYNIX-PSMA-XL-3 14.01±1.11％ 2.66±0.51％
结果表明 99mTc-HYNIX-PSMA-XL-2和 99mTc-HYNIX-PSMA-XL-3均能高度特异性结合PSMA阳性的LNCaP细胞。
实施例10
SPECT显像研究：
SCID小鼠，雄性，体重18～20g，由上海斯莱克实验动物有限公司提供，在复旦大学实验动物部SPF级动物实验室饲养。在动物房适应性饲养两天后，于裸鼠腋下注射LNCaP人前列腺癌细胞，注射方式为皮下注射，注射量为0.2ml(1×10 7cells/ml分散于50％基质胶中)。注射后继续培养4-6周，待实体瘤块长至500-600mm 3时用于显像实验。
通过尾静脉注射1mCi/0.2ml的 99mTc-HYNIC/EDDA-PSMA-XL-2或 99mTc-HYNIC/EDDA-PSMA-XL-3配合物至肿瘤鼠体内。注射后2小时用小动物SPECT/CT对实验动物进行成像实验。成像图见附图10和图11。
Balb/c裸小鼠，雄性，体重18～20g，由上海斯莱克实验动物有限公司提供，在复旦大学实验动物部SPF级动物实验室饲养。在动物房适应性饲养两天后，于裸鼠腋下注射PC-3人前列腺癌细胞，注射方式为皮下注射，注射量为0.2ml。注射后继续培养4-6周，待实体瘤块长至500-600mm 3时用于显像实验。
通过尾静脉注射1mCi/0.2ml的 99mTc-HYNIC/EDDA-PSMA-XL-2或 99mTc-HYNIC/EDDA-PSMA-XL-3配合物至肿瘤鼠体内。注射后2小时用小动物SPECT/CT对实验动物进行成像实验。成像图见附图12和图13。
实施例11：前列腺肿瘤模型鼠体内分布研究
SCID小鼠，雄性，体重18～20g，由上海斯莱克实验动物有限公司提供，在复旦大 学实验动物部SPF级动物实验室饲养。在动物房适应性饲养两天后，于裸鼠腋下注射LNCaP人前列腺癌细胞，注射方式为皮下注射，注射量为0.2ml(1×10 7cells/ml分散于50％基质胶中)。注射后继续培养4-6周，待实体瘤块长至500-600mm 3时用于体内分布实验。
通过尾静脉注射20μCi/0.2ml的 99mTc-HYNIC/EDDA-PSMA-XL-3配合物至肿瘤鼠体内。注射后0.5，1和2小时后麻醉处死小鼠，解剖取各个脏器组织称重并测量放射性计数，计算各组织的药物摄取，结果见图14。
实施例12
99mTc-HYNIC-PSMA-XL-3冻干药盒制备：
1mg HYNIX-PSMA-XL-3，1g琥珀酸二钠，0.3g琥珀酸，1g Tricine，0.5g EDDA，10mg SnCl 2，加灭菌注射用水水溶解，定容至100ml。混合溶液经无菌Millipore过滤除菌，等待分装。
取上述溶液1ml置于10ml无菌西林瓶中，供分装100瓶，于氮气保护下冷冻干燥，结束后压盖保存。
随机抽取冻干药盒进行无菌以及细菌内毒素检查。
实施例13
供人类应用的 99mTc-HYNIC-PSMA-XL-3
取 99mTc-HYNIC-PSMA-XL-3冻干药盒一瓶，加入30-100mCi Na99mTcO 4溶液，100℃反应10min。通过放射性TLC测定 99mTc-HYNIX-PSMA-XL-3的放射化学纯度。通过半衰期测量以及γ能谱法控制放射性核素纯度。测定产物溶液的pH值，澄清度，放射性浓度以及无菌和细菌内毒素。
实施例14
在前列腺癌患者中应用 99mTc-HYNIX-PSMA-XL-3。
对10位前列腺癌患者进行SPECT/CT显像，这10位患者包括初诊前列腺癌5例，生化复发3例，激素抵抗性前列腺癌2例，具体临床信息见表3。患者分别注射约740MBq 99mTc-HYNIC-PSMA-XL-3，2小时后采用Discovery 670(GE，美国)扫描器上机检查。以右侧闭孔内肌作为本底，计算靶本比值(TBR)，结果见图15。可以看出膀胱内放射性分布较低，明显低于肿瘤摄取，对于原发灶的诊断效能优良，典型示例见图16。除此之外，肿瘤靶向性强，对淋巴结/骨等转移灶的探测价值很高，典型示例见图17。
表3 10例前列腺癌患者的临床特征
Figure PCTCN2021086783-appb-000040
Figure PCTCN2021086783-appb-000041
5位初诊前列腺癌患者中4位接受了前列腺癌根治术，3例生化复发患者中1例接受了挽救性淋巴结清扫。在未知 99mTc-HYNIC-PSMA-XL-3 SPECT/CT的结果下，病理专科医师进行样本病理分析。通过免疫组化染色代表性切片，在二甲苯中对切片进行脱蜡以及在分级乙醇系列中加入再水化。借助于蒸汽锅，并利用修复缓冲液(Target Retrieval Solution，Dako)来进行抗原修复。以1：100稀释度使用针对PSMA的小鼠单克隆抗体(克隆3E6，Dako)并在4℃下温育过夜，随后利用Histostain-Plus检测试剂盒(Invitrogen)进行免疫检测。利用Nanozoomer 2.0-HT Scansystem(Hamamatsu Photonics)来扫描染色的切片以生成数字整体图像。病理PSMA表达与SPECT/CT高摄取病灶一致性强，典型病例见图18。
实施例15
99mTc-HYNIC-PSMA-XL-3与现有临床常用PSMA类显像剂对比研究
选择15例前列腺癌患者，随机平分为3组。一组行 99mTc-HYNIC-ALUG SPECT/CT，一组行 68Ga-PSMA11 PET/CT，一组行 99mTc-HYNIC-PSMA-XL3 SPECT/CT。结果显示 99mTc-HYNIC-ALUG SPECT/CT和 68Ga-PSMA11 PET/CT显像膀胱均呈现较高放射性生理性分 布(图19中的A，B)，影响前列腺肿瘤与膀胱生理性区域分辨。而 99mTc-HYNIC-PSMA-XL3SPECT/CT膀胱内放射性分布极低(图19中的C)，可以清晰区分前列腺病灶和正常组织结构，为进一步的临床穿刺、手术等应用打下基础。
实施例16
99mTc-HYNIC-PSMA-XL-3 SPECT/CT和 68Ga-PSMA11 PET/CT对比
选择10例前列腺癌生化复发患者，随机平均分为2组，2组人群临床基本信息相似，均是经过前列腺癌根治性手术后，目前PSA在1-3ng/ml，GS评分8-9分。一组行68Ga-PSMA11 PET/CT，另一组行 99mTc-PSMA-XL SPECT/CT。
表4 10例前列腺癌患者的临床特征及检查方式
编号 PSA GS 检查方式 病灶个数 有无局部复发
1 1.2 8 68Ga-PSMA11 2 无
2 2.2 8 68Ga-PSMA11 1 无
3 2.5 9 68Ga-PSMA11 4 有
4 0.8 8 68Ga-PSMA11 0 无
5 1.7 9 68Ga-PSMA11 1 无
6 2.4 9 99mTc-PSMA-XL 3 有
7 0.6 8 99mTc-PSMA-XL 1 无
8 2.1 8 99mTc-PSMA-XL 2 无
9 1.6 8 99mTc-PSMA-XL 0 无
10 0.7 9 99mTc-PSMA-XL 4 无
经过此10例患者的初步统计，68Ga-PSMA11和99mTc-PSMA-XL显像的阳性率均为80％，且同时均发现1例患者出现前列腺窝的局部复发。在这组患者中99mTc-PSMA-XL显像并不劣于68Ga-PSMA11，今后进一步扩大样本量，设计前瞻性随机对照临床试验来佐证。
文中英文缩写含义如表5所示：
Figure PCTCN2021086783-appb-000042
Figure PCTCN2021086783-appb-000043
本文描述了包括用于实施本发明的本发明人已知的最佳模式的本发明的优选实施方案。在阅读前述描述之后，那些优选的实施方案的变化形式对于本领域的普通技术人员而言可以变得明显。本发明人预期技术人员适当地利用这样的变化形式，并且本发明人意图本发明与如本文特别描述的不同地被实施。因此，如被可适用的法律允许，本发明包括在此所附的权利要求中所叙述的主题的所有的变型和等效物。此外，除非本文另外指出或另外明显地与上下文矛盾，否则上面所描述的要素以其所有可能的变化形式的任何组合被本发明包括。

Claims (18)

  1. 一种式(I)的化合物或其药用盐、前药或酯，其特征在于，所述式(I)为：
    Figure PCTCN2021086783-appb-100001
    其中：
    m是0至5的整数；
    n是0至5的整数；
    f，g为0或者1；
    R和R'各自独立选自H、烷基、卤素、-CN、-OH、-NH 2、烷氧基或者环烷基；
    Q为-COOH、-SOOH、-SO 3H、-SO 4H、-POOH、-PO 3H或-PO 4H 2；
    X为任选被取代的芳基、杂芳基，所述取代为被至少一个R基团取代；
    Y为任选被取代的芳基、任选被取代的杂环芳基、任选被取代的环烷基、或任选被取代的杂环烷基，所述取代为被至少一个R基团取代；
    AA 1为天然或非天然氨基酸、或-CH 2CH 2-。
  2. 根据权利要求1所述式(I)化合物或其药用盐、前药或酯，,其特征在于：所述式(I)为式(I-1)所示化合物：
    Figure PCTCN2021086783-appb-100002
  3. 根据权利要求1或2所述式(I)化合物或其药用盐、前药或酯，其特征在于：
    所述R和R'各自独立选自H、C 1-C 10烷基；
    所述X为任选被取代的苯基、奈基、联苯基、吲哚基、苯并噻唑基或喹啉基；
    所述任选被取代的杂环烷基选自N-哌啶基或N-甲基化的哌啶基盐。
  4. 根据权利要求1或2所述式(I)化合物或其药用盐、前药或酯，其特征在于：
    所述AA 1为
    Figure PCTCN2021086783-appb-100003
    其中
    Figure PCTCN2021086783-appb-100004
    并且R'＝H、COOH、CH 2COOH、C 2H 4COOH、CH(COOH) 2、CH(CH2COOH) 2、CH(COOH)(CH 2COOH)、CH 2CH(COOH) 2、SO 3H；
    i＝1-3；R＝H、CH 3。
  5. 根据权利要求1或2所述的化合物，具有以下结构：
    Figure PCTCN2021086783-appb-100005
    Figure PCTCN2021086783-appb-100006
    Figure PCTCN2021086783-appb-100007
    Figure PCTCN2021086783-appb-100008
    Figure PCTCN2021086783-appb-100009
    Figure PCTCN2021086783-appb-100010
    Figure PCTCN2021086783-appb-100011
    Figure PCTCN2021086783-appb-100012
    Figure PCTCN2021086783-appb-100013
    Figure PCTCN2021086783-appb-100014
    Figure PCTCN2021086783-appb-100015
    Figure PCTCN2021086783-appb-100016
  6. 如权利要求1所述的式(I)的化合物的99mTc配合物，结构如式(II)：
    Figure PCTCN2021086783-appb-100017
    其中，Q、R、X、f、Y、g、m、R’、AA 1、n如权利要求1所定义，L为N-三(羟甲基)甲基甘氨酸、乙二胺-N,N'-二乙酸、三苯基膦三间磺酸盐、3,3'-(苯基膦二基)二(苯-1-磺酸) 二钠，二苯基膦苯-3-磺酸钠、烟酸、葡庚糖酸盐，葡糖胺、甘露糖醇、或二苯基膦苯甲酸。
  7. 根据权利要求6所述配合物,其特征在于：其为式(II-1)所示化合物：
    Figure PCTCN2021086783-appb-100018
  8. 根据权利要求6或7所述配合物，其特征在于：
    所述R和R'各自独立选自H、C 1-C 10烷基；
    所述X为任选被取代的苯基、奈基、联苯基、吲哚基、苯并噻唑基或喹啉基；
    所述任选被取代的杂环烷基选自N-哌啶基或N-甲基化的哌啶基盐。
  9. 根据权利要求6或7所述配合物，其特征在于：
    所述AA 1为
    Figure PCTCN2021086783-appb-100019
    其中
    Figure PCTCN2021086783-appb-100020
    并且R'＝H、COOH、CH 2COOH、C 2H 4COOH、CH(COOH) 2、CH(CH2COOH) 2、CH(COOH)(CH 2COOH)、CH 2CH(COOH) 2、SO 3H；
    i＝1-3；R＝H、CH 3。
  10. 根据权利要求6或7所述配合物，其特征在于：选自以下化合物
    Figure PCTCN2021086783-appb-100021
    Figure PCTCN2021086783-appb-100022
    Figure PCTCN2021086783-appb-100023
    Figure PCTCN2021086783-appb-100024
    Figure PCTCN2021086783-appb-100025
    Figure PCTCN2021086783-appb-100026
    Figure PCTCN2021086783-appb-100027
    Figure PCTCN2021086783-appb-100028
    Figure PCTCN2021086783-appb-100029
    Figure PCTCN2021086783-appb-100030
    Figure PCTCN2021086783-appb-100031
  11. 一种如权利要求6-10所述化合物的制备方法，其特征在于：配制含权利要求1和2任一项化合物1-100μg，氯化亚锡0-500μg，配体L 1-50mg，琥珀酸二钠20-50mg，琥珀酸5-30mg，甘露醇0-100mg的混合液0.5-2ml于10mL西林瓶中，加入0.5-2mL的Na 99mTcO 4溶液(10-100mCi)，100℃水浴加热西林瓶反应10-20分钟，待反应结束后室温冷却10分钟，制成权利要求6-10所述化合物；
    其中，配体L选自选自N-三(羟甲基)甲基甘氨酸、乙二胺二乙酸、三苯基膦三间磺酸盐、3,3'-(苯基膦二基)二(苯-1-磺酸)二钠，二苯基膦苯-3-磺酸钠、烟酸、葡庚糖酸盐，葡糖胺、甘露糖醇、二苯基膦苯甲酸。
  12. 一种药物组合，所述药物组合物包括如权利要求1至10中任一项所述的化合物 或配合物，或其药用盐、前药或酯，以及药用载体。
  13. 如权利要求1至10中任一项所述的化合物或配合物或其药用盐、前药或酯在制备用于在患者中成像的试剂的应用。
  14. 如权利要求1至10中任一项所述的化合物或配合物或其药用盐、前药或酯在制备用于诊断前列腺癌和/或其转移灶的试剂的应用。
  15. 如权利要求1至10中任一项所述的化合物或配合物或其药用盐、前药或酯在制备用于在治疗前列腺癌和/或其转移灶的药物的应用。
  16. 如权利要求12所述的药物组合物在制备用于在患者中成像的试剂的应用。
  17. 如权利要求12所述的药物组合物在制备用于诊断前列腺癌和/或其转移灶的试剂的应用。
  18. 如权利要求12所述的药物组合物在制备用于在治疗前列腺癌和/或其转移灶的药物的应用。
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