A beta targeting chemical exchange saturation transfer magnetic resonance contrast agent and application thereof
By developing Aβ-targeted chemical exchange saturation transfer magnetic resonance contrast agents, the economic and safety issues of 18F-FDG PET have been resolved, high-sensitivity targeted imaging of Aβ amyloid protein has been achieved, endogenous signal interference has been avoided, and multimodal imaging capabilities have been acquired.
Patent Information
- Application Number
- CN202510658899.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-21
- Publication Date
- 2025-09-23
AI Technical Summary
The existing 18F-FDG PET technology has high economic costs, safety issues and insufficient accessibility in diagnosing Alzheimer's disease. In addition, traditional CEST imaging molecular probes cannot target Aβ amyloid protein, resulting in imaging effects being interfered with by endogenous signals.
Develop an Aβ-targeted chemical exchange saturation transfer magnetic resonance contrast agent with a signal located at 9.6 ppm. It generates CEST signals by inducing intramolecular hydrogen bonds, avoiding endogenous signal interference and achieving targeted imaging of Aβ amyloid protein.
It improves the sensitivity of imaging, reduces the risk of damage to the liver and kidneys caused by heavy metal ions, and can be combined with fluorescence imaging to achieve multimodal imaging.
Smart Images
Figure CN120678959A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of chemical exchange saturation transfer magnetic resonance imaging, and in particular relates to an Aβ-targeted chemical exchange saturation transfer magnetic resonance contrast agent and an application thereof. Background Art
[0002] Alzheimer's disease (AD) is the most common cause of dementia, accounting for approximately 65% of all dementia cases. Early diagnosis of AD is crucial for initiating treatment and alleviating cognitive decline. The diagnosis of dementia increasingly relies on diagnostic markers. AD is characterized by a marked decrease in glucose metabolism in the posterior cingulate gyrus and temporoparietal regions, neuritic plaques formed by abnormal deposition of Aβ-amyloid protein (Aβ42), and neurofibrillary tangles caused by hyperphosphorylation of the tau protein.
[0003] In clinical practice, 18F-Fluorodeoxyglucose positron emission tomography (18F-FDG PET) can quantitatively detect the above metabolic abnormalities, with a diagnostic sensitivity and specificity of 89.2% and 85.7%, respectively (data from the 2022 ADNI multicenter study). This technology has been incorporated into the international diagnostic criteria and is particularly suitable for the differential diagnosis of atypical dementia and the prediction of the transformation of mild cognitive impairment (MCI) to AD. However, 18F-FDG PET technology has the following significant limitations: (1) Economic cost: The cost of a single examination is 8-12 times that of conventional magnetic resonance imaging (MRI); (2) Safety issues: Radioactive tracers cause subjects to receive an effective radiation dose of (7.2±0.5) mSv; (3) Accessibility barriers: Cyclotrons are required to produce isotopes, and the penetration rate of primary medical institutions is less than 5%.
[0004] Chemical exchange saturation transfer (CEST) is a new type of MRI imaging mechanism (J. Magn. Reson. 2000, 143, 79-87). Its imaging principle is to use selective saturation pulses to pre-saturate exchangeable protons of specific chemical shifts. As the saturated protons chemically exchange with the surrounding water protons, the saturation is transferred to free water, thereby reducing the signal intensity of free water. Therefore, by detecting the signal change of water, the information of this substance can be indirectly reflected. Compared with the T1 and T2 contrast agents currently used in clinical practice, CEST imaging does not require the use of paramagnetic Gd 3+ 、Fe 3+or Mn 3+ Heavy metal ions such as ions only require diamagnetic exchangeable protons for magnetic resonance imaging. Glycoproteins, glucose, glycogen, inositol, glutamic acid, peptides, etc. all contain a large number of exchangeable protons and can be used for CEST imaging.
[0005] The magnetic resonance signals of exchangeable protons on these molecules are all within the range of 0 to 4 ppm, and detecting signals in this region is often subject to strong background interference. Furthermore, none of these molecular probes have the ability to target the AD metabolic marker (Aβ-amyloid protein). Summary of the Invention
[0006] To address the shortcomings of existing technologies, the present invention provides an Aβ-targeted chemical exchange saturation transfer (CEST) MRI contrast agent and its application. The CEST MRI technology provided by the present invention, with a magnetic resonance signal at 9.6 ppm, can effectively avoid interference from endogenous signals and achieve targeted CEST MRI imaging of Aβ amyloid protein.
[0007] The technical solutions provided by the present invention are as follows:
[0008] An Aβ-targeted chemical exchange saturation transfer magnetic resonance contrast agent, the structural formula of which is as follows:
[0009]
[0010] Wherein, R is hydrogen.
[0011] The contrast agent provided by the above technical solution, on the one hand, has the targeting property of Aβ-amyloid protein. On the other hand, when performing chemical exchange saturation transfer magnetic resonance imaging, the magnetic resonance signal is at 9.6 ppm, which can effectively avoid the interference of endogenous signals and realize targeted CEST MRI imaging of Aβ amyloid protein.
[0012] The present invention also provides an application of an Aβ-targeted contrast agent for chemical exchange saturation transfer magnetic resonance imaging, wherein the structural formula of the Aβ-targeted contrast agent is as follows:
[0013]
[0014] Wherein: R is hydrogen (H), fluorine (F) or bromine (Br).
[0015] The R group is H, F or Br, corresponding to the names 5,5'-((1E,1'E)-1,4-phenylbis(ethylene-2,1-diyl))bis(2-hydroxybenzoic acid) (HSB in Chinese), 5,5'-((1E,1'E)-(2-fluoro-1,4-phenyl)bis(ethylene-2,1-diyl))bis(2-hydroxybenzoic acid) (FSB in Chinese), and 5,5'-((1E,1'E)-(2-bromo-1,4-phenyl)bis(vinyl-2,1-diyl))bis(2-hydroxybenzoic acid) (BSB in Chinese).
[0016] On the one hand, the above-mentioned contrast agents have the targeting property of Aβ-amyloid protein. On the other hand, when performing chemical exchange saturation transfer magnetic resonance imaging, the magnetic resonance signal is at 9.6 ppm, which can effectively avoid the interference of endogenous signals and realize targeted CEST MRI imaging of Aβ amyloid protein.
[0017] Preferably, R is hydrogen.
[0018] Specifically: The Aβ-targeted contrast agent is a CEST MRI molecular probe.
[0019] Specifically: For detecting Aβ amyloid degeneration in Alzheimer's disease.
[0020] Specifically: The phenylsalicylic acid fragments at both ends of the contrast agent molecule form intramolecular hydrogen bonds, inducing a CEST signal at a low field of 9.6 ppm.
[0021] Specifically: Chemical exchange saturation transfer magnetic resonance imaging can be performed in human serum.
[0022] Specifically: during application, the pH value of the environment is 7.0-7.5, preferably 7.2.
[0023] Specifically: When used, the concentration of the Aβ-targeted contrast agent is 10-15 mM, preferably 12.5 mM.
[0024] Compared with the prior art, the advantages and beneficial effects of the present invention are:
[0025] 1) Conventional CEST molecular probes are all in the low-field range, and most are within 0-4 ppm. However, the molecular probe involved in the present invention, as a contrast agent, has a magnetic resonance signal at 9.6 ppm, which is not easily interfered by background signals, thereby improving detection sensitivity;
[0026] 2) The contrast agent of the present invention has a significant CEST signal at 9.6 ppm, which is used to improve the detection sensitivity of CEST magnetic resonance technology;
[0027] 3) The molecular probe involved in the present invention, as a contrast agent, has a planar structure and does not require complex modification, maintaining the ability of the molecule to target and bind to Aβ;
[0028] 4) The contrast agent of the present invention does not require the use of paramagnetic metal ions (such as Gd 3+ , Fe 3+ , Mn 2+ etc.), it is possible to achieve kidney imaging and avoid the damage of heavy metal ions to liver and kidney function;
[0029] 5) The contrast agent of the present invention can be combined with fluorescence imaging and applied to multimodal imaging. BRIEF DESCRIPTION OF THE DRAWINGS
[0030] Figure 1 This is the CEST spectrum of Example 1 of the present invention.
[0031] Figure 2 This is the CEST spectrum of Example 2 of the present invention. DETAILED DESCRIPTION
[0032] The principles and features of the present invention are described below. The examples given are only used to explain the present invention and are not used to limit the scope of the present invention.
[0033] Unless otherwise specified, the test methods used in the examples are conventional methods; the materials and reagents used are commercially available reagents and materials unless otherwise specified.
[0034] Human serum HSA was purchased from MacLean Reagent Co., Ltd. (Cat. No. H856832).
[0035] Preparation method of HSB: refer to the literature (European Journal of Medicinal Chemistry 39 (2004) 573–578).
[0036] Example 1
[0037] Compound HSB (5 mg) was obtained and dissolved in 1 mL of phosphate buffered saline (PBS) to a concentration of 12.5 mmol / L. The pH was adjusted using either 6 mol / L hydrochloric acid (HCl) or 10 mol / L sodium hydroxide (NaOH) to different pH values. The solution was then placed in a 0.3 mm diameter capillary tube. The sample tube was vertically fixed in a 20 cm diameter circular tube, and its relative position was recorded. The tube was then placed in an MRI probe. The temperature control unit was turned on and maintained at 37°C for 30 minutes. CEST imaging was performed at 0.25 ppm intervals between 15 and -15 ppm. Sampling parameters: slice thickness (3 mm), repetition time TR = 8 s, echo time TE = 5.1 ms, matrix size = 128 × 96, rare factor = 8, saturation irradiation power ω1 = 5.4 μT, saturation irradiation time t = 3 s. B0 field inhomogeneity correction was performed every 0.15 ppm between 1.6 and -1.6 ppm. Correction parameters: slice thickness (3 mm), repetition time TR = 5 s, echo time TE = 6.4 ms, matrix size = 128 × 96, rare factor = 8, saturation irradiation power ω1 = 0.5 μT, saturation irradiation time t = 0.3 s. Matlab was used to process the data to obtain CEST spectra of HSB at different pH values and saturation powers.
[0038] MRI experimental results:
[0039] Conventional CEST MRI contrast agent signals are all in the low field range, and most of them are within 0-4 ppm. Figure 1 Figure 2 shows the CEST spectrum of 12.5 mM HSB in PBS buffer at pH 7.2. The CEST spectrum shows that the molecular probe HSB presented in this invention exhibits a strong CEST signal at 9.6 ppm in the high field, and the CEST signal gradually increases with increasing saturation power. The relatively large chemical shift ensures that the corresponding magnetic resonance signal is minimally affected by background interference.
[0040] Example 2
[0041] Compound HSB (5 mg) was obtained and dissolved in 1 mL of phosphate buffered saline (PBS) containing 10% human serum to a concentration of 12.5 mmol / L. The solution was adjusted to pH 7.3 with 6 mol / L hydrochloric acid solution (HCl solution) or 10 mol / L sodium hydroxide solution (NaOH solution). The solution was placed in a 5.0 mm diameter capillary tube and placed in a magnetic resonance imaging probe. The temperature control unit was turned on and the temperature was controlled at 37 0 C, maintained for 30 minutes; CEST imaging was performed every 0.25 ppm between 15 and -15 ppm. Sampling parameters: slice thickness (3 mm), repetition time (TR) = 8 s, echo time (TE) = 5.1 ms, matrix size = 128 × 96, rare factor = 8, saturation irradiation power (ω1) = 1.2, 2.4, 3.6, 5.4, 7.2, 10.8, and 14.4 μT, saturation irradiation time (t) = 3 s; B0 field inhomogeneity correction was performed every 0.15 ppm between 1.6 and -1.6 ppm. Correction parameters: slice thickness (3 mm), repetition time TR = 5 s, echo time TE = 6.4 ms, sampling rectangular array matrix size = 128 × 96, acceleration factor rare factor = 8, saturation irradiation power ω1 = 0.5 μT, saturation irradiation time t = 0.3 s; Matlab program was used for data processing to obtain the CEST spectrum of HSB at saturation power.
[0042] MRI experimental results:
[0043] The CEST signal of human serum is within 0-4 ppm. Figure 2 Figure 2 shows the CEST spectrum of 12.5 mM HSB in serum at pH 7.2. The CEST spectrum shows that the molecular probe HSB, described in the present invention, exhibits a strong CEST signal at 9.6 ppm in the low field. The relatively large chemical shift ensures that the corresponding magnetic resonance signal is minimally affected by background signals.
[0044] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.
Claims
1. An Aβ-targeted chemical exchange saturation transfer magnetic resonance contrast agent, characterized in that: The structural formula is as follows: ； Wherein, R is hydrogen.
2. A use of an Aβ-targeted contrast agent, characterized by: For chemical exchange saturation transfer magnetic resonance imaging, wherein the structural formula of the Aβ-targeted contrast agent is as follows: ； Wherein: R is hydrogen, fluorine or bromine.
3. The use of the Aβ-targeted contrast agent according to claim 2, characterized in that: R is hydrogen.
4. The use of the Aβ-targeted contrast agent according to claim 2, characterized in that: The Aβ-targeted contrast agent is a CEST MRI molecular probe.
5. The use of the Aβ-targeted contrast agent according to claim 4, characterized in that: For detecting Aβ amyloid degeneration in Alzheimer's disease.
6. The use of the Aβ-targeted contrast agent according to claim 2, characterized in that: The phenylsalicylic acid fragments at both ends of the contrast agent molecule form intramolecular hydrogen bonds, inducing a CEST signal at a low field of 9.6 ppm.
7. The use of the Aβ-targeted contrast agent according to claim 2, characterized in that: Chemical exchange saturation transfer magnetic resonance imaging in human serum.
8. The use of the Aβ-targeted contrast agent according to claim 2, characterized in that: When applied, the pH value of the environment is 7.0-7.
5.
9. The use of the Aβ-targeted contrast agent according to claim 2, characterized in that: When used, the concentration of the Aβ-targeting contrast agent is 10-15 mM.