Fluorine-containing substituted aryl boronic acids 99m Tc complexes and their use in quantitative analysis of myocardial blood flow by spect

Abstract

The embodiment of the application provides a Tc complex containing fluorine-substituted aryl boronic acid and application thereof in SPECT myocardial blood flow quantitative analysis. By introducing fluorine atoms into R groups, the molecular liposolubility and metabolic characteristics are optimized. The linear relationship between myocardial uptake and myocardial blood flow of the Tc complex is significantly better than that of existing Tc-labeled drugs, and the Tc complex can support absolute quantitative analysis of SPECT myocardial blood flow. Meanwhile, the Tc complex has high cardiac uptake value and long retention time, low liver and lung uptake, and is suitable for an imaging agent for SPECT myocardial rapid dynamic imaging and blood flow quantitative analysis application.

Description

Technical Field

[0001] This application belongs to the field of nuclear medicine, and specifically relates to a fluorine-substituted arylboronic acid. Tc complexes and their application in SPECT myocardial blood flow quantitative analysis. Background Technology

[0002] Coronary artery disease (CAD) is one of the most common and prevalent cardiovascular diseases worldwide, posing a significant challenge to public health. The continuously rising incidence of CAD reflects the serious threat to public health and reveals the heavy burden it places on the socio-economic system.

[0003] In recent years, the selection of indications for interventional treatment of coronary artery disease has undergone a significant shift. It no longer relies solely on the degree of stenosis in the vascular anatomy indicated by coronary angiography, but increasingly emphasizes changes in myocardial blood flow function. Both domestic and international guidelines for the diagnosis and treatment of coronary artery disease clearly point out the decisive significance of sufficient evidence of myocardial ischemia for the selection of interventional treatment. Furthermore, a qualitative diagnosis of myocardial ischemia alone is no longer sufficient for clinical needs; accurate quantitative indicators of myocardial blood flow are now indispensable. Summary of the Invention

[0004] This application provides a fluorinated substituted arylboronic acid. Tc complexes and their application in SPECT myocardial blood flow quantitative analysis can obtain quantitative indicators of myocardial blood flow.

[0005] This application provides a fluorinated substituted arylboronic acid. Application of Tc complexes in SPECT myocardial blood flow quantitative analysis, fluorinated substituted arylboronic acids The Tc(III) complex has the structural formula shown in Formula 1. Formula 1, Wherein, R is a 4-hydroxymethylphenylboronic acid group containing 1 to 2 fluorine substituents.

[0006] According to embodiments of this application, R is selected from one or more of 2-fluoro-4-hydroxymethylphenylboronic acid, 3-fluoro-4-hydroxymethylphenylboronic acid, 2,6-difluoro-4-hydroxymethylphenylboronic acid, 3,5-difluoro-4-hydroxymethylphenylboronic acid, and 2,5-difluoro-4-hydroxymethylphenylboronic acid. Preferably, R is 2-fluoro-4-hydroxymethylphenylboronic acid or 3-fluoro-4-hydroxymethylphenylboronic acid.

[0007] According to embodiments of this application, SPECT absolute quantitative analysis of myocardial blood flow includes the detection of mild myocardial ischemia.

[0008] According to embodiments of this application, SPECT absolute quantitative analysis of myocardial blood flow includes the detection of balanced myocardial ischemia caused by multivessel coronary disease or microcirculatory disease.

[0009] According to embodiments of this application, fluorinated substituted arylboronic acids Tc(III) complexes are used to prepare developer compositions, the raw materials of which include: 1,2-cyclohexanedione dioxime, 1 mg to 3 mg; sodium chloride, 5 mg to 15 mg; R-substituted boric acid, 1 mg to 10 mg; reducing agent, 35 μg to 75 μg; pH adjuster, 8 mg to 10 mg; ligand exchanger, 1 mg to 3 mg; excipient, 30 mg to 100 mg.

[0010] According to embodiments of this application, Na is added during the labeling of the developer composition. 99m The activity of TcO4 is 370 MBq to 3700 MBq, and the volume is 0.2 mL to 3 mL.

[0011] According to the embodiments of this application, the labeling conditions for the developer composition are: reacting at 100~110°C for 10~20 min.

[0012] According to embodiments of this application, the excipients include one or more of γ-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, and mannitol.

[0013] According to embodiments of this application, the application includes: acquiring dynamic projection data collected by a SPECT / CT system, wherein the dynamic projection data is derived from a mixture of fluorinated substituted arylboronic acids. The imaging agent of the Tc(III) complex was collected after injection for a first preset time. The dynamic projection data was corrected and reconstructed to generate a cross-sectional dynamic SPECT image, resulting in list mode data. The list mode data was processed by frame segmentation to generate a first dataset and a second dataset. The first dataset is a multi-frame mixed time interval dataset, and the second dataset is a multi-frame unified time interval dataset. The time-radioactivity curve was extracted from the first dataset, and the kinetic model was fitted using the activity curve to generate kinetic parameters. The myocardial blood flow value was obtained based on the kinetic parameters. Region of interest analysis was performed on the second dataset. The region of interest was selected on the same tomographic image that simultaneously displays the myocardium and liver, and the average radioactivity count of the heart and liver regions was measured and output.

[0014] According to an embodiment of this application, the imaging agent is injected in a two-stage manner, including local injection and imaging bolus injection; wherein, the dosage of the imaging agent injected locally is 30~40 MBq and the volume is 1.5~2.5 mL; the dosage of the imaging agent injected into the imaging bolus is 350~390 MBq and the volume is 2.5~3.5 mL, and the dynamic projection data acquisition is started at a second preset time before the imaging bolus injection.

[0015] According to embodiments of this application, the correction includes The reconstruction employs at least one of the following: Tc isotope attenuation correction, photon scattering correction, collimator resolution correction, and Poisson noise modeling; the reconstruction uses an iterative reconstruction algorithm with 30-40 iterations and 1-3 subsets.

[0016] According to an embodiment of this application, the first dataset is a 20-24 frame mixed time interval dataset, the mixed time interval including a combination of 10-15 seconds / frame, 20-30 seconds / frame and 40-60 seconds / frame; and / or, the second dataset is a 12-20 frame uniform time interval dataset, the uniform time interval is 0.8-1.2 minutes / frame, and the total duration of the second dataset is consistent with the first preset time.

[0017] This application also provides a fluorinated substituted arylboronic acid. Tc complexes, fluorinated substituted arylboronic acids The Tc(III) complex has the structural formula shown in Formula 1. Formula 1, Wherein, R is a 4-hydroxymethylphenylboronic acid group containing 1 to 2 fluorine substituents.

[0018] This application also provides a fluorinated substituted arylboronic acid comprising the above-mentioned fluorinated substituted arylboronic acid. The developer composition of the Tc complex comprises the following raw materials: 1,2-cyclohexanedione dioxime, 1 mg to 3 mg; sodium chloride, 5 mg to 15 mg; R-substituted boric acid, 1 mg to 10 mg; reducing agent, 35 μg to 75 μg; pH adjuster, 8 mg to 10 mg; ligand exchanger, 1 mg to 3 mg; and excipient, 30 mg to 100 mg.

[0019] The embodiments of this application contain fluorinated substituted arylboronic acids. Tc(III) complexes, by introducing fluorine atoms into the R group, optimize molecular lipid solubility and metabolic properties, and their linear relationship between myocardial uptake and myocardial blood flow is significantly better than existing methods. Tc-labeled drugs can support absolute quantitative analysis of myocardial blood flow using SPECT. They have high cardiac uptake and long residence time, but low uptake by the liver and lungs, making them suitable imaging agents for SPECT rapid dynamic imaging and quantitative blood flow analysis of the myocardium. Attached Figure Description

[0020] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments of this application will be briefly introduced below. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0021] Figure 1 yes 99m Radioactive HPLC spectrum of Tc-2-F-4BOHboroxime (RCP>95%).

[0022] Figure 2 yes 99m Radioactive HPLC spectrum of Tc-3-F-4BOHboroxime (RCP>95%).

[0023] Figure 3 yes 99m Radioactive HPLC spectrum of Tc-2,6-DF-4BOHboroxime (RCP>95%).

[0024] Figure 4 yes 99m Radioactive HPLC spectrum of Tc-3,5-DF-4BOHboroxime (RCP>95%).

[0025] Figure 5 yes 99m Radioactive HPLC spectrum of Tc-2,5-DF-4BOHboroxime (RCP>95%).

[0026] Figure 6 yes 99m Tc-2-F-4BOHboroxime, 99m Tc-3-F-4BOHboroxime, 99m Tc-2,6-DF-4BOHboroxime, 99m Tc-3,5-DF-4BOHboroxime, 99m Tc-2,5-DF-4BOHboroxime and 99m SPECT dynamic planar imaging of Tc-Teboroxime in miniature pigs.

[0027] Figure 7 It means 99m Tc-2-F-4BOHboroxime and 99m SPECT dynamic tomographic images of Tc-3-F-4BOHboroxime in normal miniature pigs.

[0028] Figure 8 This is a coronary angiography image of a miniature pig model of acute myocardial infarction.

[0029] Figure 9 This is a coronary angiography image of another miniature pig model of acute myocardial infarction.

[0030] Figure 10 It means 99m Tc-2-F-4BOHboroxime and 99m SPECT dynamic tomographic images of Tc-3-F-4BOHboroxime in a pig model of myocardial infarction.

[0031] Figure 11 It means 99m Tc-3-F-4BOHboroxime, 99m Tc-Teboroxime and 99m The first-pass extraction rate of Tc-Sestamibi from rat isolated hearts at different perfusion rates was compared, and representative time-radioactivity curves of the three tracers at 8.4 mL / min were presented. Detailed Implementation

[0032] To make the purpose, technical solution, and beneficial technical effects of this application clearer, the following detailed description is provided in conjunction with embodiments. It should be understood that the implementation details described in this specification are merely for illustrative purposes and are not intended to limit the scope of this application.

[0033] For simplicity, this application only explicitly discloses some numerical ranges. However, any lower limit can be combined with any upper limit to form a range not explicitly stated; and any lower limit can be combined with other lower limits to form a range not explicitly stated, just as any upper limit can be combined with any other upper limit to form a range not explicitly stated. Furthermore, although not explicitly stated, every point or individual value between the endpoints of the range is included within that range. Therefore, each point or individual value can be used as its own lower or upper limit and combined with any other point or individual value or with other lower or upper limits to form a range not explicitly stated.

[0034] It should be noted that the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0035] Unless otherwise stated, the values ​​of the parameters mentioned in this application can be measured using various measurement methods commonly used in the art (e.g., they can be tested according to the methods given in the embodiments of this application). Unless otherwise stated, the test temperature for all parameters mentioned in this application is 25°C and the test pressure is standard atmospheric pressure.

[0036] The foregoing description of this application is not intended to describe every disclosed implementation or method. Instead, the following description provides more specific examples of exemplary embodiments. Throughout the application, guidance is provided through a series of embodiments, which can be used in various combinations. The examples listed are representative only and should not be construed as exhaustive.

[0037] Clinical studies have shown that a fractional flow reserve (FFR) ≤0.8, measured using a pressure guidewire, can serve as a quantitative standard for revascularization therapy and has been gradually adopted by relevant guidelines. However, FFR measurement requires invasive procedures and carries risks such as infection. Therefore, non-invasive absolute quantitative techniques for myocardial blood flow are receiving increasing attention. Furthermore, myocardial microcirculatory dysfunction is also gaining importance; research data shows that up to 70% of patients undergoing coronary angiography do not have obstructive lesions in the large coronary vessels. Compared to FFR, which only reflects functional changes in the large coronary vessels, assessing myocardial microcirculatory lesions requires non-invasive imaging measurements of myocardial flow reserve (CFR or MFR). This method not only provides an important supplement to clinical diagnosis but also lays the foundation for precise treatment decisions.

[0038] Single-photon emission computed tomography (SPECT) of myocardial perfusion imaging is an important non-invasive imaging technique for diagnosing myocardial ischemia, guiding decisions on revascularization treatment for coronary artery disease, and evaluating treatment efficacy, and is widely used in clinical practice. However, the development of this technology is still limited by the performance of imaging drugs. An ideal myocardial perfusion imaging drug has not yet been realized, which restricts the application potential of SPECT technology in precise quantitative analysis of myocardial blood flow.

[0039] In view of the above problems, embodiments of this application provide a fluorinated substituted arylboronic acid The application of Tc complexes in SPECT myocardial blood flow quantitative analysis can be used for SPECT rapid dynamic imaging of the myocardium and quantitative blood flow analysis.

[0040] The fluorinated substituted arylboronic acid provided in the embodiments of this application In the application of Tc complexes in SPECT myocardial blood flow quantitative analysis, fluorinated substituted arylboronic acids are used. The Tc(III) complex has the structural formula shown in Formula 1. Formula 1, Wherein, R is a 4-hydroxymethylphenylboronic acid group containing 1 to 2 fluorine substituents.

[0041] The fluorinated substituted arylboronic acid in the embodiments of this application The structural formula of the Tc(III) complex is shown in Formula 1, where R is a 4-hydroxymethylphenylboronic acid group containing 1-2 fluorine substituents. In the application of SPECT myocardial blood flow (MBF) quantitative analysis, through the synergistic optimization of molecular structure design and SPECT / CT quantitative analysis technology, the technical problems of insufficient targeting of existing myocardial imaging agents, large interference from non-target organ uptake, and low accuracy of quantitative analysis have been solved.

[0042] The 4-hydroxymethylphenylboronic acid group in the ligand structure possesses myocardial tissue-specific recognition properties, enabling it to specifically bind to receptors or transport proteins highly expressed on the surface of cardiomyocytes. Simultaneously, the introduction of fluorine substituents optimizes the molecule's lipid solubility and metabolic properties through electronic effects and steric hindrance, further enhancing the affinity of the ligand for cardiomyocytes. Tc(III) complexes can rapidly and efficiently accumulate in myocardial tissue, enabling specific imaging of myocardial tissue. The linear relationship between myocardial uptake and myocardial blood flow is significantly superior to existing methods. Tc-labeled drugs can support absolute quantitative analysis of myocardial blood flow using SPECT.

[0043] Specifically, in coordination compounds Tc(III) forms a stable structure with its ligands through coordinating atoms such as N and O. The strong coordination bonds prevent dissociation in the physiological environment of the body, thus avoiding [the formation of] high-strength coordination bonds. The shedding and redistribution of Tc improves the reliability of MBF quantitative analysis.

[0044] The hydrophobicity regulation of the fluorine substituents and the spatial configuration optimization of the molecular structure effectively suppressed the non-specific uptake of the complex in non-target organs such as the liver and lungs, especially reducing the radioactive accumulation in liver tissue. This significantly reduced the scattering interference of radioactive signals from non-target organs on the myocardial region, avoided myocardial image artifacts caused by high uptake in the liver, and improved the accuracy of radioactive counting measurements in the myocardial region.

[0045] The complex exhibits a moderate clearance rate in the blood and minimal radioactive residue in the blood pool. This allows for rapid separation of radioactive signals from myocardial tissue and the blood pool, reducing interference from blood pool overflow on the extraction of myocardial time-radioactivity curves (TACs). This provides a high-quality data foundation for the accurate acquisition of arterial input function (AIF) and accurate fitting of myocardial TACs.

[0046] The complex in this embodiment has a fast uptake rate and suitable retention time in myocardial tissue. After injection, it can quickly form a radioactivity concentration difference between the myocardium and surrounding tissues, significantly improving the contrast and clarity of myocardial imaging, and making anatomical and functional information such as myocardial boundaries and ischemic areas easier to identify.

[0047] In some embodiments, R is selected from one or more of 2-fluoro-4-hydroxymethylphenylboronic acid, 3-fluoro-4-hydroxymethylphenylboronic acid, 2,6-difluoro-4-hydroxymethylphenylboronic acid, 3,5-difluoro-4-hydroxymethylphenylboronic acid, or 2,5-difluoro-4-hydroxymethylphenylboronic acid.

[0048] In the embodiments of this application, R can be monofluorinated, including one or more of 2-fluoro-4-hydroxymethylphenylboronic acid group and 3-fluoro-4-hydroxymethylphenylboronic acid group.

[0049] In the 2-fluoro-4-hydroxymethylphenylboronic acid group, the fluorine atom is located ortho-position to the 4-hydroxymethylphenylboronic acid group. This ortho-position electronic effect moderately modifies the electrophilicity of the boric acid group, while minimizing steric hindrance and ensuring no interference with the specific binding of the 4-hydroxymethyl group to target sites on the surface of cardiomyocytes. This substituent enables the complex to maintain high myocardial uptake while possessing good water solubility, allowing for rapid transport to myocardial tissue via the bloodstream. Clear myocardial imaging can be achieved shortly after injection, making it suitable for rapid early-stage dynamic signal capture in dynamic acquisition.

[0050] In the 3-fluoro-4-hydroxymethylphenylboronic acid group, the fluorine atom is located at the meta position of the 4-hydroxymethylphenylboronic acid group. The meta-substitution has a milder electronic effect, which can stabilize the molecular configuration of the complex and avoid structural changes caused by the physiological environment in vivo. This substituent makes the residence time of the complex in myocardial tissue more suitable, covering a 20-minute dynamic acquisition cycle, ensuring the stability of the radioactive signal in the later clearance phase, and providing reliable data for full-cycle fitting of the time-to-radioactivity curve (TAC).

[0051] In the embodiments of this application, R can be a difluorosubstituted substance, including one or more of 2,6-difluoro-4-hydroxymethylphenylboronic acid, 3,5-difluoro-4-hydroxymethylphenylboronic acid, and 2,5-difluoro-4-hydroxymethylphenylboronic acid.

[0052] In the 2,6-difluoro-4-hydroxymethylphenylboronic acid group, two fluorine atoms are symmetrically substituted at the bi-ortho positions of the 4-hydroxymethylphenylboronic acid group. This significantly optimizes the binding affinity of the boronic acid group to the myocardial target site through symmetric electronic effects. Simultaneously, the difluoro substitution enhances the hydrophobic balance of the molecule, effectively inhibiting non-specific uptake by liver tissue. This substituent significantly increases the myocardial / liver radioactivity ratio of the complex, reduces interference from non-target organ scattering, and improves the accuracy of radioactivity counting measurements in the myocardial region. It is particularly suitable for clinical quantitative analysis scenarios with high imaging specificity requirements.

[0053] In the 3,5-difluoro-4-hydroxymethylphenylboronic acid group, two fluorine atoms are symmetrically substituted at the bi-meta position of the 4-hydroxymethylphenylboronic acid group. This symmetrical structure makes the spatial configuration of the complex molecule more stable. The coordination binding of Tc(III) is more robust, ensuring the integrity of the molecular structure during in vivo metabolism. At the same time, the bi-meta-fluorine substitution can reduce the plasma protein binding rate of the complex, accelerate the blood clearance rate, reduce the interference of residual radioactivity in the blood pool on myocardial TAC extraction, make the fitting of the arterial input function (AIF) more accurate, and thus improve the accuracy of myocardial blood flow (MBF) calculation.

[0054] In the 2,5-difluoro-4-hydroxymethylphenylboronic acid group, two fluorine atoms are substituted at the ortho and meta positions of the 4-hydroxymethylphenylboronic acid group, respectively. The electronic effect of the asymmetric substitution and the steric hindrance work synergistically, preserving the moderate adjustment of the electrophilicity of the boronic acid group by the ortho-fluorine while stabilizing the overall conformation of the molecule through the fluorine near the meta position. This substituent gives the complex the combined advantages of high myocardial uptake, suitable residence time, and low uptake by non-target organs, adapting to the imaging needs of different experimental subjects and improving the versatility and comparability of quantitative analysis results.

[0055] The aforementioned substituents can be used individually or in combination depending on the specific application. For example, simultaneously introducing 2-fluoro-4-hydroxymethylphenylboronic acid and 3,5-difluoro-4-hydroxymethylphenylboronic acid groups can further optimize the targeting, stability, and metabolic properties of the complex through the complementary properties of different substituents. For instance, the combination of monofluoro and difluoro substituents can balance the complex's rapid blood transport capability with its long-term myocardial stability, satisfying both rapid signal capture in the early stages of dynamic acquisition and ensuring the accuracy of subsequent kinetic analysis. This allows the complex to be adapted to the acquisition parameters and quantitative analysis procedures of different SPECT / CT devices, expanding its application scope in clinical diagnosis and scientific research.

[0056] In some embodiments, SPECT absolute quantitative analysis of myocardial blood flow includes the detection of mild myocardial ischemia.

[0057] Based on the fluorinated substituted arylboronic acid in the embodiments of this application The superior performance of Tc(III) complexes enables accurate detection of mild myocardial ischemia through SPECT absolute quantitative analysis of myocardial blood flow.

[0058] In clinical diagnosis and research, mild myocardial ischemia typically manifests as a slight decrease in local myocardial blood perfusion without obvious myocardial cell necrosis or morphological changes. It represents a crucial point for early diagnosis, risk stratification, and intervention efficacy assessment in coronary artery disease. Traditional myocardial imaging techniques, due to insufficient imaging agent targeting, significant interference from non-target organs, and limited quantitative accuracy, often struggle to distinguish between mild blood flow decreases and physiological fluctuations, leading to missed diagnoses or misjudgments. However, the SPECT absolute quantitative analysis of myocardial blood flow described in this application, through synergistic optimization of imaging agent performance and quantitative methods, achieves highly sensitive and specific detection of mild myocardial ischemia.

[0059] This application Tc(III) complexes exhibit strong myocardial targeting and low uptake in non-target organs, creating a high-contrast radioactive distribution between myocardial tissue and surrounding normal tissue. Even slight decreases in local myocardial blood flow can be accurately detected through subtle differences in myocardial radioactive signals. Combined with CT anatomical data correction using a SPECT / CT system, physical interferences such as tissue attenuation and scattering can be eliminated, keeping the error in local myocardial radioactivity counting measurement at a low level. This ensures that minor blood flow changes can be accurately converted into quantifiable differences in myocardial blood flow (MBF) values, preventing ischemic lesions from being masked by signal interference.

[0060] Unlike traditional semi-quantitative analyses that rely on visual comparison or relative ratios, the absolute quantitative analysis in this application can directly output the absolute MBF value (unit: mL / min / g) of the local myocardium and establish a reference range for the MBF of normal myocardium. For areas of mild myocardial ischemia, the MBF value will be significantly lower than that of the normal myocardial area of ​​the same individual, and will fall within the ischemia threshold range. The presence of ischemia can be clearly determined through objective numerical comparison, without relying on subjective visual judgment, thus avoiding the ambiguity in the qualitative assessment of mild abnormalities.

[0061] In some embodiments, SPECT absolute quantitative analysis of myocardial blood flow includes the detection of balanced myocardial ischemia caused by multivessel coronary disease or microcirculatory disease.

[0062] Based on the fluorinated substituted arylboronic acid in the embodiments of this application The technical characteristics of Tc(III) complexes and SPECT absolute quantitative analysis of myocardial blood flow can effectively solve the problems of difficulty in detecting and accurately assessing balanced myocardial ischemia caused by multi-vessel coronary artery disease or microcirculation disease.

[0063] Balanced myocardial ischemia caused by multivessel coronary artery disease refers to the presence of similar degrees of stenosis in two or more coronary arteries, resulting in a widespread and uniform slight decrease in myocardial blood flow perfusion in the corresponding blood-supply areas. Balanced myocardial ischemia caused by microcirculatory disorders is due to abnormalities in the structure or function of the myocardial microcirculation, leading to a uniform decrease in the overall myocardial blood flow perfusion level. Both types of ischemia, due to the uniform slight decrease in blood flow across the entire myocardium or a wide area, lack a clear visual contrast between normal myocardium and ischemic areas, and are easily misinterpreted as normal by traditional qualitative / semi-quantitative imaging.

[0064] The absolute quantitative analysis in this application achieves accurate detection and evaluation through the matching of quantitative indicators and mechanisms.

[0065] Dynamic SPECT scanning acquires dynamic data on the entire process of tracer uptake in the myocardium, allowing for the direct calculation of two core quantitative indicators: absolute myocardial blood flow and coronary flow reserve. For balanced myocardial ischemia caused by multivessel disease or microcirculatory disorders, although blood flow in different myocardial regions shows a "uniform" decrease and lacks visual contrast, the absolute value of blood flow and reserve function will be significantly reduced. By identifying this overall quantitative abnormality, the limitations of traditional visual assessment can be overcome, enabling accurate detection of balanced ischemia caused by multivessel disease and microcirculatory disorders.

[0066] In some embodiments, fluorinated substituted arylboronic acids Tc(III) complexes are used to prepare developer compositions, the raw materials of which include: 1,2-cyclohexanedione dioxime, 1 mg to 3 mg; sodium chloride, 5 mg to 15 mg; R-substituted boric acid, 1 mg to 10 mg; reducing agent, 35 μg to 75 μg; pH adjuster, 8 mg to 10 mg; ligand exchanger, 1 mg to 3 mg; excipient, 30 mg to 100 mg.

[0067] The fluorinated substituted arylboronic acid in the embodiments of this application Tc(III) complexes are used to prepare imaging agents for SPECT myocardial blood flow quantitative analysis. The raw materials of the matching lyophilized kit ensure the stability of the imaging agent preparation, the radionuclide binding efficiency, and the in vivo targeting performance through the ratio and functional synergy of each component.

[0068] Fluorine-substituted arylboronic acids Tc(III) complexes are used to prepare imaging agents. The raw materials for the imaging agent composition include: 1,2-cyclohexanedione dioxime, 1 mg to 3 mg; sodium chloride, 5 mg to 15 mg; R-substituted boric acid, 1 mg to 10 mg; reducing agent, 35 μg to 75 μg; pH adjuster, 8 mg to 10 mg; ligand exchanger, 1 mg to 3 mg; and excipient, 30 mg to 100 mg. The above are the proportions for a single part of the imaging agent, which can be used to prepare radiopharmaceutical lyophilized kits for imaging agents.

[0069] 1,2-Cyclohexanedione dioxime was used as an auxiliary coordinating ligand to co-construct fluorinated substituted arylboronic acids. The stable coordination structure of Tc(III) allows 1,2-cyclohexanedione dioxime to react with R-substituted boronic acid to form fluorinated substituted arylboronic acid. Tc(III) complexes. Cyclohexanedione dioxime can provide N and O dual-coordination atoms, enhancing the in vivo metabolic stability of the complex, preventing the radionuclide from detaching from the blood or tissues, and ensuring the consistency of the radioactive signal with the myocardial target distribution. Cyclohexanedione dioxime can also form a synergistic coordination effect with R-substituted boric acid, and through spatial configuration optimization, make the molecular structure of the complex more suitable for the recognition needs of target sites on the surface of cardiomyocytes, indirectly improving the myocardial targeting affinity.

[0070] The chloride ions in sodium chloride act as another auxiliary ligand, which can react with... Tc(III) coordinates to maintain the electroneutrality of the entire complex system, making it easier for the complex to be transported from the blood pool to the myocardial tissue, thereby ensuring its high myocardial uptake characteristics.

[0071] R-substituted boric acid, specifically 4-hydroxymethylphenylboronic acid containing 1-2 fluorine substituents, is a core targeting component of imaging agents. The 4-hydroxymethylphenylboronic acid group in its molecular structure possesses myocardial-specific recognition properties, specifically binding to transport proteins or receptors highly expressed on the surface of cardiomyocytes, forming the core basis for the complex's targeted uptake in the myocardium. The fluorine substituents optimize the hydrophilic-hydrophobic balance of the ligand through electronic effects and steric hindrance regulation, reducing non-specific uptake in non-target organs such as the liver and lungs, and increasing the myocardial / non-target organ radioactivity ratio, thus minimizing interference for accurate quantitative analysis.

[0072] The reducing agent is the starter. A key component of the Tc coordination reaction, it can remove +7 valent molybdenum from the molybdenum-technetium generator eluent. TcO Reduced to a +3 valence that can coordinate with ligands Tc, destruction TcO The stable Tc=O bond in the medium creates conditions for coordination reactions. For example, SnCl2 can be used as the reducing agent. 2H2O.

[0073] The core function of pH adjusters is to stabilize the acidity or alkalinity of the coordination reaction system. They are used to maintain the pH of the reconstituted reaction system within the range of 3.3–4.1. This pH environment enhances the coordination activity of R-substituted boric acid with 1,2-cyclohexanedione dioxime, promoting the interaction between the ligand and the surrounding environment. Tc(III) rapidly forms the target complex while inhibiting Tc hydrolysis precipitation. Citric acid can be used as an example pH adjuster.

[0074] In the intermediate process of coordination reactions, ligand exchangers act as auxiliary ligands, first reacting with the reduced ligand... Tc(III) forms a soluble temporary intermediate, avoiding low-cost... Tc oxidizes or aggregates in the early stages of the reaction, improving the utilization rate of the nuclide. In the reaction system, the ligand exchanger undergoes a ligand exchange reaction with the target ligand (R-substituted boric acid, 1,2-cyclohexanedione dioxime), thus... Tc(III) is efficiently transferred to the target ligand, promoting the formation of the target complex and improving the reaction conversion rate. For example, diethyltriaminepentaacetic acid is used as the ligand exchanger.

[0075] Excipients are key inactive components in lyophilized pharmaceutical kits used to ensure the physical form and stability of the formulation. During lyophilization, they form a loose, porous solid framework that encapsulates and protects active ingredients such as R-substituted arylboronic acid, reducing agents, and pH adjusters, preventing denaturation, aggregation, or structural damage during the lyophilization process. Furthermore, this excipient can react with the ultimately formed fluorinated arylboronic acid... Tc(III) complexes form complexes, thereby altering their water solubility and in vivo metabolic characteristics.

[0076] According to embodiments of this application, the excipients include one or more of γ-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, and mannitol.

[0077] For example, the excipient may be γ-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin or mannitol.

[0078] Existing drug kits typically use γ-cyclodextrin as an excipient. During the preparation of the injection solution, a significant amount of radioactive material, sometimes exceeding 40%, is retained by the filter during the sterile filtration stage after preparation (e.g., using a hydrophilic sterile PVDF needle filter, 0.22μm, 33mm, Merk). To ensure the recovery rate of the radioactive imaging agent, rinsing with physiological saline containing propylene glycol is an indispensable step. The inventors of this application have noted that the introduction of organic solvents such as propylene glycol has adverse effects on subsequent quality control and biocompatibility. Therefore, the inventors of this application have observed that when preparing the injection solution, 2-hydroxypropyl-γ-cyclodextrin is preferably used as an excipient, which can reduce filter membrane residue to <20% during sterile filtration and eliminate the need for treatment with organic solvents such as propylene glycol to achieve superior imaging agent performance.

[0079] Preferably, the excipient is 2-hydroxypropyl-γ-cyclodextrin. The loose structure formed after lyophilization of 2-hydroxypropyl-γ-cyclodextrin allows for rapid dissolution during reconstitution of the drug, without precipitation or suspension, ensuring the homogeneity of the reaction system and guaranteeing the full progress of the coordination reaction.

[0080] In some embodiments, the labeling conditions for the developer composition are: reacting at 100-110°C for 10-20 min.

[0081] In some embodiments, Na is added during the labeling of the developer composition. 99mThe activity of TcO4 is 370 MBq to 3700 MBq, and the volume is 0.2 mL to 3 mL.

[0082] In some embodiments, the application includes: acquiring dynamic projection data acquired by a SPECT / CT system, wherein the dynamic projection data comprises fluorinated substituted arylboronic acid. The imaging agent of the Tc(III) complex was collected after injection for a first preset time. The dynamic projection data was corrected and reconstructed to generate a cross-sectional dynamic SPECT image, resulting in list mode data. The list mode data was processed by frame segmentation to generate a first dataset and a second dataset. The first dataset is a multi-frame mixed time interval dataset, and the second dataset is a multi-frame unified time interval dataset. The time-radioactivity curve was extracted from the first dataset, and the kinetic model was fitted using the activity curve to generate kinetic parameters. The myocardial blood flow value was obtained based on the kinetic parameters. Region of interest analysis was performed on the second dataset. The region of interest was selected on the same tomographic image that simultaneously displays the myocardium and liver, and the average radioactivity count of the heart and liver regions was measured and output.

[0083] Fluorine-substituted arylboronic acids In an example of using Tc(III) complexes for SPECT myocardial blood flow quantification, the accuracy of myocardial blood flow (MBF) quantification and target / non-target organ distribution comparison is ensured through synergistic optimization of each step.

[0084] In this embodiment, dynamic projection data acquisition is used to obtain high-quality raw signals, and the SPECT / CT system is used to capture fluorine-substituted arylboronic acid. The dynamic radioactive distribution signal of Tc(III) complex in vivo provides basic data support for subsequent analysis.

[0085] For example, the dynamic acquisition mode of the SPECT / CT system is activated, and after 10 seconds, fluorine-substituted arylboronic acid is... Tc(III) complex imaging agents are administered intravenously to laboratory animals or humans. Due to the inclusion of a myocardial-specific targeting group (4-hydroxymethylphenylboronic acid group with 1-2 fluorine substituents) in its molecular structure, this imaging agent can rapidly accumulate in myocardial tissue. Simultaneously, its low uptake by non-target organs reduces interference signals, laying the foundation for acquiring high-quality data. The imaging agent can be prepared by reconstitution of a lyophilized kit, and its radioactivity is adapted to the body weight of the experimental subject.

[0086] The acquisition duration is set to a first preset time, exemplarily 12-20 minutes, to match the uptake-clearance kinetics of the imaging agent in the myocardium. During acquisition, the SPECT probe rotates continuously at a preset angle, synchronously recording two-dimensional dynamic projection data at different angles. Each frame of projection data corresponds to the radioactivity distribution at a specific time point and includes key information such as the probe rotation angle and photon count. Simultaneously, the CT system acquires anatomical data for subsequent physical correction and organ localization, ensuring the spatial accuracy of the projection data.

[0087] The acquired dynamic projection data is temporarily stored in the form of a three-dimensional matrix of time, angle and count, which not only retains the dynamic change information in the time dimension, but also records the projection distribution in the spatial dimension, providing a complete original signal for subsequent correction and reconstruction.

[0088] The dynamic projection data is corrected and reconstructed to generate a cross-sectional dynamic SPECT image, resulting in list-mode data. This step eliminates technical interference through physical correction and combines iterative reconstruction algorithms to transform the two-dimensional projection data into a three-dimensional cross-sectional dynamic SPECT image, while simultaneously outputting list-mode data. The goal is to improve image quality and data reliability.

[0089] In some embodiments, correction includes At least one of the following: Tc isotope attenuation correction, photon scattering correction, collimator resolution correction, and Poisson noise modeling.

[0090] Attenuation correction: Based on the density differences of different tissues (myocardium, bone, lungs), and combined with synchronously acquired CT anatomical data, attenuation correction is calculated. The attenuation coefficient of the γ-rays emitted by the Tc(III) complex in vivo compensates for the count loss caused by tissue absorption and avoids the underestimation of the signal in the myocardial region. Scattering correction: By using energy discrimination and scattering models, photon signals scattered from non-target organs (such as the liver and lungs) to the myocardial region are eliminated, reducing artifact interference; Resolution correction: Based on the collimator response function, it corrects the signal blurring caused by the collimator resolution limitation of the probe, improves the spatial resolution of the image, and makes the myocardial boundary clearer.

[0091] Meanwhile, Poisson noise modeling is introduced, and statistical optimization algorithms are used to suppress noise amplification during the reconstruction process, ensuring the stability of the image signal.

[0092] An iterative reconstruction algorithm adapted to dynamic data is employed. For example, the OSEM algorithm, with 30-40 iterations and 1-3 subsets, is used to reconstruct the corrected dynamic projection data into a sequence of cross-sectional dynamic SPECT images. Each frame corresponds to a time point and contains multiple consecutive tomographic planes, which can intuitively present the changes in the radioactive distribution of myocardial tissue at different time points. For instance, the image at 5 minutes after injection can clearly show the peak of myocardial uptake, and the image at 15 minutes can reflect the initial clearance trend of the imaging agent.

[0093] During the reconstruction process, the system synchronously converts the corrected original signal into list-mode data. This data is stored in the form of original records of photon decay time, detection position, and energy, retaining all dynamic information that has not been time-divided, providing a data template for subsequent flexible framing, and ensuring that framing processing does not lose the details of the original signal.

[0094] The list-mode data is processed by frame segmentation to generate a first dataset and a second dataset. The first dataset is a multi-frame mixed time interval dataset, and the second dataset is a multi-frame uniform time interval dataset. The purpose is to generate datasets that are adapted to different analysis objectives.

[0095] This step generates two datasets based on the timestamp information of the list-mode data, respectively adapting to the needs of MBF quantification and target / non-target distribution comparison. The first dataset is a multi-frame mixed time interval dataset, designed to accurately capture rapid dynamic processes and handle slow changes in MBF quantification, employing mixed time interval frame division.

[0096] In some embodiments, the first dataset is a 20-24 frame mixed time interval dataset, where the mixed time interval includes a combination of 10-15 seconds / frame, 20-30 seconds / frame, and 40-60 seconds / frame.

[0097] For example, the framing rule is set to 20-24 frames. In the early stage, a short interval of 10-15 seconds per frame is used to capture the dynamic process of the imaging agent rapidly entering the myocardium and blood pool to reach its peak. In the middle stage, a transition interval of 20-30 seconds per frame is used to adapt to the slow decline stage after the peak uptake. In the later stage, a long interval of 40-60 seconds per frame is used to smooth out noise in the stage and reduce data redundancy.

[0098] The first dataset, adapted to the time resolution of kinetic analysis, is used to extract time-radioactivity curves (TACs) to support MBF calculations.

[0099] The second dataset is a multi-frame unified time interval dataset. To meet the need for standardization and easy comparison of the radioactive distribution of the heart and liver, a unified time interval frame division is adopted.

[0100] In some embodiments, the second dataset is a dataset with 12 to 20 frames at uniform time intervals, with a uniform time interval of 0.8 to 1.2 minutes per frame, and the total duration of the second dataset is consistent with the first preset time. This ensures that the time span of each frame of data is consistent, avoiding comparison bias caused by differences in intervals. Because the time nodes of this dataset are uniform, it is convenient to intuitively compare the radioactivity counts of the heart and liver at the same time point, supporting the analysis of target / non-target organ distribution.

[0101] In some embodiments, the imaging agent is injected in a two-stage manner, including local injection and imaging bolus injection; wherein, the local injection uses an imaging agent dose of 30-40 MBq and a volume of 1.5-2.5 mL; the imaging bolus injection uses an imaging agent dose of 350-390 MBq and a volume of 2.5-3.5 mL, and dynamic projection data acquisition is initiated at a second preset time before the imaging bolus injection.

[0102] In this embodiment, the two-stage injection combines low-dose localization and high-dose imaging to resolve the contradiction between insufficient localization accuracy and the imbalance of imaging signal stability in traditional single-stage injection.

[0103] During localization injection, a low dose and small volume of imaging agent are used to quickly determine the anatomical location of the heart, providing a reference for the acquisition field of view and angle calibration of the SPECT probe, and avoiding invalid subsequent acquisition data due to organ position deviation; during imaging bolus injection, a high dose and appropriate volume of imaging agent are used to provide sufficient radioactive signal, ensuring a stable and detectable signal intensity in the myocardial region within the dynamic acquisition cycle (12~20 minutes), supporting MBF quantitative analysis and target / non-target distribution comparison.

[0104] By linking the two in a timely manner, the accuracy of the acquisition field of view is ensured, and the signal quality requirements of quantitative analysis are met. This is a key operational step to improve the overall reliability of the analysis.

[0105] This application provides a fluorinated substituted arylboronic acid. Tc complexes, fluorinated substituted arylboronic acids The Tc(III) complex has the structural formula shown in Formula 1. Formula 1, Wherein, R is a 4-hydroxymethylphenylboronic acid group containing 1 to 2 fluorine substituents.

[0106] The fluorinated substituted arylboronic acid provided in the embodiments of this application Tc complexes can be used for SPECT quantitative analysis of myocardial blood flow. By introducing fluorine atoms into the R group, the molecular lipid solubility and metabolic properties are optimized, and the linear relationship between myocardial uptake and myocardial blood flow is significantly better than existing methods. Tc-labeled drugs can support absolute quantitative analysis of myocardial blood flow using SPECT. They have high cardiac uptake and long residence time, but low uptake by the liver and lungs, making them suitable imaging agents for SPECT rapid dynamic imaging and quantitative blood flow analysis of the myocardium.

[0107] This application also provides a fluorinated substituted arylboronic acid comprising the above-mentioned fluorinated substituted arylboronic acid. The formulation of the Tc complex contains: 1,2-cyclohexanedione dioxime, 1 mg to 3 mg; sodium chloride, 5 mg to 15 mg; R-substituted boric acid, 1 mg to 10 mg; reducing agent, 35 μg to 75 μg; pH adjuster, 8 mg to 10 mg; ligand exchanger, 1 mg to 3 mg; and excipient, 30 mg to 100 mg.

[0108] The formulation of the kit in this application embodiment contains the above-mentioned fluorinated substituted arylboronic acid. Tc complexes, by introducing fluorine atoms into the R group, optimize molecular lipid solubility and metabolic properties, and their linear relationship between myocardial uptake and myocardial blood flow is significantly better than existing methods. Tc-labeled drugs can support absolute quantitative analysis of myocardial blood flow using SPECT, while exhibiting high cardiac uptake and long residence time, and low uptake by the liver and lungs.

[0109] Example The following is based on 99m Tc-2-F-4BOHboroxime, 99m Tc-3-F-4BOHboroxime, 99m Tc-2,6-DF-4BOHboroxime, 99m Tc-3,5-DF-4BOHboroxime and 99m Taking Tc-2,5-DF-4BOHboroxime as an example, the details are illustrated through specific examples.

[0110] Preparation of compounds Materials: CDOH2 (1,2-cyclohexanedione dioxime), methylboric acid, SnCl2 2H₂O, citric acid, DTPA (diethylenetriaminepentaacetic acid), γ-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, 2-F-4BOH (2-fluoro-4-hydroxymethylphenylboronic acid), 3-F-4BOH (3-fluoro-4-hydroxymethylphenylboronic acid), 2,6-DF-4BOH (2,6-DF-4-hydroxymethylphenylboronic acid), 3,5-DF-4BOH (3,5-DF-4-hydroxymethylphenylboronic acid), 2,5-DF-4BOH (2,5-DF-4-hydroxymethylphenylboronic acid). All were purchased from Sigma / Aldrich. Na 99m TcO4 was purchased from Atom High Technology Co., Ltd.

[0111] HPLC Instruments and Methods: Instruments: Waters 1525 binary high-performance liquid chromatography system, 2998 full-wavelength UV detector, Raytest GabiStar radioactivity detector.

[0112] Column: SUNFIREC 185μm 4.6×150mm Flow rate: 1 mL / min Mobile phase: A: 10mM ammonium acetate buffer (pH=6.8) B: Methanol.

[0113] Method: Gradient elution, 0–5 min, 30% A; 5–15 min, 30–10% A.

[0114] Example 1: A fluorinated substituted arylboronic acid Tc complexes [ 99m [TcCl(CDO)(CDOH)2B-2-F-4BOH], the preparation method is as follows: [ 99m TcCl(CDO)(CDOH)2B-2-F-4BOH] was prepared using a kitting method, containing 22 mg CDOH, 2 mg 2-F-4BOH (2-fluoro-4-hydroxymethylphenylboronic acid), and SnCl2. Add 60 μg of 2H₂O, 9 mg of citric acid, 2 mg of DTPA, 10 mg of sodium chloride, and 45 mg of 2-hydroxypropyl-γ-cyclodextrin to a vial. 99m TcO4 – 1.0 mL of solution (370–1110 MBq) was added at 100 mL. o The reaction was carried out at C for 10–20 min. Then, it was diluted with physiological saline to 3.7 MBq / mL. The final labeled product required no further purification and was analyzed by HPLC. Figure 1 The process is as shown in Route 1.

[0115] Route 1. 99m Preparation route of Tc-2-F-4BOHboroxime Example 2: A fluorinated substituted arylboronic acid Tc complexes [ 99m [TcCl(CDO)(CDOH)2B-3-F-4BOH], the preparation method is as follows: [ 99mTcCl(CDO)(CDOH)2B-3-F-4BOH] was prepared using a kitting method, containing 22 mg CDOH, 2 mg 3-F-4BOH (3-fluoro-4-hydroxymethylphenylboronic acid), and SnCl2. Add 60 μg of 2H₂O, 9 mg of citric acid, 2 mg of DTPA, 10 mg of sodium chloride, and 45 mg of 2-hydroxypropyl-γ-cyclodextrin to a vial. 99m TcO4 – 1.0 mL of solution (370–1110 MBq) was added at 100 mL. o The reaction was carried out at C for 10–20 min. Then, it was diluted with physiological saline to 3.7 MBq / mL. The final labeled product required no further purification and was analyzed by HPLC. Figure 2 The process is as shown in Route 2.

[0116] Route 2. 99m Preparation route of Tc-3-F-4BOHboroxime Example 3: A fluorinated substituted arylboronic acid Tc complexes [ 99m [TcCl(CDO)(CDOH)2B-2,6-DF-4BOH], prepared by the following method: [ 99m TcCl(CDO)(CDOH)2B-2,6-DF-4BOH] was prepared using a kitting method, containing 2 mg of CDOH, 2 mg of 2,6-DF-4BOH (2,6-DF-4-hydroxymethylphenylboronic acid), and SnCl2. Add 60 μg of 2H₂O, 9 mg of citric acid, 2 mg of DTPA, 10 mg of sodium chloride, and 45 mg of 2-hydroxypropyl-γ-cyclodextrin to a vial. 99m TcO4 – 1.0 mL of solution (370–1110 MBq) was added at 100 mL. o The reaction was carried out at C for 10–20 min. Then, it was diluted with physiological saline to 3.7 MBq / mL. The final labeled product required no further purification and was analyzed by HPLC. Figure 3 The process is shown in Route 3.

[0117] Route 3. 99m Preparation route of Tc-2,6-DF-4BOHboroxime Example 4: A fluorinated substituted arylboronic acid Tc complexes [ 99m[TcCl(CDO)(CDOH)2B-3,5-DF-4BOH], the preparation method is as follows: [ 99m TcCl(CDO)(CDOH)2B-3,5-DF-4BOH] was prepared using a kitting method, containing 2 mg of CDOH, 2 mg of 3,5-DF-4BOH (3,5-DF-4-hydroxymethylphenylboronic acid), and SnCl2. Add 60 μg of 2H₂O, 9 mg of citric acid, 2 mg of DTPA, 10 mg of sodium chloride, and 45 mg of 2-hydroxypropyl-γ-cyclodextrin to a vial. 99m TcO4 – 1.0 mL of solution (370–1110 MBq) was added at 100 mL. o The reaction was carried out at C for 10–20 min. Then, it was diluted with physiological saline to 3.7 MBq / mL. The final labeled product required no further purification and was analyzed by HPLC. Figure 4 The process is shown in Route 4.

[0118] Route 4. 99m Preparation route of Tc-3,5-DF-4BOHboroxime Example 5: A fluorinated substituted arylboronic acid Tc complexes [ 99m [TcCl(CDO)(CDOH)2B-2,5-DF-4BOH], the preparation method is as follows: [ 99m TcCl(CDO)(CDOH)2B-2,5-DF-4BOH] was prepared using a kitting method, containing 2 mg of CDOH, 2 mg of 2,5-DF-4BOH (2,5-DF-4-hydroxymethylphenylboronic acid), and SnCl2. Add 60 μg of 2H₂O, 9 mg of citric acid, 2 mg of DTPA, 10 mg of sodium chloride, and 45 mg of 2-hydroxypropyl-γ-cyclodextrin to a vial. 99m TcO4 – 1.0 mL of solution (370–1110 MBq) was added at 100 mL. o The reaction was carried out at C for 10–20 min. Then, it was diluted with physiological saline to 3.7 MBq / mL. The final labeled product required no further purification and was analyzed by HPLC. Figure 5 The process is shown in Route 5.

[0119] Route 5. 99m Preparation route of Tc-2,5-DF-4BOHboroxime Example 6: A fluorinated substituted arylboronic acid Preparation of Tc complex [99mTcCl(CDO)(CDOH)2B-3-F-4BOH]: The preparation process is similar to that in Example 1, except that 45 mg of 2-hydroxypropyl-γ-cyclodextrin is replaced with 20 mg of γ-cyclodextrin.

[0120] Preparation of the injection solution: The above includes 99m The radioactive injection solution of Tc was passed through a 0.22 μm sterile filter membrane, which was then rinsed with 2 mL of physiological saline. The resulting filtrate was then diluted to 370–550 MBq / mL. In biodistribution experiments, the injection dose was approximately 1.1 MBq / mL, with an injection volume of 0.1 mL per animal. In imaging studies, the injection dose was approximately 370 MBq / mL, with an injection volume of 0.2–0.5 mL.

[0121] 2. Experimental Testing Dynamic collection: Animals were first intravenously injected with approximately 37 MBq, in a volume of 2 mL, as described in Examples 1-5. 99m The heart was located using a Tc radioactive tracer, and then approximately 370 MBq in 3 mL volume was injected intravenously via a bolus injection. 99m Tc radioactive tracer. List-mode acquisition was initiated 10 seconds before injection and continued for 20 minutes, followed by a CT scan (GE Discovery 640 SPECT / CT system).

[0122] Quantitative analysis: To achieve quantitative analysis of myocardial blood flow (MBF), dynamic projection data were first analyzed. 99m Tc isotope attenuation correction was performed, followed by an iterative reconstruction algorithm (35 iterations, 2 subsets) to generate cross-sectional dynamic SPECT images. During reconstruction, comprehensive physical corrections were made for photon attenuation, scattering, and collimator resolution, while Poisson noise modeling was introduced to suppress reconstruction noise. In the single-day resting / adenosine loading protocol, since prepositional scanning and resting injection may result in residual radioactivity in the myocardium, the residual myocardial activity was estimated using the first frame image and subtracted from subsequent frames to improve the accuracy of kinetic analysis.

[0123] Subsequently, the list-mode data was re-framed to generate a 22-frame dynamic dataset (10 seconds × 10 frames; 20 seconds × 5 frames; 60 seconds × 6 frames; 40 seconds × 1 frame), from which the time-activity curve (TAC) was extracted. The TAC for the arterial input function (AIF) was automatically generated by the system and could be manually fine-tuned by placing rectangular volumes of interest (VOIs) in the left ventricle and atrium regions. Simultaneously, the myocardial TAC could be obtained through dynamic polar map transformation of the myocardial region.

[0124] In dynamic analysis, 99m The Tc tracer was fitted using a single-tissue (dual-chamber) model, and three key kinetic parameters were estimated using the Levenberg–Marquardt numerical optimization algorithm: input rate constant. K Output rate constant k And fractional blood volume (FBV) used for blood pool overflow correction. In the model, the myocardial radioactivity concentration C myo (t) and the radioactive concentration C in the blood pool a The relationship between (t) can be expressed as: C myo (t)=FBV*C a (t)+(1-FBV)* K 1e -k2t *C a (t) Among them, the first term FBV*C a (t) represents the radioactive contribution from blood pool overflow into the myocardium, the latter term being (1-FBV)* K 1e -k2t *C a (t) represents the actual radioactive concentration taken up by the myocardium. This formula takes into account both blood pool overflow and myocardial volume effects, making the quantitative analysis of MBF more accurate.

[0125] To further compare the radioactivity distribution in the heart and liver, the list pattern data was re-divided into 20 frames (1 minute per frame) to generate raw dynamic data, and the mean radioactivity counts in the heart and liver regions were measured using ImageJ1.49 (National Institutes of Health, NIH). The region of interest (ROI) for each experimental animal was selected from the same level simultaneously displaying the myocardium and liver to ensure the comparability and consistency of the measurement results.

[0126] Filter membrane residue test during filtration: Tests were conducted on samples included in Examples 1-3 and Example 6, respectively. 99m The radioactive injection solution of Tc was passed through a 0.22 μm sterile filter membrane, and the radioactivity of the filter membrane was tested after rinsing with 2 mL of physiological saline. The radioactivity of the solution was then tested in Examples 1-3 and Example 6, respectively. 99m The radioactive injection solution of Tc was passed through a 0.22 μm sterile filter membrane and the radioactivity of the filtrate was removed after rinsing with 2 mL of physiological saline.

[0127] 3. Experimental Results (1) Results of biodistribution of major organs in CD-1 mice: CD-1 mice (n=5) weighing 18–20 g were injected intravenously with ~0.740 MBq of imaging agent. They were then euthanized after being anesthetized with isoflurane at 2, 5, 15, 30, and 60 minutes post-injection. Radioactivity counts were measured in organs including the heart, liver, spleen, lungs, kidneys, stomach, small intestine, large intestine, muscles, bones, brain, thyroid gland, blood vessels, and blood using a PerkinElmerWizard–2470-counter. The biodistribution data (%ID / g) were then calculated.

[0128] Tables 1 to 6 list respectively... 99m Tc-2-F-4BOHboroxime, 99m Tc-3-F-4BOHboroxime, 99m Tc-2,6-DF-4BOHboroxime, 99m Tc-3,5-DF-4BOHboroxime and 99m %ID / g values ​​of Tc-2,5-DF-4BOHboroxime in key organs at 2, 5, 15, 30 and 60 min in CD-1 mice, as well as heart-liver ratio and heart-lung ratio data.

[0129] Table 1. 99m %ID / g values ​​of Tc-2-F-4BOHboroxime in various organs of CD-1 mice Table 2. 99m %ID / g values ​​of Tc-3-F-4BOHboroxime in various organs of CD-1 mice Table 3. 99m %ID / g values ​​of Tc-2,6-DF-4BOHboroxime in various organs of CD-1 mice Table 4. 99m%ID / g values ​​of Tc-3,5-DF-4BOHboroxime in various organs of CD-1 mice Table 5. 99m %ID / g values ​​of Tc-2,5-DF-4BOHboroxime in various organs of CD-1 mice Table 6. Heart-to-liver ratio and heart-to-lung ratio of imaging agent at different time points in CD-1 mice As mentioned above, Tables 1 to 6 list the developing agents respectively. 99m Biodistribution data of TcCl(CDO)(CDOH)2B-R](R=2-F-4BOH,3-F-4BOH,2,6-DF-4BOH,3,5-DF-4BOH and 2,5-DF-4BOH) in major organs of CD-1 mice. From the above data, myocardial uptake at 2 minutes post-injection is as follows: 99m Tc-2-F-4BOHboroxime 99m Tc-3-F-4BOHboroxime> 99m Tc-2,6-DF-4BOHboroxime> 99m Tc-3,5-DF-4BOHboroxime≈ 99m Tc-2,5-DF-4BOHboroxime; Heart-to-liver ratio: 99m Tc-2-F-4BOHboroxime 99m Tc-3-F-4BOHboroxime≈ 99m Tc-2,6-DF-4BOHboroxime≈ 99m Tc-3,5-DF-4BOHboroxime 99m Tc-2,5-DF-4BOHboroxime; Cardiopulmonary ratio: 99m Tc-3-F-4BOHboroxime> 99m Tc-2-F-4BOHboroxime≈ 99m Tc-2,6-DF-4BOHboroxime> 99m Tc-2,5-DF-4BOHboroxime≈ 99m Tc-3,5-DF-4BOHboroxime. Myocardial uptake at 5 minutes: 99m Tc-2-F-4BOHboroxime 99m Tc-3-F-4BOHboroxime≈99m Tc-2,5-DF-4BOHboroxime 99m Tc-3,5-DF-4BOHboroxime 99m Tc-2,6-DF-4BOHboroxime; Heart-to-liver ratio: 99m Tc-2,5-DF-4BOHboroxime 99m Tc-2-F-4BOHboroxime≈ 99m Tc-3,5-DF-4BOHboroxime 99m Tc-3-F-4BOHboroxime> 99m Tc-2,6-DF-4BOHboroxime; Cardiopulmonary ratio: 99m Tc-2,5-DF-4BOHboroxime 99m Tc-3-F-4BOHboroxime≈ 99m Tc-2,6-DF-4BOHboroxime> 99m Tc-2-F-4BOHboroxime≈ 99m Tc-3,5-DF-4BOHboroxime. The biodistribution data above show that the introduction of R-substituted boronic acid significantly affects the initial cardiac uptake and retention, as well as the hepatic and pulmonary uptake of this type of imaging agent. A comprehensive analysis of cardiac uptake, heart-liver ratio, and heart-lung ratio at 2 and 5 minutes reveals… 99m Tc-2-F-4BOHboroxime and 99m Tc-3-F-4BOHboroxime exhibits better overall biological performance in mice.

[0130] (2) Study of SPECT dynamic planar imaging in normal miniature pigs.

[0131] Miniature pigs (30kg) were used as research subjects and injected with imaging agents. 99m [TcCl(CDO)(CDOH)2B-R](R = Me, 2-F-4BOH, 3-F-4BOH, 2,6-DF-4BOH, 3,5-DF-4BOH, and 2,5-DF-4BOH) was used for SPECT / CT dynamic planar imaging studies. It should be noted that when R is Me, it refers to the form already reported in the prior art. 99mTc-Teboroxime. Experimental animals were anesthetized by intravenous injection of 1.25 mg / kg of Teboroxime 100 (teratamine and the muscle relaxant zolazepam) and 1 mg / kg of celazine. After anesthesia, the animals were placed in a supine position on the examination table. The imaging instrument was a Symbia T16 SPECT / CT (Siemens, Germany). 5 mL of radioactive imaging agent was injected intravenously via bolus. 99m TcCl(CDO)(CDOH)2B-R] (R=Me, 2-F-4BOH, 3-F-4BOH, 2,6-DF-4BOH, 3,5-DF-4BOH and 2,5-DF-4BOH) is about 370MBq.

[0132] Table 7 Table 8 Data acquisition and processing scheme: parallel aperture low-energy high-resolution collimator, matrix 128×128, magnification 1.45, window width ±20%, peak energy 140keV. Subsequently, two experienced nuclear medicine physicians used Siemens' built-in software to analyze the images, delineating regions of interest in the myocardium, liver, and lungs, obtaining radioactive uptake results, correcting for injection dose, and calculating the heart / liver and heart / lung ratios.

[0133] Table 7 shows the average radioactivity counts of the imaging agent uptake in key organs of miniature pigs. Table 8 shows the... 99m Tc-2-F-4BOHboroxime and 99m Tc-3-F-4BOHboroxime K and k Parameter values ​​and 13 N-NH Comparative analysis of measured myocardial blood flow (MBF).

[0134] In miniature pigs, a higher heart / background ratio is beneficial for obtaining high-quality myocardial perfusion images. Figure 6 And in Table 7, the following are listed 99m Tc-2-F-4BOHboroxime, 99m Tc-3-F-4BOHboroxime, 99m Tc-2,6-DF-4BOHboroxime, 99m Tc-3,5-DF-4BOHboroxime, 99m Tc-2,5-DF-4BOHboroxime and 99mTc-Teboroxime uptake in key tissues such as the heart, liver, lungs, and blood, and the heart / background ratio. Overall, 99m Tc-2-F-4BOHboroxime, 99m Blood background of Tc-3-F-4BOHboroxime and 99m Tc-Teboroxime is close (see...) Figure 6 ); Myocardial uptake 5 minutes after injection 99m Tc-2-F-4BOHboroxime 99m Tc-Teboroxime> 99m Tc-2,6-DF-4BOHboroxime≈ 99m Tc-3,5-DF-4BOHboroxime 99m Tc-2,5-DF-4BOHboroxime≈ 99m Tc-3-F-4BOHboroxime; uptake in the liver 99m Tc-2,6-DF-4BOHboroxime> 99m Tc-Teboroxime> 99m Tc-3,5-DF-4BOHboroxime≈ 99m Tc-2,5-DF-4BOHboroxime 99m Tc-2-F-4BOHboroxime 99m Tc-3-F-4BOHboroxime; uptake in the lungs 99m Tc-2-F-4BOHboroxime 99m Tc-Teboroxime> 99m Tc-2,5-DF-4BOHboroxime 99m Tc-3-F-4BOHboroxime> 99m Tc-2,6-DF-4BOHboroxime≈ 99m Tc-3,5-DF-4BOHboroxime (see also Tc-3,5-DF-4BOHboroxime) Figure 6 (Table 7). From the above analysis and imaging results, it can be seen that... 99m [TcCl(CDO)(CDOH)2B-R](R=2-F-4BOH,3-F-4BOH) showed superior myocardial retention within 20 minutes after injection into miniature pigs compared to previously reported methods. 99m Tc-Teboroxime, although the initial myocardial uptake at 2 minutes is slightly lower than 99mTc-Teboroxime, but thanks to the imaging agent's better myocardial retention and lower liver and lung background, its heart-liver ratio is lower at 2 minutes. 99m Tc-Teboroxime is comparable, and both are superior after 5 minutes. 99m Tc-Teboroxime. 99m [TcCl(CDO)(CDOH)2B-R] (R=2,6-DF-4BOH, 3,5-DF-4BOH, and 2,5-DF-4BOH) showed a high liver background, resulting in a lower heart-liver ratio after 5 minutes. Furthermore, in planar imaging, 99m Tc-2-F-4BOHboroxime and 99m Tc-3-F-4BOHboroxime myocardial contour ratio 99m Tc-2,6-DF-4BOHboroxime, 99m Tc-3,5-DF-4BOHboroxime and 99m Tc-2,5-DF-4BOHboroxime was clearer, and myocardial retention was more pronounced than... 99m Tc-Teboroxime is more stable. Therefore, [ 99m TcCl(CDO)(CDOH)2B-R](R=2-F-4BOH,3-F-4BOH) is a superior myocardial perfusion imaging agent compared to 99m Tc-Teboroxime. Based on comparable initial extraction rates, the imaging agent of this application exhibits good biological properties and broad development prospects.

[0135] (3) Study on dynamic tomographic imaging of miniature pigs using CZTSPECT.

[0136] Miniature pigs (30kg) were used as the research subjects, and imaging agents were injected into them. 99m [TcCl(CDO)(CDOH)2B-R](R=2-F-4BOH,3-F-4BOH) was used for SPECT / CT dynamic tomographic imaging studies. Experimental animals were anesthetized by intravenous injection of 1.25 mg / kg of telatamine 100 (telostatin and the muscle relaxant zolazepam) and 1 mg / kg of celazine. After anesthesia, the experimental animals were placed in a supine position on an examination bed, and ECG leads were connected to monitor respiration and heart rate. The imaging instrument was a CZTS SPECT system (Discovery NM530c, USA). Approximately 37 MBq (2 mL) of imaging agent was pre-injected via a cannula inserted into the marginal ear vein for cardiac localization, followed by "pellet" injections of 370 MBq (3 mL). 99m[TcCl(CDO)(CDOH)2B-R](R=2-F-4BOH,3-F-4BOH) was injected, and dynamic image acquisition was performed in list mode for 20 minutes simultaneously. The matrix was 32×32, window width ±6%, peak energy 140keV, and 16 frames / cardiac cycle. After SPECT image acquisition, chest CT scans were acquired using a GE Discovery 640 SPECT / CT, with the miniature pigs maintaining the same body position during both acquisitions. Reconstruction and post-processing were performed using MyoFlowQ (Beijing Bailing Cloud Biomedical Technology Co., Ltd., China), a dedicated SPECT image processing software, followed by image analysis using ImageJ 1.49 software (National Institutes of Health, USA).

[0137] Normal miniature pig injection 99m Tc-2-F-4BOHboroxime and 99m Tomographic images of one frame per minute at the same short-axis plane within 20 minutes after Tc-3-F-4BOHboroxime are shown below. Figure 7 . 99m Tc-2-F-4BOHboroxime and 99m Tc-3-F-4BOHboroxime rapidly achieved peak uptake in the myocardial tissue of miniature pigs and remained stably retained for up to 20 minutes post-injection, maintaining a clear and uniform myocardial contour. This performance is consistent with previously reported myocardial perfusion imaging agents. 99m Compared to Tc-Teboroxime, liver uptake was significantly lower, meeting the criteria for SPECT blood flow quantification while also allowing for myocardial perfusion imaging. Furthermore, two miniature pig models of acute myocardial infarction were established via left anterior descending artery balloon occlusion, and the model's establishment was validated by electrocardiographic and imaging assessments. Figure 8 and Figure 9 The results of coronary angiography show occlusion of the left anterior descending artery. Pigs with an acute myocardial infarction model were injected with... 99m Tc-2-F-4BOHboroxime and 99m Tomographic images taken 3–8 minutes after Tc-3-F-4BOHboroxime are shown below. Figure 10 .exist 99m Tc-2-F-4BOHboroxime and 99m In the tomographic images of Tc-3-F-4BOHboroxime, it can be observed that the areas of impaired myocardial blood flow perfusion shown highly overlap with the areas innervated by the occluded vessels. This result indicates that using... 99m Tc-2-F-4BOHboroxime and 99mTc-3-F-4BOHboroxime, as an imaging drug, can accurately reflect the occurrence and distribution characteristics of myocardial ischemia in myocardial blood flow perfusion imaging, which strongly verifies the reliability and accuracy of this technology in accurately identifying and locating myocardial ischemia areas.

[0138] A single-compartment model was used to fit the time-radioactivity curves (TACs) of the blood pool and myocardium obtained from dynamic acquisition, thereby obtaining kinetic parameters. K 1 、k 2 (Table 8). In the resting state, 99m Tc-3-F-4BOHboroxime K 1 The value (0.95±0.25mL / min / g) is higher than 99m Tc-2-F-4BOHboroxime (0.72±0.20 mL / min / g) was also higher than previously reported. 99m Tc-4BOHboroxime (0.81±0.03mL / min / g), 99m Tc-3SPboroxime (0.63±0.11mL / min / g), 99m Tc-Teboroxime (0.69±0.35 mL / min / g) and 99m Tc-Sestamibi (0.40±0.04 mL / min / g). In comparison, 99m Tc-3-F-4BOHboroxime k 2 Value (0.20±0.07min) ¹) lower than 99m Tc-Teboroxime (0.33±0.11min) ¹), suggesting that it remains relatively stable within the myocardium.

[0139] In 13 In a comparative study of N-NH3PET, 99m Tc-3-F-4BOHboroxime K 1 Value and 13 N-NH3-measured myocardial blood flow (MBF) showed better consistency (compared to 99m Tc-2-F-4BOHboroxime). It is worth noting that, 99m Tc-3-F-4BOHboroxime K 1 The values ​​are generally higher than the corresponding MBF measurements. HighK 1 (Reflecting higher myocardial uptake) combined with low k 2 (Reflecting a longer myocardial retention time) indicates that, 99m Tc-3-F-4BOHboroxime possesses ideal kinetic properties, making it suitable for SPECT-based rapid dynamic imaging of the myocardium and quantitative blood flow analysis. Based on this, we further conducted an isolated rat heart perfusion experiment to determine... 99m The first-pass extraction rate (EF) of Tc-3-F-4BOHboroxime was measured to verify its potential as a novel imaging agent for rapid dynamic imaging of the myocardium and quantitative analysis of blood flow in SPECT.

[0140] Table 9 (4) Study on perfusion of isolated rat heart.

[0141] Male Sprague-Dawley (SD) rats (n=28) weighing 275-325g were used in the experiment. A Langendorff isolated heart perfusion model was established by aortic cannulation after anesthesia. The hearts were perfused at a constant flow rate using non-circulating Krebs-Henseleit buffer, with three precisely controlled flow rates: 5.0 mL / min, 8.4 mL / min, and 16.0 mL / min. At each flow rate, three to four isolated hearts were used independently to test the imaging agent. 99m Tc-3-F-4BOHboroxime, 99m Tc-Teboroxime and 99m Tc-Sestamibi. The imaging agent was administered via a single bolus injection at a dose of 37 MBq (0.1 ml). Time-radioactivity curves of the cardiac region were continuously recorded over 10 minutes using a handheld autocollimating gamma camera. Extraction fraction (EF) was quantified using the Raichle B / A ratio method. Variations in EF for each imaging agent at different flow rates were statistically evaluated using one-way ANOVA. Data are expressed as mean ± standard deviation, and p < 0.05 was considered statistically significant.

[0142] Table 9 shows the concentration of different perfusion rates in isolated rat hearts. 99m Tc-3-F-4BOHboroxime, 99m Tc-Teboroxime and 99m Average first-pass extraction rate of Tc-Sestamibi.

[0143] pass Figure 11As shown in Table 9, 99m The overall EF of Tc-3-F-4BOHboroxime is as high as 95.98% ± 2.58% (n=9), compared with 99m The overall EF of Tc-Teboroxime (96.90% ± 1.95%, n=9) showed no statistically significant difference (P > 0.05), but was significantly higher than that of Tc-Teboroxime. 99m Tc-Sestamibi (30.70%±7.31%, n=10; P<0.05). When assessing the blood flow dependence of EF, the following was found: 99m The ejection fraction (EF) values ​​of Tc-3-F-4BOHboroxime at three isolated heart perfusion rates of 5.0 mL / min, 8.4 mL / min, and 16.0 mL / min were 94.54%±0.43% (n=3), 95.44%±2.34% (n=3), and 97.96%±0.15% (n=3), respectively. One-way ANOVA showed that changes in flow rate had no significant effect on the EF (P>0.05). 99m The EF values ​​of Tc-Teboroxime at the corresponding flow rates were 97.40%±0.57% (n=3), 98.10%±2.44% (n=3), and 95.18%±1.41% (n=3), respectively, with no statistically significant difference between groups (P>0.05). Conversely, 99m The EF of Tc-Sestamibi decreased significantly with increasing flow rate (P < 0.05): it was 39.19% ± 4.93% (n=3) at 5.0 mL / min, decreased to 30.88% ± 2.68% (n=3) at 8.4 mL / min, and further decreased to 24.20% ± 3.25% (n=4) at 16.0 mL / min. This indicates... 99m Tc-3-F-4BOHboroxime has the same... 99m Tc-Teboroxime has similar myocardial uptake properties, but its myocardial retention capacity is significantly better than that of Tc-Teboroxime. 99m Tc-Teboroxime is more suitable for SPECT-based rapid dynamic imaging of the myocardium and quantitative blood flow analysis.

[0144] Table 10 shows the filter membrane residue rates during sterilization filtration of the formulations in Examples 1-3 and Example 6. The data in the table show that after sterilization filtration using a sterile filter membrane (0.22μm, PVDF, Merk) and rinsing the membrane with 2mL of physiological saline, approximately 82% of the developer was recovered, resulting in a filter membrane residue rate of less than 20%. In Example 6, after sterilization filtration using a sterile filter membrane (0.22μm, PVDF, Merk) and rinsing the membrane with 2mL of physiological saline, only about 55% of the developer was recovered, resulting in a filter membrane residue rate exceeding 40%.

[0145] Table 10 As shown in Table 10, after the preparation of the filter membrane using 2-hydroxypropyl-γ-cyclodextrin as an excipient, the filter membrane residue during sterilization filtration is <20%, and no treatment with organic solvents such as propylene glycol is required.

[0146] In summary, the formulation in this application... 99m Tc-3-F-4BOHboroxime exhibits superior imaging and quantitative performance, demonstrating significant advantages in SPECT myocardial rapid dynamic phenomena, blood flow quantification, and myocardial perfusion function assessment.

[0147] The results above show that the fluorinated substituted arylboronic acid of this application... 99m Tc(III) complexes and currently reported 99m Compared to Tc-Teboroxime, it has significant advantages in several aspects, including 99m Tc-3-F-4BOHboroxime exhibits superior biological performance, demonstrating excellent SPECT rapid dynamic imaging of the myocardium and quantitative blood flow analysis capabilities, making it suitable for clinical applications.

[0148] The above description is merely a specific implementation of this application. Those skilled in the art will clearly understand that, for the sake of convenience and brevity, the specific working process described above can be referred to the corresponding process in the foregoing method embodiments, and will not be repeated here. It should be understood that the protection scope of this application is not limited thereto. Any person skilled in the art can easily conceive of various equivalent modifications or substitutions within the technical scope disclosed in this application, and these modifications or substitutions should all be covered within the protection scope of this application.

Claims

1. A developer composition, characterized in that, Raw materials include: 1,2-Cyclohexanedione dioxime, 1 mg to 3 mg; Sodium chloride, 5mg~15mg; R-substituted boric acid, 1mg~10mg; Reducing agent, 35μg~75μg; pH adjuster, 8mg~10mg; Ligand exchanger, 1mg~3mg; Excipients, 30mg~100mg; The 1,2-cyclohexanedione dioxime reacts with the R-substituted boric acid to form a Tc(III) complex containing a fluorinated substituted arylboronic acid. The fluorinated substituted arylboronic acid 99 The Tc(III) complex has the structural formula shown in Formula 1. Formula 1, R is selected from one of 2-fluoro-4-hydroxymethylphenylboronic acid, 3-fluoro-4-hydroxymethylphenylboronic acid, 2,6-difluoro-4-hydroxymethylphenylboronic acid, 3,5-difluoro-4-hydroxymethylphenylboronic acid, and 2,5-difluoro-4-hydroxymethylphenylboronic acid; the excipient includes 2-hydroxypropyl-γ-cyclodextrin.

2. The developer composition according to claim 1, characterized in that, The developing agent composition contains Na added during labeling. 99m The activity of TcO4 is 370 MBq to 3700 MBq, and the volume is 0.2 mL to 3 mL.

3. The developer composition according to claim 2, characterized in that, The labeling conditions for the developer composition are: reaction at 100~110℃ for 10~20 min.

4. The use of the imaging agent composition according to any one of claims 1-3 in the preparation of an imaging agent for SPECT quantitative analysis of myocardial blood flow, characterized in that, The applications include: Acquire dynamic projection data from a SPECT / CT system, wherein the dynamic projection data comprises fluorinated substituted arylboronic acid. 99 The imaging agent of the ᵐTc(III) complex was collected after injection, and the collection time was the first preset time; The dynamic projection data is corrected and reconstructed to generate a cross-sectional dynamic SPECT image, resulting in list-mode data. The list-mode data is processed by frame segmentation to generate a first dataset and a second dataset. The first dataset is a multi-frame mixed time interval dataset, and the second dataset is a multi-frame unified time interval dataset. Time-radioactivity curves are extracted from the first dataset. A kinetic model is fitted using the activity curves to generate kinetic parameters. Myocardial blood flow values ​​are obtained based on the kinetic parameters. Region of interest analysis was performed on the second dataset. Regions of interest were selected on the same tomographic image that simultaneously displayed the myocardium and liver. The average radioactivity counts of the heart and liver regions were measured and output.

5. The application according to claim 4, characterized in that, The imaging agent is injected in a two-stage manner, including a local injection and an imaging bolus injection; wherein, the local injection uses an imaging agent dose of 30-40 MBq and a volume of 1.5-2.5 mL; the imaging bolus injection uses an imaging agent dose of 350-390 MBq and a volume of 2.5-3.5 mL, and the dynamic projection data acquisition is initiated at a second preset time before the imaging bolus injection.

6. The application according to claim 4, characterized in that, The correction includes 99 The reconstruction employs at least one of the following: Tc isotope attenuation correction, photon scattering correction, collimator resolution correction, and Poisson noise modeling; the reconstruction uses an iterative reconstruction algorithm, which has 30-40 iterations and 1-3 subsets.

7. The application according to claim 4, characterized in that, The first dataset is a mixed time interval dataset of 20-24 frames, wherein the mixed time interval includes a combination of 10-15 seconds / frame, 20-30 seconds / frame and 40-60 seconds / frame. The second dataset is a uniform time interval dataset of 12-20 frames, wherein the uniform time interval is 0.8-1.2 minutes / frame, and the total duration of the second dataset is consistent with the first preset time.

8. A fluorinated substituted arylboronic acid 99 ᵐTc complex, characterized in that, The fluorinated substituted arylboronic acid 99 The Tc(III) complex has the structural formula shown in Formula 1. Formula 1, Wherein, R is selected from one of 2-fluoro-4-hydroxymethylphenylboronic acid, 3-fluoro-4-hydroxymethylphenylboronic acid, 2,6-difluoro-4-hydroxymethylphenylboronic acid, 3,5-difluoro-4-hydroxymethylphenylboronic acid and 2,5-difluoro-4-hydroxymethylphenylboronic acid.

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