Application of near-infrared fluorescent probe in preparation of diagnosis, prevention and / or treatment medicine

Abstract

The invention discloses an application of a near-infrared fluorescent probe in preparation of a near-infrared first region and near-infrared second region diagnosis, prevention and / or treatment medicine, and belongs to the technical field of organic fluorescent molecules. The near-infrared fluorescent probe specifically targets a skin growth factor receptor (EGFR), has good near-infrared first-region and second-region capabilities, can be developed for in vivo diagnosis, can also be used for intraoperative positioning, can be applied to operations such as fluorescent near-infrared first-region and second-region guided tumor and the like, has a certain clinical application prospect, and has a wide application prospect. The method is applied to clinical near-infrared first-zone and second-zone intraoperative navigation.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic fluorescent molecules, and particularly relates to application of a near-infrared fluorescent probe in preparation of a diagnosis, prevention and / or treatment drug. BACKGROUND

[0002] With the rapid development of the economic society and the continuous improvement of the living standard, high-oil and high-fat dietary habits directly affect people's health, and the incidence of cancer, cardiovascular diseases and other diseases increases year by year. The World Health Organization statistics report shows that cancer control and prevention is facing an unprecedented challenge, and it has become the main cause of death, and its burden is increasing. Typical examples are lung cancer, esophageal cancer, pancreatic cancer and ovarian cancer, which are common malignant tumors worldwide and the main cause of cancer-related deaths. And with the development of malignant tumors, the incidence and primary tumor type, stage, the probability and time of lymph node metastasis of different types of malignant tumors are different. Generally speaking, the higher the malignancy and the later the stage of the tumor, the more likely it is to have lymph node metastasis. Urinary tract disease is also one of the common diseases, especially in women, and its incidence increases with age, and the incidence of pregnant women is even higher. The incidence of urinary tract infection in people over 60 years old can reach 40%-50%. The main reason for this phenomenon is that the efforts in early screening of cancer are insufficient, so that appropriate treatment is not obtained before the early stage of cancer or before the cancer worsens, ultimately resulting in the patient being diagnosed at an intermediate or advanced stage, which greatly shortens the effective survival period of the patient.

[0003] In the diagnosis and treatment of lung cancer, esophageal cancer, pancreatic cancer, ovarian cancer, positive metastatic lymph nodes, and urinary tract disease imaging, current clinical practice still faces many challenges that urgently need to be addressed. For example, early lung cancer lesions are often hidden within complex lung tissue, making it easy for conventional imaging to miss small primary lesions or positive mediastinal metastatic lymph nodes. In esophageal cancer, the boundary between the primary lesion and the surrounding esophageal wall is often blurred, making it difficult to accurately locate the tumor extent and perigastric positive metastatic lymph nodes preoperatively, and leading to misjudgment of resection boundaries during surgery. Pancreatic cancer, located deep in the abdominal cavity, has a complex relationship with peripancreatic blood vessels and nerves, making it difficult for current imaging to clearly distinguish the extent of tumor infiltration, and also hindering the diagnosis of retroperitoneal positive metastatic lymph nodes. The detection rate of metastatic lymph nodes is low; primary pelvic lesions of ovarian cancer often adhere to organs such as the uterus and ureter, making it difficult to accurately identify ureteral invasion using traditional imaging preoperatively. During surgery, damage is easily caused due to the inability to clearly track the course of the ureter, and small positive metastatic lymph nodes in the pelvis are also easily missed. In the diagnosis and treatment of urinary tract diseases, the localization of lesions such as urinary tract stones, obstruction, and tumors often relies on iodine-containing contrast agents or ultrasound. The former is contraindicated in patients with renal insufficiency, and the latter has insufficient imaging clarity for lesions in the upper ureter and renal pelvis. Furthermore, due to physiological structure, ureteral probe imaging is a core challenge in urinary molecular imaging. The ureter, with a diameter of only 2-4 mm, a winding course, and narrow areas, makes it difficult for probes to be diluted by urine or pass through transiently, resulting in poor imaging throughout its entire length. The rhythmic peristalsis of its smooth muscle (1-5 times / min) and the rapid flushing of urine (1-3 ml / min) reduce probe dwell time to the minute level, leading to poor binding stability. Furthermore, the thin ureteral wall and scarcity of specific targets limit targeted probe design. Background interference is another issue; acids, enzymes, and proteins in urine easily damage probes and induce non-specific binding, quenching the signal and increasing background noise. Signals from adjacent kidneys, bladders, and intestines can mask ureteral imaging, bone scattering can cause signal distortion, and pathological reflux can easily lead to false positives. In addition, the lack of ureter-specific high-expression targets results in a high off-target rate for probes, and their optical properties (penetration and resolution) and size (nanomolecules / small molecules) are difficult to adapt to the physiological characteristics of the ureter. Dynamic processes within the ureter are difficult to capture in imaging, and respiratory movements can produce artifacts, further exacerbating imaging difficulties. These combined problems constitute the imaging bottleneck.

[0004] Furthermore, for positive metastatic lymph nodes in the aforementioned cancers, current detection methods mostly rely on postoperative pathological biopsy, lacking effective tools for preoperative non-invasive precise localization and intraoperative real-time visual tracking. This leads to some patients having inappropriate treatment plans due to the lack of clear information about the extent of lymph node metastasis before surgery, or incomplete removal of metastatic lymph nodes during surgery due to the inability to accurately identify them, thus affecting prognosis.

[0005] Traditional contrast agents (such as iodine-containing contrast agents and sodium fluorescein) either pose risks of allergies and nephrotoxicity, or can only be visualized in the visible light region or short wavelength range of the near-infrared region, with shallow tissue penetration depth (usually <1cm), and are easily interfered with by the autofluorescence of biological tissues, making it difficult to meet the needs of deep lesions (such as pancreatic tumors and retroperitoneal lymph nodes) or real-time intraoperative visualization.

[0006] Near-infrared I (NIR-I, 700-900nm) and near-infrared II (NIR-II, 1000-1700nm) light have advantages such as deeper tissue penetration (NIR-II penetration depth can reach 3-5cm), lower absorption and scattering in biological tissues, and weaker autofluorescence interference. Probes developed based on these two bands can effectively overcome the shortcomings of traditional imaging techniques: NIR-I probes can improve the imaging clarity of superficial and moderate-depth lesions (such as peripheral nodules of lung cancer and lesions in the middle and lower segments of the urinary tract), while NIR-II probes can achieve high-resolution imaging of deep tissues (such as pancreatic tumors, positive metastatic lymph nodes in the mediastinum / retroperitoneum, and lesions in the upper segment of the ureter), and both can reduce radiation exposure and contrast agent-related adverse reactions. Meanwhile, designing probes to be targeted (such as targeting specific targets on the surface of tumor cells like EGFR, HER-2, and mesothelin, or targeting ligands for macrophages and ureteral epithelial cells in lymph nodes) can further enhance the specific identification capabilities of primary tumor lesions, positive metastatic lymph nodes, and urinary tract lesions, achieving an integrated system of "precise localization, real-time tracking, and efficacy evaluation." For example, NIR-II probes targeting EGFR can specifically bind to lung cancer and esophageal cancer tumor cells, providing real-time visualization of tumor boundaries and micrometastases during surgery; NIR-I probes targeting mesothelin can accurately identify primary pancreatic cancer lesions and peritoneal metastatic nodules; and near-infrared probes targeting ureteral epithelial cells can track the course of the ureter in real-time during gynecological and urological surgeries, avoiding damage. In the field of precision oncology diagnosis and treatment, the signal-to-noise ratio of intraoperative or diagnostic imaging directly determines the accuracy of lesion identification and the completeness of surgical resection. The tumor-to-background ratio (TBR) is a core indicator for measuring the specific enrichment ability of fluorescent probes. Its value directly affects the imaging contrast, the clarity of lesion boundary definition, and the effectiveness of subsequent intervention strategies. For example, near-infrared II imaging (wavelength 1000-1700nm) is beneficial for minimizing background interference and has a higher tumor-to-background ratio (TBR) compared with near-infrared I imaging (wavelength 650-900nm).

[0007] TBR essentially reflects the probe's distribution selectivity between target and non-target tissues. Generally, a TBR > 1.5 is sufficient to distinguish between target and paratarget tissues, while a TBR ≥ 2 is considered to have preliminary intraoperative visualization potential (Feng, J., Qin, H., Yang, W., Cheng, H., Xu, J., Han, J., Mou, J., Wang, H., & Ni, X. (2022). Frontiers in Pediatrics. (https: / / doi.org / 10.3389 / fped.2022.875688). Furthermore, a larger TBR (e.g., TBR ≥ 3–4) is more conducive to high-contrast imaging, supporting reliable detection of sub-millimeter-scale small lesions. Taking hepatocellular carcinoma (HCC) as an example, the humanized anti-GPC3 antibody-conjugated ICG NIR-II probe (GPC3-ICG) developed by Shi et al. achieved a TBR ≈ 3 in a GPC3-positive Huh-7 tumor-bearing mouse model, significantly superior to the isotype control IgG-ICG. Its specific enrichment of tumor tissue was verified by ex vivo organ imaging (Shi, H., Huttad, LV, Tan, M., Liu, H., Chua, M.-S., Cheng, Z., & So, S. (2021). MedChemComm (https: / / doi.org / 10.1039 / d1md00313e). This result shows that even with the same disease course and imaging window, the molecular design of the probe can still lead to orders of magnitude differences in TBR.

[0008] In summary, developing contrast agents with stronger tumor targeting capabilities, which are beneficial for high-contrast imaging, and which also have ureteral imaging capabilities, is of great clinical significance. Summary of the Invention

[0009] 1. Purpose of the invention To address the issues of poor tumor targeting capability or unsatisfactory imaging contrast of existing mature probes such as ICG, this invention provides a near-infrared fluorescent probe, particularly for use in drugs for the diagnosis, prevention, and / or treatment of tumors and / or urinary tract diseases in the near-infrared II region.

[0010] 2. Technical Solution To solve the above problems, the technical solution adopted in this application is as follows: Application of near-infrared fluorescent probes, wherein the near-infrared fluorescent probe is a compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I); In formula (Ⅰ): X is a linker molecule, selected from any one of the following: no chain, polyethylene glycol chain, and polyglycine chain; Y is a dye molecule with fluorescence excitation and emission spectra in the near-infrared range; the structural formula of Y is shown in formula (II) below: Formula (II); In formula (II): R1 and R2 are selected from (CH2)nSO3H, where n=3 or 4; Z is selected from 3-mercaptopropionic acid or 4-hydroxyphenylpropionic acid.

[0011] Furthermore, the applications include the use in the preparation of medicaments for the diagnosis, prevention, and / or treatment of tumors and / or urinary tract diseases in the near-infrared I and / or near-infrared II regions; specifically, the applications include, but are not limited to, any one or more of the following a) to m): a) Application in the preparation of drugs for diagnosing tumors in the near-infrared spectroscopy region I; b) Application in the preparation of drugs for diagnosing urinary tract diseases in the near-infrared zone I; c) Application in the preparation of near-infrared 1 region drugs for tumor prevention; d) Application in the preparation of drugs for the prevention of urinary tract diseases in the near-infrared zone I; e) Application in the preparation of near-infrared 1 region drugs for tumor treatment; f) Application in the preparation of near-infrared zone I drugs for treating urinary tract diseases; g) Its application in the preparation of drugs for near-infrared II diagnosis of tumors; h) Application in the preparation of drugs for diagnosing urinary tract diseases in the near-infrared second region; j) Application in the preparation of near-infrared II zone tumor prevention drugs; k) Application in the preparation of drugs for the prevention of urinary tract diseases in the near-infrared second zone; l) Application in the preparation of near-infrared II zone drugs for tumor treatment; m) Application in the preparation of near-infrared II zone drugs for treating urinary tract diseases; As a preferred embodiment of the first aspect of the present invention, the near-infrared fluorescent probe is selected from compounds represented by the following formula (Ⅰ-01) or pharmaceutically acceptable salts thereof: Formula (Ⅰ-01).

[0012] As a preferred embodiment of the first aspect of the present invention, the near-infrared fluorescent probe is selected from compounds represented by the following formula (Ⅰ-02) or pharmaceutically acceptable salts thereof: Formula (Ⅰ-02).

[0013] As a preferred embodiment of the first aspect of the present invention, the near-infrared fluorescent probe is selected from compounds represented by the following formula (Ⅰ-03) or pharmaceutically acceptable salts thereof: Formula (Ⅰ-03).

[0014] As a preferred embodiment of the first aspect of the present invention, the near-infrared fluorescent probe is selected from compounds represented by the following formula (Ⅰ-04) or pharmaceutically acceptable salts thereof: Formula (Ⅰ-04).

[0015] As a preferred embodiment of the first aspect of the present invention, the near-infrared fluorescent probe is selected from any plurality of compounds shown in formulas (I-01) to (I-04) or pharmaceutically acceptable salts thereof: Formula (Ⅰ-01), Formula (Ⅰ-02), Formula (Ⅰ-03), Formula (Ⅰ-04).

[0016] As a preferred embodiment of any of the first aspects of the present invention, the application includes its use in the preparation of near-infrared I region fluorescent contrast agents, fluorescent imaging agents and / or fluorescent tracers.

[0017] As any preferred embodiment of the first aspect of the present invention, the application includes its use in the preparation of near-infrared II fluorescent contrast agents, fluorescent imaging agents, and / or fluorescent tracers.

[0018] As a preferred embodiment of the first aspect of the present invention, the near-infrared fluorescent probe is a near-infrared fluorescent probe that targets the epidermal growth factor receptor.

[0019] As a preferred embodiment of any of the first aspects of the present invention, the tumor is a tumor that overexpresses epidermal growth factor receptor.

[0020] As a preferred embodiment of any of the first aspects of the present invention, the tumor is one or more of lung cancer, esophageal cancer, ovarian cancer, and pancreatic cancer, and their positive metastatic lymph nodes.

[0021] As a preferred embodiment of any of the first aspects of the present invention, the tumor includes one or more of the following: lung adenocarcinoma, pancreatic ductal adenocarcinoma, epithelial ovarian cancer, and esophageal squamous cell carcinoma.

[0022] As a preferred embodiment of any of the first aspects of the present invention, the tumor includes types associated with positive lymph node metastasis.

[0023] As a preferred embodiment of any of the first aspects of the present invention, the urinary tract disease includes one or more of the following: kidney and renal pelvis diseases, ureteral diseases, bladder diseases, urethral diseases, and systemic / cross-site urinary tract diseases.

[0024] As described herein, “urinary tract diseases” are classified according to the anatomical location of the urinary tract. In general, the urinary tract covers the entire urination pathway, including the kidneys, renal pelvis / calyces, ureters, bladder, and urethra. Related diseases can be classified according to the location of onset and pathological type, including kidney and renal pelvis diseases, ureteral diseases, bladder diseases, urethral diseases, and systemic / cross-site urinary tract diseases.

[0025] The "kidney and renal pelvis diseases" described herein primarily refer to conditions located at the beginning of the upper urinary tract, including pyelonephritis, ureteropelvic junction obstruction, renal pelvis stones, renal pelvis tumors, and hydronephrosis. Specifically: Pyelonephritis: an infectious disease of the renal pelvis and renal parenchyma, which is divided into acute (caused by pathogens such as Escherichia coli, accompanied by fever, back pain, urinary frequency and urgency) and chronic (recurrent infection leads to renal parenchyma damage, which can progress to renal insufficiency).

[0026] Ureteral pelvis obstruction: Congenital or acquired stenosis obstructs the outflow of urine from the renal pelvis, leading to hydronephrosis. In the long term, it can compress the renal parenchyma and cause renal function decline.

[0027] Kidney pelvis stones: Crystalline substances in urine deposit in the renal pelvis to form stones, which can block the urinary tract and cause renal colic, hematuria, and even hydronephrosis.

[0028] Renal pelvis tumors: mostly urothelial carcinomas, which manifest as painless gross hematuria and can easily spread along the urinary tract mucosa to the ureter and bladder.

[0029] Hydronephrosis: Various causes (stones, obstruction, tumors) lead to urine retention in the renal pelvis, dilation of the renal calyces, and compression of the renal parenchyma, which impairs kidney function.

[0030] As described herein, "ureteral diseases" are located in the middle of the upper urinary tract and include ureteral stones, ureteral strictures, ureteritis, ureteral tumors, ureteral reflux, and ureteral diverticula. Specifically: Ureteral stones: mostly formed by the dislodging of kidney stones, they are prone to becoming lodged in physiological narrowings of the ureter (ureteropelvic junction, iliac vessel crossing, ureterovesical junction), causing renal colic, hematuria, and in severe cases, hydronephrosis.

[0031] Ureteral stricture: Congenital developmental abnormalities, inflammatory scars (such as sequelae of ureteritis), surgical damage, etc. can lead to narrowing of the ureteral lumen and obstruction of urine outflow.

[0032] Ureteral inflammation: Infectious (ascent / hematogenous infection of pathogens) or non-infectious (autoimmune, radiation damage) inflammation, manifested as urinary frequency and back pain, which can lead to thickening and stenosis of the ureteral wall in the long term.

[0033] Ureteral tumors: mainly urothelial carcinoma, which can occur unilaterally or bilaterally. The typical symptom is painless hematuria, and it is prone to invading surrounding tissues or metastasizing.

[0034] Ureteral reflux: When the anti-reflux mechanism at the ureterovesical junction fails, urine from the bladder refluxes into the ureter and even the renal pelvis. Repeated infections can lead to renal parenchymal damage (reflux nephropathy).

[0035] Ureteral diverticulum: A localized outward bulge of the ureteral wall to form a sac-like structure, which easily retains urine, leading to stones, infection, and even malignant transformation.

[0036] As described herein, "bladder diseases" refer to the core storage organs of the lower urinary tract and include cystitis, bladder stones, bladder tumors, overactive bladder, bladder neck obstruction, and neurogenic bladder. Specifically: Cystitis: The most common lower urinary tract infection, divided into acute bacterial cystitis (more common in women, accompanied by urinary frequency, urgency, dysuria, and lower abdominal distension) and interstitial cystitis (chronic non-infectious inflammation, manifested as persistent urinary frequency and pelvic pain).

[0037] Bladder stones: These are formed by crystal deposits in urine or by the dislodging of upper urinary tract stones. They can cause urinary interruption, painful urination, and hematuria. Long-term irritation of the bladder mucosa increases the risk of malignant transformation.

[0038] Bladder tumors: Urothelial carcinoma accounts for more than 90% of cases, presenting as painless gross hematuria, which may be accompanied by urinary frequency and urgency. In advanced stages, it may invade the bladder wall or metastasize to pelvic lymph nodes.

[0039] Overactive bladder: Excessive contraction of the bladder detrusor muscle, manifested as urinary frequency, urgency, increased nocturia, and even urge incontinence, without any clear organic lesions.

[0040] Bladder neck obstruction: In women, it is often due to bladder neck sclerosis, while in men it is often due to prostatic hyperplasia causing compression, leading to difficulty urinating and incomplete urination. Over time, this can result in increased residual urine in the bladder and hydronephrosis.

[0041] Neurogenic bladder: Spinal cord injury, diabetic neuropathy, etc. lead to bladder nerve dysfunction, which manifests as difficulty urinating, urinary retention, or urinary incontinence.

[0042] As described herein, "urethral diseases" are located in the terminal segment of the lower urinary tract and include urethritis, urethral stricture, urethral stones, urethral tumors, and urinary incontinence. Specifically: Urethritis: Gonococcal urethritis (a sexually transmitted disease, accompanied by purulent discharge from the urethra and dysuria) or non-gonococcal urethritis (chlamydia / mycoplasma infection, with milder symptoms) can easily ascend to the bladder and ureters.

[0043] Urethral stricture: Congenital urethral developmental abnormalities, trauma (such as pelvic fracture), and inflammatory scars (sequelae of urethritis) can lead to narrowing of the urethral lumen, causing difficulty in urination and a thin urine stream.

[0044] Urethral stones: mostly formed by bladder stones falling out and becoming lodged in the narrow part of the urethra, causing painful urination, interruption of urination, or even urinary retention.

[0045] Urethral tumors: more common in men, and are divided into benign (urethral polyps) and malignant (urethral cancer, which manifests as hematuria, difficulty urinating, and easily invades surrounding tissues).

[0046] Urinary incontinence: stress incontinence (leakage when abdominal pressure increases, such as coughing or laughing), urge incontinence (sudden urge to urinate that cannot be controlled), and mixed incontinence, which are associated with urethral sphincter dysfunction.

[0047] As described herein, “systemic / transsite urinary tract disease” includes urinary tract infection (UTI), urinary tuberculosis, congenital urinary tract malformations, and urinary tract obstruction. Specifically; Urinary tract infection (UTI): refers to any infection in the urinary tract, including upper urinary tract infection (pyelonephritis) and lower urinary tract infection (cystitis, urethritis). The pathogens are mostly Escherichia coli, and repeated infections can lead to chronic kidney disease.

[0048] Urinary tract tuberculosis: Mycobacterium tuberculosis invades the urinary tract, often secondary to pulmonary tuberculosis. It first affects the kidneys and then spreads along the ureters to the bladder, manifesting as low-grade fever, night sweats, hematuria, and urinary frequency. In the late stage, it can lead to urinary tract stricture and renal failure.

[0049] Congenital urinary tract malformations, such as horseshoe kidney (renal fusion malformation), duplicated ureters (unilateral or bilateral ureteral duplication), and hypospadias (abnormal male urethral opening), are prone to causing infection, stones, and obstruction.

[0050] Urinary tract obstruction: Any blockage or compression of the urinary tract lumen that obstructs the flow of urine can be classified as upper urinary tract obstruction (kidney, ureter) and lower urinary tract obstruction (bladder, urethra). Long-term obstruction can lead to irreversible damage to kidney function.

[0051] As a preferred embodiment of any of the first aspects of the present invention, the urinary tract disease preferably includes ureteral disease.

[0052] As any preferred technical solution of the first aspect of the present invention, the ureteral disease includes one or more of ureteral stones, ureteral stricture, ureteritis, ureteral tumor, ureteral reflux, and ureteral diverticulum.

[0053] As a preferred technical solution of the first aspect of the present invention, its application in the preparation of near-infrared ureteral fluorescent contrast agent, ureteral fluorescent imaging agent, ureteral fluorescent contrast agent and / or ureteral fluorescent tracer.

[0054] As a preferred technical solution of any of the first aspects of the present invention, the application in the preparation of near-infrared II ureteral fluorescent contrast agents, ureteral fluorescent imaging agents, ureteral fluorescent contrast agents and / or ureteral fluorescent tracers.

[0055] A second aspect of this invention provides a method for diagnosing, preventing, and / or treating tumors and / or urinary tract diseases using a near-infrared fluorescent probe in the near-infrared I and / or near-infrared II regions, wherein the near-infrared fluorescent probe is a compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I); In formula (Ⅰ): X is a linker molecule, selected from any one of the following: no chain, polyethylene glycol chain, and polyglycine chain; Y is a dye molecule with fluorescence excitation and emission spectra in the near-infrared range; the structural formula of Y is shown in formula (II) below: Formula (II); In formula (II): R1 and R2 are selected from (CH2)nSO3H, where n=3 or 4; Z is selected from 3-mercaptopropionic acid or 4-hydroxyphenylpropionic acid.

[0056] As a preferred embodiment of the second aspect of the present invention, the near-infrared fluorescent probe is selected from compounds represented by the following formula (Ⅰ-01) or pharmaceutically acceptable salts thereof: Formula (Ⅰ-01).

[0057] As a preferred embodiment of the second aspect of the present invention, the near-infrared fluorescent probe is selected from compounds represented by the following formula (Ⅰ-02) or pharmaceutically acceptable salts thereof: Formula (Ⅰ-02).

[0058] As a preferred embodiment of the second aspect of the present invention, the near-infrared fluorescent probe is selected from compounds represented by the following formula (I-03) or pharmaceutically acceptable salts thereof: Formula (Ⅰ-03).

[0059] As a preferred embodiment of the second aspect of the present invention, the near-infrared fluorescent probe is selected from compounds represented by the following formula (I-04) or pharmaceutically acceptable salts thereof: Formula (Ⅰ-04).

[0060] As a preferred embodiment of the second aspect of the present invention, the near-infrared fluorescent probe is selected from any plurality of compounds shown in formulas (I-01) to (I-04) or pharmaceutically acceptable salts thereof: Formula (Ⅰ-01), Formula (Ⅰ-02), Formula (Ⅰ-03), Formula (Ⅰ-04).

[0061] As a preferred embodiment of the second aspect of the present invention, a method for diagnosing, preventing and / or treating tumors and / or urinary tract diseases by using a near-infrared fluorescent probe to perform fluorescence imaging, fluorescence tracing and / or fluorescence imaging in the near-infrared region.

[0062] As any preferred technical solution of the first aspect of the present invention, a method for diagnosing, preventing and / or treating tumors and / or urinary tract diseases by using near-infrared fluorescent probes to perform fluorescence imaging, fluorescence tracing and / or fluorescence imaging in the near-infrared II region.

[0063] As a preferred embodiment of the second aspect of the present invention, the near-infrared fluorescent probe is a near-infrared fluorescent probe that targets the epidermal growth factor receptor.

[0064] As a preferred embodiment of the second aspect of the present invention, the tumor is a tumor that overexpresses epidermal growth factor receptor.

[0065] As a preferred embodiment of the second aspect of the present invention, the tumor is one or more of lung cancer, esophageal cancer, ovarian cancer, and pancreatic cancer.

[0066] As a preferred embodiment of any of the second aspects of the present invention, the tumor includes one or more of the following: lung adenocarcinoma, pancreatic ductal adenocarcinoma, epithelial ovarian cancer, and esophageal squamous cell carcinoma.

[0067] As a preferred embodiment of any second aspect of the present invention, the tumor includes types associated with positive lymph node metastasis.

[0068] As a preferred embodiment of any of the second aspects of the present invention, the urinary tract disease includes one or more of the following: kidney and renal pelvis diseases, ureteral diseases, bladder diseases, urethral diseases, and systemic / cross-site urinary tract diseases.

[0069] As described herein, “urinary tract diseases” are classified according to the anatomical location of the urinary tract. In general, the urinary tract covers the entire urination pathway, including the kidneys, renal pelvis / calyces, ureters, bladder, and urethra. Related diseases can be classified according to the location of onset and pathological type, including kidney and renal pelvis diseases, ureteral diseases, bladder diseases, urethral diseases, and systemic / cross-site urinary tract diseases.

[0070] The "kidney and renal pelvis diseases" described herein primarily refer to conditions located at the beginning of the upper urinary tract, including pyelonephritis, ureteropelvic junction obstruction, renal pelvis stones, renal pelvis tumors, and hydronephrosis. Specifically: Pyelonephritis: an infectious disease of the renal pelvis and renal parenchyma, which is divided into acute (caused by pathogens such as Escherichia coli, accompanied by fever, back pain, urinary frequency and urgency) and chronic (recurrent infection leads to renal parenchyma damage, which can progress to renal insufficiency).

[0071] Ureteral pelvis obstruction: Congenital or acquired stenosis obstructs the outflow of urine from the renal pelvis, leading to hydronephrosis. In the long term, it can compress the renal parenchyma and cause renal function decline.

[0072] Kidney pelvis stones: Crystalline substances in urine deposit in the renal pelvis to form stones, which can block the urinary tract and cause renal colic, hematuria, and even hydronephrosis.

[0073] Renal pelvis tumors: mostly urothelial carcinomas, which manifest as painless gross hematuria and can easily spread along the urinary tract mucosa to the ureter and bladder.

[0074] Hydronephrosis: Various causes (stones, obstruction, tumors) lead to urine retention in the renal pelvis, dilation of the renal calyces, and compression of the renal parenchyma, which impairs kidney function.

[0075] As described herein, "ureteral diseases" are located in the middle of the upper urinary tract and include ureteral stones, ureteral strictures, ureteritis, ureteral tumors, ureteral reflux, and ureteral diverticula. Specifically: Ureteral stones: mostly formed by the dislodging of kidney stones, they are prone to becoming lodged in physiological narrowings of the ureter (ureteropelvic junction, iliac vessel crossing, ureterovesical junction), causing renal colic, hematuria, and in severe cases, hydronephrosis.

[0076] Ureteral stricture: Congenital developmental abnormalities, inflammatory scars (such as sequelae of ureteritis), surgical damage, etc. can lead to narrowing of the ureteral lumen and obstruction of urine outflow.

[0077] Ureteral inflammation: Infectious (ascent / hematogenous infection of pathogens) or non-infectious (autoimmune, radiation damage) inflammation, manifested as urinary frequency and back pain, which can lead to thickening and stenosis of the ureteral wall in the long term.

[0078] Ureteral tumors: mainly urothelial carcinoma, which can occur unilaterally or bilaterally. The typical symptom is painless hematuria, and it is prone to invading surrounding tissues or metastasizing.

[0079] Ureteral reflux: When the anti-reflux mechanism at the ureterovesical junction fails, urine from the bladder refluxes into the ureter and even the renal pelvis. Repeated infections can lead to renal parenchymal damage (reflux nephropathy).

[0080] Ureteral diverticulum: A localized outward bulge of the ureteral wall to form a sac-like structure, which easily retains urine, leading to stones, infection, and even malignant transformation.

[0081] As described herein, "bladder diseases" refer to the core storage organs of the lower urinary tract and include cystitis, bladder stones, bladder tumors, overactive bladder, bladder neck obstruction, and neurogenic bladder. Specifically: Cystitis: The most common lower urinary tract infection, divided into acute bacterial cystitis (more common in women, accompanied by urinary frequency, urgency, dysuria, and lower abdominal distension) and interstitial cystitis (chronic non-infectious inflammation, manifested as persistent urinary frequency and pelvic pain).

[0082] Bladder stones: These are formed by crystal deposits in urine or by the dislodging of upper urinary tract stones. They can cause urinary interruption, painful urination, and hematuria. Long-term irritation of the bladder mucosa increases the risk of malignant transformation.

[0083] Bladder tumors: Urothelial carcinoma accounts for more than 90% of cases, presenting as painless gross hematuria, which may be accompanied by urinary frequency and urgency. In advanced stages, it may invade the bladder wall or metastasize to pelvic lymph nodes.

[0084] Overactive bladder: Excessive contraction of the bladder detrusor muscle, manifested as urinary frequency, urgency, increased nocturia, and even urge incontinence, without any clear organic lesions.

[0085] Bladder neck obstruction: In women, it is often due to bladder neck sclerosis, while in men it is often due to prostatic hyperplasia causing compression, leading to difficulty urinating and incomplete urination. Over time, this can result in increased residual urine in the bladder and hydronephrosis.

[0086] Neurogenic bladder: Spinal cord injury, diabetic neuropathy, etc. lead to bladder nerve dysfunction, which manifests as difficulty urinating, urinary retention, or urinary incontinence.

[0087] As described herein, "urethral diseases" are located in the terminal segment of the lower urinary tract and include urethritis, urethral stricture, urethral stones, urethral tumors, and urinary incontinence. Specifically: Urethritis: Gonococcal urethritis (a sexually transmitted disease, accompanied by purulent discharge from the urethra and dysuria) or non-gonococcal urethritis (chlamydia / mycoplasma infection, with milder symptoms) can easily ascend to the bladder and ureters.

[0088] Urethral stricture: Congenital urethral developmental abnormalities, trauma (such as pelvic fracture), and inflammatory scars (sequelae of urethritis) can lead to narrowing of the urethral lumen, causing difficulty in urination and a thin urine stream.

[0089] Urethral stones: mostly formed by bladder stones falling out and becoming lodged in the narrow part of the urethra, causing painful urination, interruption of urination, or even urinary retention.

[0090] Urethral tumors: more common in men, and are divided into benign (urethral polyps) and malignant (urethral cancer, which manifests as hematuria, difficulty urinating, and easily invades surrounding tissues).

[0091] Urinary incontinence: stress incontinence (leakage when abdominal pressure increases, such as coughing or laughing), urge incontinence (sudden urge to urinate that cannot be controlled), and mixed incontinence, which are associated with urethral sphincter dysfunction.

[0092] As described herein, “systemic / transsite urinary tract disease” includes urinary tract infection (UTI), urinary tuberculosis, congenital urinary tract malformations, and urinary tract obstruction. Specifically; Urinary tract infection (UTI): refers to any infection in the urinary tract, including upper urinary tract infection (pyelonephritis) and lower urinary tract infection (cystitis, urethritis). The pathogens are mostly Escherichia coli, and repeated infections can lead to chronic kidney disease.

[0093] Urinary tract tuberculosis: Mycobacterium tuberculosis invades the urinary tract, often secondary to pulmonary tuberculosis. It first affects the kidneys and then spreads along the ureters to the bladder, manifesting as low-grade fever, night sweats, hematuria, and urinary frequency. In the late stage, it can lead to urinary tract stricture and renal failure.

[0094] Congenital urinary tract malformations, such as horseshoe kidney (renal fusion malformation), duplicated ureters (unilateral or bilateral ureteral duplication), and hypospadias (abnormal male urethral opening), are prone to causing infection, stones, and obstruction.

[0095] Urinary tract obstruction: Any blockage or compression of the urinary tract lumen that obstructs the flow of urine can be classified as upper urinary tract obstruction (kidney, ureter) and lower urinary tract obstruction (bladder, urethra). Long-term obstruction can lead to irreversible damage to kidney function.

[0096] As a preferred embodiment of any of the second aspects of the present invention, the urinary tract disease preferably includes ureteral disease.

[0097] As a preferred embodiment of any of the second aspects of the present invention, the ureteral disease includes one or more of the following: ureteral stones, ureteral stricture, ureteritis, ureteral tumor, ureteral reflux, and ureteral diverticulum.

[0098] The third aspect of the present invention provides a medicament or kit for diagnosing, preventing and / or treating tumors and / or urinary tract diseases in the near-infrared I and / or near-infrared II regions, comprising any one or more compounds of formulas (I-01) to (I-04) or pharmaceutically acceptable salts thereof; Formula (Ⅰ-01), Formula (Ⅰ-02), Formula (Ⅰ-03), Formula (Ⅰ-04); As a preferred embodiment of any of the third aspects of the present invention, the tumor is a tumor that overexpresses epidermal growth factor receptor, or the tumor includes one or more of lung cancer, esophageal cancer, ovarian cancer, and pancreatic cancer and types associated with positive lymph node metastasis, or the tumor includes one or more of lung adenocarcinoma, pancreatic ductal adenocarcinoma, epithelial ovarian cancer, and esophageal squamous cell carcinoma and types associated with positive lymph node metastasis.

[0099] As a preferred embodiment of any third aspect of the present invention, the urinary tract disease includes one or more of the following: kidney and renal pelvis diseases, ureteral diseases, bladder diseases, urethral diseases, and systemic / cross-site urinary tract diseases.

[0100] Preferably, the urinary tract disease includes ureteral disease.

[0101] As a preferred embodiment of any third aspect of the present invention, the urinary tract disease includes one or more of the following: ureteral stones, ureteral stricture, ureteritis, ureteral tumor, ureteral reflux, and ureteral diverticulum.

[0102] 3. Beneficial effects Compared with the prior art, the advantages of this application are as follows: (1) The near-infrared fluorescent probe provided by the present invention can actively target the epidermal growth factor receptor and has the potential for imaging in the near-infrared I and near-infrared II regions. Compared with the existing indocyanine green (ICG), it has higher fluorescence efficiency and better near-infrared II imaging capability. It can be applied to the diagnosis, prevention and / or treatment of tumors and / or urinary tract diseases in the near-infrared I and near-infrared II regions. It can provide a higher tumor-to-background ratio (TBR) and a deeper penetration depth, effectively improving the success rate of tumor surgical resection and effectively improving the postoperative quality of life of patients.

[0103] (2) The near-infrared fluorescent probe provided by the present invention is particularly suitable for use in near-infrared I and II fluorescent contrast agents, fluorescent imaging agents and / or fluorescent tracers in the diagnosis, prevention and / or treatment of one or more of the tumors, such as lung cancer, esophageal cancer, ovarian cancer, and pancreatic cancer and their positive metastatic lymph nodes.

[0104] (3) The near-infrared fluorescent probe provided by the present invention has good in vivo metabolic characteristics. After entering the body, it is excreted in the form of urine through the kidney. It has good ureter imaging potential and can be used to prepare drugs such as urinary tract (especially ureter) contrast agents, imaging agents (contrast agents), and tracers. It has application potential in clinical fields such as gynecology and urology for ureter localization or protection. Attached Figure Description

[0105] Figure 1 The results are for near-infrared fluorescence detection of probes NY-EGF-02, NY-EGF-03, NY-EGF-05, NY-EGF-06 and ICG in the second region. Figure 2 Near-infrared 1 and 2 region in vivo imaging results of compounds NY-EGF-02, NY-EGF-03, NY-EGF-05 and NY-EGF-06 in HCC827 lung cancer-bearing mice; Figure 3 The results of in vivo near-infrared imaging in regions I and II of the probes NY-EGF-02 and NY-EGF-05 in KYSE30 esophageal cancer-bearing mice. Figure 4 The results of in vivo near-infrared imaging in regions I and II of the probes NY-EGF-02 and NY-EGF-05 in mice bearing OVCAR3 subcutaneous ovarian cancer tumors; Figure 5 The results of in vivo near-infrared I and II imaging of probes NY-EGF-02 and NY-EGF-05 in IGROV-1 subcutaneous tumor-bearing mice with ovarian cancer; Figure 6 The results of in vivo near-infrared imaging in regions I and II of the probes NY-EGF-02, NY-EGF-05 and NY-EGF-06 in mice bearing OVCAR3-positive groin metastatic lymph nodes of ovarian cancer. Figure 7 The results of in vivo near-infrared imaging in regions I and II of the probes NY-EGF-02, NY-EGF-03, and NY-EGF-05 in ASPC-1 subcutaneous tumor-bearing mice with pancreatic cancer are shown. Figure 8 The results of in vivo near-infrared imaging in regions I and II of the probes NY-EGF-02, NY-EGF-03, NY-EGF-05 and NY-EGF-06 in mice bearing subcutaneous pancreatic cancer PANC1 tumors. Figure 9 The ureter of the probe NY-EGF-05 was visualized in a healthy rabbit. Detailed Implementation

[0106] The present application will be further described below with reference to specific embodiments.

[0107] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains; the term “and / or” as used herein includes any and all combinations of one or more of the associated listed items.

[0108] Unless otherwise specified in the examples, the procedures should be performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0109] As used herein, the term “about” is used to provide for the flexibility and imprecision associated with a given term, measure, or value. Those skilled in the art can readily determine the degree of flexibility for a particular variable. As used herein, the term “at least one of…” is intended to be synonymous with “one or more of…”. For example, “at least one of A, B, and C” explicitly includes only A, only B, only C, and combinations thereof. Concentration, amount, and other numerical data may be presented in range format herein. It should be understood that such range format is used solely for convenience and brevity and should be flexibly interpreted to include not only the values ​​explicitly stated as the limits of the range, but also all individual values ​​or subranges encompassed within the range, as if each value and subrange were explicitly stated. For example, a range of values ​​from about 1 to about 4.5 should be interpreted to include not only the explicitly stated limits of 1 to 4.5, but also individual numbers (such as 2, 3, 4) and subranges (such as 1 to 3, 2 to 4, etc.). The same principle applies to ranges that describe only a single value, such as "less than about 4.5," which should be interpreted to include all the values ​​and ranges described above. Furthermore, this interpretation should apply regardless of the breadth of the range or characteristic described.

[0110] 1. The synthesis steps of the near-infrared fluorescent probe NY-EGF-02 are as follows:

[0111] 2. The synthesis steps of the near-infrared fluorescent probe NY-EGF-03 are as follows:

[0112] 3. The synthesis steps of the near-infrared fluorescent probe NY-EGF-05 are as follows:

[0113] 4. The synthesis steps of the near-infrared fluorescent probe NY-EGF-06 are as follows:

[0114] The HCC827, KYSE30, ASPC-1, PANC-1, OVCAR3, and IGROW-1 subcutaneous tumor-bearing mouse models used in the experiment were all constructed in the laboratory. Balb / c tumor-bearing mice (female, 4-6 weeks old, weighing 18-22g) were selected. Cells obtained from cell culture (approximately 1.0 × 10⁵) were injected into the axilla of the upper limb of immunodeficient tumor-bearing mice, and allowed to grow to 100 mm. 3 Around 3-4 weeks after the start of the experiment, the mice were given the cells and the drug was administered. The positive lymph node metastasis model involved injecting cells into the hind limb paw pads of mice, followed by drug administration 3-4 weeks later.

[0115] Example 1 Near-infrared II fluorescence efficiency detection of compounds NY-EGF-02, NY-EGF-03, NY-EGF-05, NY-EGF-06 and ICG Compounds NY-EGF-02, NY-EGF-03, NY-EGF-05, NY-EGF-06, and ICG were prepared into a 10 nmol / 100 μL solution using 5% glucose injection. The solutions were then analyzed using a small animal in vivo drug screening system (Suzhou Yingrui Optical Technology Co., Ltd., Dali-IGS-600). The instrument parameters were: LP1000 filter, 2W power, and 100ms exposure time. The results are as follows: Figure 1 As shown, under the experimental conditions, compounds NY-EGF-02, NY-EGF-03, NY-EGF-05, and NY-EGF-06 exhibit stronger near-infrared II luminescence efficiency than ICG, and thus possess better potential for near-infrared II imaging.

[0116] Example 2 Near-infrared spectroscopy (NIRS) in vivo imaging of the HCC827 subcutaneous tumor-bearing mouse model (human lung cancer cells) in regions I and II was performed in this embodiment. The NY-EGF-02, NY-EGF-03, NY-EGF-05 and NY-EGF-06 probes were selected for the experiment.

[0117] In a subcutaneous tumor-bearing mouse model (HCC827), NY-EGF-02, NY-EGF-03, NY-EGF-05, and NY-EGF-06 probes (10 nmol / mouse, 100 μL glucose injection) were administered via tail vein. 120 h after administration, near-infrared fluorescence imaging was performed in the near-infrared I and near-infrared II regions using a surgical fluorescence imaging system (Nanjing Nuoyuan Medical Instrument Co., Ltd., 10B) and a small animal in vivo drug screening system (Suzhou Yingrui Optical Technology Co., Ltd., Dali-IGS-600). The results are as follows: Figure 2 As shown.

[0118] The results showed (combined with)Figure 2 (as shown) (1) In HCC827 subcutaneous tumor-bearing mice, four probes, NY-EGF-02, NY-EGF-03, NY-EGF-05 and NY-EGF-06, showed good tumor targeting ability and the tumor imaging window exceeded 120 h. (2) The four probes NY-EGF-02, NY-EGF-03, NY-EGF-05 and NY-EGF-06 have good near-infrared imaging potential in regions I and II; (3) Among the four probes NY-EGF-02, NY-EGF-03, NY-EGF-05 and NY-EGF-06, the near-infrared region II imaging has a higher tumor-to-background ratio (TBR) compared to the near-infrared region I. (4) The four probes NY-EGF-02, NY-EGF-03, NY-EGF-05 and NY-EGF-06 have good imaging potential in the near-infrared I and II regions and have good prospects for clinical near-infrared II fluorescent indole tumor surgical resection.

[0119] After processing and calculation, the imaging results showed that near-infrared II imaging had a higher tumor-to-background ratio (TBR), such as... Figure 2 As shown in the table, the compounds represented by formula (I) of this invention, especially compounds NY-EGF-02, NY-EGF-03, NY-EGF-05, and NY-EGF-06, have the potential for further development as probes, with the aim of applying them to clinical near-infrared spectral guidance for tumor resection in lung cancer.

[0120] Example 3 Near-infrared 1 and 2 in vivo imaging of the KYSE30 subcutaneous tumor-bearing mouse model (human esophageal cancer cells) was performed. In this embodiment, NY-EGF-02 and NY-EGF-05 probes were selected for the experiment.

[0121] In the KYSE30 subcutaneous tumor-bearing mouse model, NY-EGF-02 and NY-EGF-05 (10 nmol / mouse, 100 μL glucose injection) were administered via tail vein, respectively. 72 h after administration, near-infrared fluorescence imaging was performed in the near-infrared I and near-infrared II regions using a surgical fluorescence imaging system (Nanjing Nuoyuan Medical Instrument Co., Ltd., 10B) and a small animal in vivo drug screening system (Suzhou Yingrui Optical Technology Co., Ltd., Dali-IGS-600), respectively. The results are as follows: Figure 3 As shown.

[0122] The results showed (combined with) Figure 3 (as shown) (1) In the KYSE30 subcutaneous tumor-bearing mouse model, probes NY-EGF-02 and NY-EGF-05 have good near-infrared imaging potential in regions I and II, with imaging time exceeding 72 hours. (2) Near-infrared II imaging can improve the tumor-to-background ratio. Compared with near-infrared I imaging, it has a lower background signal and a deeper detection depth, resulting in a higher tumor-to-background ratio (TBR value).

[0123] After processing and calculation, the imaging results showed that, for example Figure 3 As shown in the table, the compound probes of formula (I) of the present invention, especially probes NY-EGF-02 and NY-EGF-05, have good near-infrared II imaging potential and can be further developed for clinical near-infrared II fluorescence-guided intraoperative tumor navigation.

[0124] Example 4 Near-infrared 1 and 2 region in vivo imaging of subcutaneous tumor OVCAR3 and IGROWV-1 tumor-bearing mouse models (human ovarian cancer cells) was performed. In this embodiment, NY-EGF-02 and NY-EGF-05 probes were selected for the experiment.

[0125] In subcutaneous tumor-bearing mouse models OVCAR3 and IGROW-1, NY-EGF-02 and NY-EGF-05 probes (10 nmol / mouse, 100 μL glucose injection) were administered via tail vein, respectively. After 48 hours, near-infrared fluorescence imaging was performed using a surgical fluorescence imaging system (Nanjing Nuoyuan Medical Instrument Co., Ltd., 10B) and a small animal in vivo drug screening system (Suzhou Yingrui Optical Technology Co., Ltd., Dali-IGS-600). The results are as follows: Figure 2 As shown.

[0126] The results showed (combined with) Figure 4 and Figure 5 (as shown) (1) The compound probes shown in formula (I) of the present invention, especially probes NY-EGF-02 and NY-EGF-05, have good tumor targeting ability in ovarian cancer-bearing mice and have good potential for near-infrared I and II imaging applications. (2) Near-infrared II imaging can improve the tumor-to-background ratio. Compared with near-infrared I imaging, it has a lower background signal and a deeper detection depth, resulting in a higher tumor-to-background ratio (TBR value).

[0127] After processing and calculation, the imaging results showed that, for example Figure 4 , 5As shown in the table, the compound probes of formula (I) of the present invention, especially probes NY-EGF-02 and NY-EGF-05, have good near-infrared II imaging potential and can be further developed for clinical near-infrared I and II fluorescence-guided tumor surgical resection.

[0128] Example 5 Near-infrared spectroscopy (NIRS) in vivo imaging of OVCAR3 tumor-bearing mouse model (human ovarian cancer cells) in groin positive metastatic lymph nodes was performed using probes NY-EGF-02, NY-EGF-05, and NY-EGF-06.

[0129] In the OVCAR3 tumor-bearing mouse model of positive metastatic lymph nodes in the groin, NY-EGF-02, NY-EGF-05 and NY-EGF-06 probes (3 nmol / mouse, 30 μL glucose injection) were administered to the paw of the modeling side 24 h later. Near-infrared I and near-infrared II fluorescence imaging were performed using a surgical fluorescence imaging system (Nanjing Nuoyuan Medical Instrument Co., Ltd., 10B) and a small animal in vivo drug screening system (Suzhou Yingrui Optical Technology Co., Ltd., Dali-IGS-600).

[0130] The results showed (combined with) Figure 6 (as shown) (1) The compound probes shown in formula (I) of the present invention, especially probes NY-EGF-02, NY-EGF-05 and NY-EGF-06, have good ability to detect positive lymph nodes in mice bearing ovarian cancer-positive metastatic lymph nodes; (2) The compound probes shown in formula (I) of the present invention, especially probes NY-EGF-02, NY-EGF-05 and NY-EGF-06, have good potential for near-infrared I and II imaging in mice with ovarian cancer-positive metastatic lymph nodes. (3) Near-infrared II imaging can improve the tumor-to-background ratio. Compared with near-infrared I imaging, it has a lower background signal and a deeper detection depth, resulting in a higher tumor-to-background ratio (TBR value).

[0131] After processing and calculation, the imaging results showed that, for example Figure 6 As shown in the table, the compound probes of formula (I) of the present invention, especially probes NY-EGF-02, NY-EGF-05 and NY-EGF-06, have good near-infrared I and II imaging potential and can be further developed for clinical positive lymph node dissection, improving the success rate of tumor surgical resection and reducing the postoperative recurrence rate.

[0132] Example 6 Near-infrared spectroscopy (NIRS) in vivo imaging of the ASPC-1 subcutaneous tumor-bearing mouse model (human pancreatic cancer cells) in regions I and II was performed. In this embodiment, NY-EGF-02, NY-EGF-03, and NY-EGF-05 probes were selected for the experiment.

[0133] In the ASPC-1 subcutaneous tumor-bearing mouse model, NY-EGF-02, NY-EGF-03, and NY-EGF-05 probes (10 nmol / mouse, 100 μL glucose injection) were administered via tail vein, respectively. 48 h after administration, near-infrared fluorescence imaging in the near-infrared I and near-infrared II regions was performed using a surgical fluorescence imaging system (Nanjing Nuoyuan Medical Instrument Co., Ltd., 10B) and a small animal in vivo drug screening system (Suzhou Yingrui Optical Technology Co., Ltd., Dali-IGS-600).

[0134] The results showed (combined with) Figure 7 (as shown) (1) The compound probes shown in Formula (I) of the present invention, especially probes NY-EGF-02, NY-EGF-03 and NY-EGF-05, showed good tumor uptake in the ASPC-1 subcutaneous tumor-bearing mouse model, with an imaging time of more than 72 hours.

[0135] (2) Probes NY-EGF-02, NY-EGF-03 and NY-EGF-05 have good near-infrared I and II imaging capabilities. Compared with near-infrared I, near-infrared II imaging has lower background signal and higher tumor-to-background ratio.

[0136] After processing and calculation, the imaging results showed that, for example Figure 7 As shown in the table, the compound probes of formula (I) of the present invention, especially probes NY-EGF-02, NY-EGF-03 and NY-EGF-06, have potential for clinical near-infrared I and II imaging and good prospects for clinical fluorescence-guided tumor surgical resection.

[0137] Example 7 Near-infrared spectroscopy (NIRS) in vivo imaging of the subcutaneous tumor PANC-1 tumor-bearing mouse model (human pancreatic cancer cells) was performed in this embodiment. The NY-EGF-02, NY-EGF-03 and NY-EGF-05 probes were selected for the experiment.

[0138] In the subcutaneous tumor PANC-1 tumor-bearing mouse model, NY-EGF-02, NY-EGF-03, NY-EGF-05 and NY-EGF-06 probes (10 nmol / mouse, 100 μL glucose injection) were administered via tail vein, respectively. 48 h after administration, near-infrared fluorescence imaging in the near-infrared I and near-infrared II regions was performed using a surgical fluorescence imaging system (Nanjing Nuoyuan Medical Instrument Co., Ltd., 10B) and a small animal in vivo drug screening system (Suzhou Yingrui Optical Technology Co., Ltd., Dali-IGS-600).

[0139] The results showed (combined with) Figure 8 (as shown) (1) Probes NY-EGF-02, NY-EGF-03, NY-EGF-05 and NY-EGF-06 showed good tumor uptake in the ASPC-1 subcutaneous tumor-bearing mouse model, with imaging time exceeding 48 hours.

[0140] (2) Probes NY-EGF-02, NY-EGF-03, NY-EGF-05 and NY-EGF-06 have good near-infrared imaging capabilities in regions I and II. (3) Compared with the near-infrared region I, the near-infrared region II imaging of probes NY-EGF-02, NY-EGF-03, NY-EGF-05 and NY-EGF-06 has lower background signal and higher tumor-to-background ratio.

[0141] After processing and calculation, the imaging results showed that, for example Figure 7 As shown in the table, the compound probes of formula (I) of the present invention, especially probes NY-EGF-02, NY-EGF-03, NY-EGF-05 and NY-EGF-06, have potential clinical near-infrared I and II imaging potential and good prospects for clinical fluorescence-guided tumor surgical resection.

[0142] Example 8 In vivo fluorescence imaging of the ureter of a healthy New Zealand rabbit was performed using the NY-EGF-05 probe in this embodiment.

[0143] Healthy New Zealand rabbits were anesthetized with sodium pentobarbital. The abdomen of the rabbits was opened to expose the kidneys and bladder. The intestines were dissected to one side. NY-EGF-05 (100 nmol / rabbit, 1 mL glucose injection) was administered via the marginal ear vein. After the administration, about 50 mL of glucose injection was injected via the marginal ear vein. Fluorescence imaging was performed using a surgical fluorescence imaging system (Nanjing Nuoyuan Medical Instrument Co., Ltd., 10B) and near-infrared I and near-infrared II fluorescence imaging using a small animal in vivo drug screening system (Suzhou Yingrui Optical Technology Co., Ltd., Dali-IGS-600).

[0144] The results showed (combined with) Figure 9 (as shown) In normal rabbits, after administration of the probe NY-EGF-05, a significant fluorescent signal was observed in the ureter, and this signal continued to appear in the ureter as urine was excreted from the kidneys. After processing and calculation, the imaging results showed that near-infrared II imaging had a higher tumor-to-background ratio (TBR), such as... Figure 9 As shown in the table, the compound probes represented by formula (I) of this invention, especially the probe NY-EGF-05, have potential clinical application prospects and applications in ureteral imaging, specifically NIR-I and NIR-II, with the aim of being used for intraoperative ureteral localization and protection.

[0145] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. The application of near-infrared fluorescent probes, characterized in that, The near-infrared fluorescent probe is a compound of formula (I) or a pharmaceutically acceptable salt thereof: Equation (I); In formula (Ⅰ): X is a linker molecule, selected from non-chain, polyethylene glycol, and polyglycine chains, and Y is a dye molecule with fluorescence excitation and emission spectra in the near-infrared range; the structural formula of Y is shown in formula (II) below: Formula (II); In formula (II): R1 and R2 are selected from (CH2)nSO3H, where n=3 or 4; Z is selected from 3-mercaptopropionic acid or 4-hydroxyphenylpropionic acid; The applications include the use in the preparation of medicaments for the detection, diagnosis, prevention, and / or treatment of tumors and / or urinary tract diseases in the near-infrared I and / or near-infrared II regions.

2. The application of the near-infrared fluorescent probe according to claim 1, characterized in that, The near-infrared fluorescent probe is selected from any one or more of the compounds shown in Formulas (I-01) to (I-04) or their pharmaceutically acceptable salts: Formula (Ⅰ-01), Formula (Ⅰ-02), Formula (Ⅰ-03), Formula (Ⅰ-04).

3. The application of the near-infrared fluorescent probe according to claim 2, characterized in that, Including applications in the preparation of near-infrared II fluorescent contrast agents, fluorescent imaging agents, and / or fluorescent tracers; And / or, in the preparation of near-infrared I region fluorescent contrast agents, fluorescent imaging agents and / or fluorescent tracers.

4. The application of the near-infrared fluorescent probe according to any one of claims 1 to 3, characterized in that, The near-infrared fluorescent probe is a near-infrared fluorescent probe that targets the epidermal growth factor receptor.

5. The application of the near-infrared fluorescent probe according to any one of claims 1 to 3, characterized in that, The tumor in question is one that overexpresses epidermal growth factor receptor.

6. The application of the near-infrared fluorescent probe according to any one of claims 1 to 3, characterized in that, The tumor is one or more of the following: lung cancer, esophageal cancer, ovarian cancer, and pancreatic cancer.

7. The application of the near-infrared fluorescent probe according to any one of claims 1 to 3, characterized in that, The tumor includes one or more of the following: lung adenocarcinoma, pancreatic ductal adenocarcinoma, epithelial ovarian cancer, and esophageal squamous cell carcinoma.

8. The application of the near-infrared fluorescent probe according to claim 6 or 7, characterized in that, The tumors include types associated with positive lymph node metastasis.

9. The application of the near-infrared fluorescent probe according to any one of claims 1 to 3, characterized in that, The urinary tract diseases include one or more of the following: kidney and renal pelvis diseases, ureteral diseases, bladder diseases, urethral diseases, and systemic / cross-site urinary tract diseases; preferably, the urinary tract diseases include ureteral diseases.

10. The application of the near-infrared fluorescent probe according to claim 9, characterized in that, The ureteral diseases include one or more of the following: ureteral stones, ureteral stricture, ureteritis, ureteral tumor, ureteral reflux, and ureteral diverticulum.

11. A drug or reagent kit for diagnosing, preventing, and / or treating tumors and / or urinary tract diseases in the near-infrared I and / or near-infrared II regions, characterized in that, Including any one or more of the compounds shown in formulas (I-01) to (I-04) or their pharmaceutically acceptable salts; Formula (Ⅰ-01), Formula (Ⅰ-02), Formula (Ⅰ-03), Formula (Ⅰ-04); The tumor is a tumor that overexpresses epidermal growth factor receptor, or the tumor includes one or more of lung cancer, esophageal cancer, ovarian cancer, and pancreatic cancer and types associated with positive lymph node metastasis, or the tumor includes one or more of lung adenocarcinoma, pancreatic ductal adenocarcinoma, epithelial ovarian cancer, and esophageal squamous cell carcinoma and types associated with positive lymph node metastasis. The urinary tract disease includes one or more of the following: kidney and renal pelvis disease, ureteral disease, bladder disease, urethral disease, systemic / cross-site urinary tract disease, or the urinary tract disease includes one or more of the following: ureteral stones, ureteral stricture, ureteritis, ureteral tumor, ureteral reflux, and ureteral diverticulum.

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