18 Application of F-FAPI-42 in the preparation of products for diagnosing pulmonary lymphangioleiomyomatosis

Abstract

The present application relates to 18 The application of F-FAPI-42 in the preparation of a product for diagnosing pulmonary lymphangioleiomyomatosis belongs to the technical field of contrast imaging agents. 18 The application of F-FAPI-42 in the preparation of a product for diagnosing pulmonary lymphangioleiomyomatosis. FAPI is a new type of PET tracer, and the PET / CT of FAPI has the characteristics of low radiation exposure, fast in vivo metabolism, and is not affected by blood sugar level changes, and the patient has better tolerance. Radioisotope 18 F has a longer half-life and higher electron energy than 68 Ga, and has more advantages in clinical use. 18 As a new type of PET / CT tracer, F-FAPI-42 is significantly better than the traditional tracer 18 F-FDG in evaluating the condition of LAM patients, identifying lesions in LAM patients, including renal vascular smooth muscle lipomas, mediastinal lymphangioleiomyomas, abdominal lymphangioleiomyomas and pelvic lymphangioleiomyomas.

Description

Technical Field

[0001] This invention relates to the field of contrast imaging agents, and more particularly to... 18 Application of F-FAPI-42 in the preparation of products for diagnosing pulmonary lymphangioleiomyomatosis. Background Technology

[0002] Lymphangioleiomyomatosis (LAM) is a rare disease characterized by diffuse cystic lesions in the lungs, which may have distant metastases. It includes two clinical subtypes: sporadic LAM (S-LAM) and tuberous sclerosis complex associated lymphangioleiomyomatosis (TSC-LAM). LAM is a systemic disease affecting multiple organs. Early symptoms are often subtle, typically presenting as progressively worsening dyspnea, which may be accompanied by pneumothorax, chylothorax, hemoptysis, and other pulmonary symptoms. Extrapulmonary manifestations are most commonly angiomyolipoma (AML), and may also include meningiomas and lymphangioleiomyomas (extrapulmonary lymphadenopathy and axial lymphatic cystic masses).

[0003] Currently, diagnostic methods for LAM include lung biopsy, high-resolution computed tomography (HRCT), and positron emission tomography / computed tomography (PET / CT).

[0004] Lung biopsy is the gold standard for diagnosing LAM, but because pathological examination is an invasive procedure and carries risks such as inducing complications like pneumothorax and hemoptysis, it has certain limitations in clinical diagnosis and treatment.

[0005] High-resolution CT is a commonly used imaging technique for diagnosing cystic changes in the lungs. When HRCT reveals typical diffuse cystic changes in the lungs, the presence of one or more of the following features is sufficient to diagnose lung aneurysm (LAM): tuberous sclerosis complex (TSC), angiomyolipoma (AML), serum vascular endothelial growth factor-D ≥ 800 pg / ml, chylothorax or chylous ascites, lymphangiomyoma, the presence of LAM cells or LAM cell clusters in serous cavity effusions or lymph nodes, or histopathological confirmation of LAM (lung, retroperitoneal, or pelvic tumor). Because LAM is a low-grade malignant tumor that affects multiple organs and has a metastatic potential, a whole-body scan is usually required to assess tumor invasion. However, HRCT has limitations in detecting smaller lesions and lymphatic system lesions.

[0006] Positron emission tomography (PET) is often combined with computed tomography (CT) and has become an important advanced imaging technology in oncology. In PET / CT, a radioactive tracer is injected into the bloodstream. Due to the specific cellular biological characteristics of tumors, the radioactive tracer will accumulate, thus accurately locating the tumor and helping to accurately determine the extent of tumor metastasis. 18 F-deoxyglucose ( 18 F-FDG is a commonly used injectable radioactive tracer, and has been used by scholars in the past. 18 F-FDG evaluation of LAM revealed that LAM and AMLs did not show positive results in FDG-PET scans.

[0007] Cancer-associated fibroblasts (CAFs) are a major component of the stroma surrounding epithelial cancer cells and a key factor in cancer progression. They produce fibroblast activation protein (FAP), and FAP-positive CAFs play an important role in tumor progression and metastasis. FAP is expressed in wound healing, fibrosis, and the stroma of many malignant tumors, but its expression is low in normal adult tissues. Quinoline-based fibroblast activation protein inhibitors (FAPIs) specifically bind to the FAP-related enzyme domain. FAPI is a novel PET tracer; PET / CT using FAPI has the advantages of low radiation exposure, rapid in vivo metabolism, and insensitivity to changes in blood glucose levels, resulting in better patient tolerance. FAPI can bind to the type II transmembrane serine protease FAP expressed by CAFs and is now used for the evaluation of various tumors and interstitial lung diseases.

[0008] However, CAFs exhibit significant heterogeneity, and various subgroups lack clear biomarkers. Therefore, the precise cellular origin of CAFs remains unclear, and not all tumors are suitable for PET / CT scan diagnosis using FAPI as a tracer. Summary of the Invention

[0009] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a better method for identifying disease lesions. 18 Application of F-FAPI-42 in the preparation of products for diagnosing pulmonary lymphangioleiomyomatosis.

[0010] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0011] In a first aspect, the present invention provides 18 Application of F-FAPI-42 in the preparation of products for diagnosing pulmonary lymphangioleiomyomatosis.

[0012] This invention uses 18 F-FAPI-42, used to prepare a product for diagnosing pulmonary lymphangioleiomyomatosis (LAM), is significantly superior to other products in diagnosing LAM patients. 18 F-FDG.

[0013] Furthermore, the product is a developer.

[0014] Furthermore, the product is a PET / CT imaging agent.

[0015] Furthermore, the products include those for diagnosing sporadic lymphangioleiomyomatosis and / or hereditary tuberous sclerosis-associated pulmonary lymphangioleiomyomatosis.

[0016] Furthermore, the product is for identifying lesions of pulmonary lymphangioleiomyomatosis.

[0017] In a specific embodiment of the present invention, the lesion includes renal angiomyolipoma.

[0018] In a specific embodiment of the present invention, the lesion includes a mediastinal lymphangioma.

[0019] In a specific embodiment of the present invention, the lesion includes an abdominal lymphangiomyoma.

[0020] In a specific embodiment of the present invention, the lesion includes a pelvic lymphangioma.

[0021] Furthermore, the product is based on the 18 F-FAPI-42 is an imaging formulation made by adding an active ingredient to an additive and / or carrier that is acceptable for the preparation of an imaging agent.

[0022] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0023] FAPI is a novel PET tracer. PET / CT using FAPI features low radiation exposure, rapid metabolism, and is unaffected by changes in blood glucose levels, resulting in better patient tolerance. (Radioisotopes) 18 F compared to 68 Ga, with its longer half-life and higher electronic energy, is more advantageous in clinical use. 18 F-FAPI-42, a novel PET / CT tracer, is significantly superior to traditional tracers in assessing the condition of patients with laryngeal muscular adenoma (LAM) and identifying lesions, including renal angiomyolipoma, mediastinal lymphangiofibroid, abdominal lymphangiofibroid, and pelvic lymphangiofibroid. 18 F-FDG.

[0024] LAM nodules contain a large number of LAM-associated fibroblasts (LAFs), which are similar to CAFs and play an important role in LAM cell growth and disease progression. In this invention, 18 F-FAPI-42 and 18 When evaluating cystic lesions in the lungs of patients with lung atrophy (LAM) using both F-FDG and scintigraphy agents, there was no statistically significant difference in SUVmax and MTV / FTV. Although CAFs (calcified artery foci) exhibit similar characteristics in LAM lesions, CAFs are significantly heterogeneous, and various subpopulations lack clear biomarkers; therefore, the precise cellular origin of CAFs remains unclear. Based on the experimental results of this invention, it is suggested that LAFs in lung LAM lesions may not actually be CAFs. Clinically, this characteristic can be used to differentiate between cystic changes in LAM lungs and cystic changes caused by tumors or inflammation. Attached Figure Description

[0025] Figure 1 Maximum intensity projection (MIP) of the whole body for 4 typical S-LAM patients and 4 typical TSC-LAM patients 18 F-FAPI-42 and 18 F-FDG contrast imaging. In this case, A represents patients with S-LAM. 18 F-FAPI-42 contrast imaging; B represents a TSC-LAM patient. 18 F-FAPI-42 contrast imaging; C represents S-LAM patients. 18 F-FDG contrast imaging; D represents a TSC-LAM patient. 18 F-FDG contrast imaging. Black arrow: lymphangioleiomyomas; Red arrow: renal angiomyolipomas. The numbers below the images represent patient numbers.

[0026] Figure 2For a TSC-LAM patient (No. 23) with typical renal angiomyolipoma. 18 F-FDG and 18 F-FAPI-42 imaging. A is a whole-body coronal fusion image; B is a whole-body coronal CT image; C is a whole-body coronal PET image; D is a fusion image of lung window and abdominal transverse section; E is a lung window and abdominal CT transverse section image; F is a lung window and abdominal transverse section PET image. Red arrow: AML; white arrow: cystic lesions in the lungs.

[0027] Figure 3 For a 26-year-old typical S-LAM patient (No. 29) 18 F-FDG and 18 F-FAPI-42 images. Among them, A is a whole-body coronal fusion image; B is a whole-body coronal CT image; C is a whole-body coronal PET image; D is a lung window and pelvic transverse fusion image; E is a lung window and pelvic transverse CT image; F is a lung window and pelvic transverse PET image.

[0028] Figure 4 Visual assessment of lymphangiomyoma using SUVmax. Detailed Implementation

[0029] To better illustrate the purpose, technical solution, and advantages of this invention, the invention will be further described below with reference to specific embodiments. Unless otherwise specified, other materials and reagents used in the embodiments are commercially available.

[0030] 1. Study Subjects: All procedures performed in studies involving human participants complied with the ethical standards of the Clinical Research Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University and the Chinese Clinical Trial Registry (ChiCTR2100044944), and with the ethical standards of the Declaration of Helsinki 1964 and its subsequent revisions. Informed consent was obtained from all participants. Patients included in this study were recruited at the First Affiliated Hospital of Guangzhou Medical University between May 2021 and February 2024. The inclusion criteria were as follows: (1) patients newly diagnosed with S-LAM or TSC-LAM according to the 2017 American Thoracic Society and Japanese Respiratory Society Clinical Practice Guidelines; (2) patients who had received treatment within one month of the initial diagnosis using the following methods. 18 F-FAPI-42 (Fluoro-18-fluoro-1, ... 18 F-FDG (fluoro-18-fluorodeoxyglucose) was used for PET-CT dual-nuclide examination. Exclusion criteria are as follows: (1) 18 F-FAPI-42 and 18(1) Patients who did not agree to be included in the study. A total of 37 patients were included, of whom 37 were female (100%), with a median age of 33 years (range 22-45 years). Among them, 25 had S-LAM and 12 had TSC-LAM. Among the 37 patients, there were mediastinal lymphangioma (10), abdominal lymphangioma (24), pelvic lymphangioma (17), and renal angiomyolipoma (13), as shown in Table 1.

[0031] Table 1 Summary of Patient Characteristics

[0032]

[0033]

[0034] 2. Developer: 18 F-FDG and 18 The radiochemical purity of F-FAPI-42 exceeds 95%. The final product is diluted with physiological saline and filtered through a 0.22μm Millipore filter before being sterilized in a sterile multi-dose syringe. After testing confirms that the final product is sterile and pyrogen-free, it is then used clinically.

[0035] Example 1: PET-CT Imaging and Image Reconstruction

[0036] All patients used it for 7 consecutive days. 18 F-FAPI-42 and 18 F-FDG is used for PET-CT scanning. Patients must fast for at least 6 hours before the PET-CT scan. 18 Before undergoing a PET-CT scan with F-FDG, blood glucose levels should be adjusted to below 7.0 mmol / L (for diabetic patients, blood glucose should be below 11.1 mmol / L). 18 No special preparation (such as fasting or normal blood glucose levels) is required on the day of a PET-CT scan using the F-FAPI-42. The results are calculated based on the patient's weight. 18 F-FDG and 18 The injection dose of F-FAPI-42 is 3.7 MBq / kg.

[0037] Intravenous injection 18 F-FDG or 18Approximately 60 minutes (45–105 minutes) after F-FAPI-42, a head-to-mid-thigh PET-CT scan was performed. Following the whole-body PET-CT scan, a thin-slice CT scan of the chest was performed after breath-holding. All PET-CT scans were performed on two PET-CT scanners (uMi Panorama 35S, United Imaging Healthcare, Shanghai, China or Discovery MI; GE Healthcare, WI, USA) using the same standard protocols.

[0038] The Discovery MIPET-CT scanner parameters were: tube voltage 120kV, current 100mA, overall slice thickness 3.75mm; thin-slice chest CT tube voltage 120kV, current 150mA, slice thickness 1.25mm; tube voltage 120kV, current 150mA, end cap slice thickness 3.75mm. The uMi Panorama 35S PET-CT scanner parameters were: tube voltage 120kV; current, modulation mA; slice thickness 2.90mm. All patients underwent whole-body CT scans, and all acquired data were transferred to advanced workstations (uMl, R002, United Imaging Healthcare) and reconstructed using the Ordered Subset Expectation-Maximization (OSEM) algorithm (including 4 iterations, 10 subsets, and a 360*360 matrix).

[0039] Before the imaging agent is injected, medical staff check the patient's standard vital signs (such as blood pressure, heart rate, and body temperature) and ask the patient to report any symptoms within 2 hours after the PET-CT scan. All patients are responsive to the treatment. 18 F-FDG, 18 F-FAPI-42 was well tolerated during PET-CT scans, with no adverse reactions. 18 F-FDG, 18 There were no signs of adverse reactions related to F-FAPI-42, and no patients reported any abnormal symptoms.

[0040] Example 2: PET-CT Image Analysis and Statistics

[0041] 1. Analysis

[0042] use 18 F-FDG and 18 Images obtained from PET-CT scans performed on the F-FAPI-42 are interpreted by two nuclear medicine physicians with extensive experience in PET-CT diagnosis, and any disagreements are resolved through consultation.

[0043] To prevent bias, the study was conducted in groups (different physicians) according to study type: Group 1 physicians treated all patients using... 18The second group of physicians reviewed all images obtained from PET-CT scans using F-FDG. 18 Images from PET-CT scans performed using the F-FAPI-42 were reviewed.

[0044] A positive lesion is defined as one with higher radioactive uptake than the surrounding or contralateral normal tissue. A region of interest (ROI) is created for each lesion to obtain its maximum standard uptake (SUVmax). For lesions with negative uptake, ROIs are also created based on localization from other radiological examinations. If there are more than one lesion in a single organ, only the highest SUVmax is recorded. On PET-CT images, areas of tracer uptake that are visually above the background (mediastinal blood pool) are considered positive (the positivity rate for pulmonary cystic lesions and renal angiomyolipoma (RAML) is assessed visually by CT). The number of focal lesions (positive lesions) and their SUVmax are recorded. This invention evaluates some common organs and sites of LAM accumulation: lung, kidney, mediastinum, retroperitoneum, and pelvic lesions.

[0045] 2. Statistical analysis

[0046] All statistical analyses were performed using SPSS 22.5 and Graphpad Prism 9.5.0. The Shapiro-Wilk test was used to verify the normality of the samples. All continuous data were expressed as median (interquartile range). Paired-samples t-test and Wilcoxon rank-sum test were used for comparisons. 18 F-FAPI-42 and 18 Differences in SUVmax, TBR, MTV / FTV, and TLG / TLF between F-FDG and T-FDG were analyzed. Independent samples t-test and Mann-Whitney U test were used to compare SUVmax, TBR, MTV / FTV, and TLG / TLF between S-LAM and TSC-LAM. 18 F-FAPI-42 and 18 (F-FDG comparisons). A two-tailed p-value less than 0.05 was considered statistically significant.

[0047] II. Experimental Results

[0048] 1. General Clinical Data: 37 patients with LAM diagnosed according to guidelines were included, all female. Among them, 25 had S-LAM (67.57%), 12 had TSC-LAM (32.43%), and 13 had AML (35.14%), including 3 with S-LAM (23.08%) and 10 with TSC-LAM (76.92%). Three patients underwent allogeneic double lung transplantation (see Table 1). Figure 1 As shown, typical use 18 F-FAPI-42 and18 Maximum intensity projection imaging of PET-CT scans using F-FDG. In 8 patients... 18 In F-FAPI-42 images, varying degrees of hypermetabolic lesions were observed in the abdomen (retroperitoneum, including the area around the abdominal aorta and bilateral iliac arteries) and pelvis. Some patients also showed involvement of the mediastinum and bilateral inguinal regions. These lesions were... 18 F-FDG( Figure 1 C and Figure 1 No significant uptake was observed in D). Among them, 4 typical TSC-LAM patients ( Figure 1 B and Figure 1 D) All of them were accompanied by renal angiomyolipomas of varying degrees, and these lipomas were... 18 F-FAPI-42 imaging ( Figure 1 B) showed significant radioactive uptake, while 18 F-FDG imaging ( Figure 1 No significant uptake was observed in D). Furthermore, cystic lesions in the lungs of LAM patients... 18 F-FDG( Figure 1 C and Figure 1 D) and 18 F-FAPI-42 ( Figure 1 A and Figure 1 The radioactive uptake in B) was not significant.

[0049] 2. Imaging indicators assessment of cystic lesions in the lungs

[0050] After excluding 3 patients who underwent lung transplantation, lung images of 34 LAM patients were ultimately collected, using two imaging agents ( 18 F-FDG and 18 F-FAPI-42 showed no statistically significant difference in SUVmax and MTV / FTV in cystic lesions of the lungs of LAM patients [SUVmax: 2.17 (1.80-3.21) vs. SUVmax: 2.20 (1.76-2.54), P = 0.4365; FTV: 2122 (1921-2700) vs. MTV: 2159 (1826-2520), P = 0.2854]; for TBR and TLG / TLF, 18 The F-FAPI-42 is superior to 18 F-FDG showed statistically significant differences between the two [TBR: 1.71 (1.26-2.53) vs. TBR: 1.13 (0.95-1.38), P < 0.0001; TLF: 1228 (923.2-1544) vs. TLG: 952.6 (797.4-1153), P < 0.0001], see Table 2. All data are expressed as median.

[0051] Table 2. Patient lesions18 F-FDG and 18 Comparison of PET scan parameters for F-FAPI-42

[0052]

[0053]

[0054] In Table 2-4, “TBR” stands for target-background ratio; “MTV” stands for metabolic tumor volume; “TLG” stands for total lesion glycolysis; and “FTV” stands for FAPI-42-avid tumor volume. 18 F-FAPI-42 affinity tumor volume; "TLF": ​​Total lesion fibroblast activation protein expression; "Positive": Positive lesion; "No. of Positive Lesions / All": Number of positive lesions / all lesions.

[0055] 3. Imaging parameters assessment of renal angiomyolipoma (AML)

[0056] Of the 37 patients, 13 had AML, including 3 with S-LAM (23.08%) and 10 with TSC-LAM (76.92%). Among the four semi-quantitative parameters—SUVmax, TBR, MTV / FTV, and TLG / TLF—[…]. 18 F-FAPI-42 is significantly superior to both 18 F-FDG [SUVmax: 13.41 (11.29-18.14) compared with SUVmax: 3.8 (2.65-4.6); TBR: 10.7 (8.13-15.18) compared with TBR: 2.06 (1.63-2.58); FTV: 15.4 (3.70-199.7) compared with MTV: 12.30 (1.90-92.95); TLF: 72.34 (12.20-440.4) compared with TLG: 16.72 (2.81-109.6), all P values ​​< 0.001]. See Table 2. Typical AML patients 18 F-FAPI-42 and 18 Comparison of F-FDG PET / CT scans, see [link / image] Figure 2 AF. AML patients 18 The uptake of F-FAPI-42 (indicated by the red arrow) was significantly higher than that of other drugs.18 For F-FDG, the SUVmax of the former was approximately 11.1, and that of the latter was approximately 3.7. The uptake of cystic lesions in both groups was close to the background level. 18 The F-FAPI-42 SUV max is 1.73. 18 The F-FDG SUVmax is 1.58.

[0057] 4. Imaging assessment of lymphangiofibroids: Among the 37 patients, lymphangiofibroids were distributed in the mediastinum (10 patients, 27.03%), abdomen (24 patients, 64.86%), and pelvis (17 patients, 45.95%). 18 The detection rate of F-FAPI-42 was significantly better than that of other products. 18 F-FDG (mediastinal proportions: 100% and 29.41%; retroperitoneal proportions: 100% and 45.68%; pelvic proportions: 98.97% and 34.02%). In lymphangioma (mediastinal, retroperitoneal, and pelvic) 18 F-FAPI-42 and 18 In the comparison of semi-quantitative F-FDG indicators (SUVmax, TBR, MTV / FTV, and TLG / TLF), except for the mediastinal region's MTV / FTV [FTV: 1.21 (0.75-2.14) vs. MTV: 0.72 (0.63-1.48), P value = 0.0784 > 0.05], all other P values ​​were < 0.001. In lymphangioma imaging, 18 F-FAPI-42 imaging is significantly superior to... 18 F-FDG. See Table 2. Typical LAM patients 18 F-FAPI-42 and 18 For comparison of F-FDG PET / CT imaging, see Figure 3 AF. 18 F-FAPI-42 showed nodular and linear hypermetabolic lesions in the abdominal aorta, bilateral iliac vessels, and bilateral inguinal regions (as indicated by arrows). 18 F-FDG showed no significant radioactive uptake at the aforementioned sites. The SUVmax of the cystic lesions in the patient's lungs was close to background values ​​under both imaging agents (FAPI = 3.0, FDG = 1.6). For visual assessment of the SUVmax of the lymphangioma, see [link to relevant documentation]. Figure 4 .

[0058] 5. Comparative Analysis of Imaging Indicators between S-LAM and TSC-LAM: Among the 37 patients, 25 had S-LAM and 12 had TSC-LAM. Semi-quantitative comparative analysis of imaging indicators was performed on the two subgroups of lymphangiofibroids (mediastinal, retroperitoneal, and pelvic) and AML (S-LAM 3 patients, TSC-LAM 10 patients). The RAML and lymphangiofibroid lesions in these two subgroups... 18F-FDG, 18 Overall, there were no significant statistical differences in the PET / CT scan parameters of the F-FAPI-42, with only slight differences in a few semi-quantitative PET indicators.

[0059] 18 Regarding F-FAPI-42: only mediastinal lymphangioma SUVmax and TBR [SUVmax: 8.12 (6.88-10.58) vs SUVmax: 4.78 (4.02-6.51), P value < 0.05; TBR: 7.38 (6.25-9.61) vs TBR: 3.62 (2.93-4.65), P value < 0.0001], and pelvic lymphangioma MTV / FTV and TLG / TLF [MTV / FTV: 3.70 (1.67-8.12) vs 0.91 (0.54-1.34), P value < 0.001; TLG / TLF: 10.66 (4.86-36.77) vs 2.94 (2.01-7.68), P value < 0.05].

[0060] 18 Regarding F-FDG: only the SUVmax of abdominal lymphangioma [1.97 (1.60-2.41) vs. 1.74 (1.56-2.06), P < 0.05], and the MTV / FTV and TLG / TLF of pelvic lymphangioma [MTV / FTV: 2.33 (0.72-5.28) vs. 0.44 (0.23-1.07), P < 0.001; TLG / TLF: 2.30 (0.62-6.46) vs. 0.44 (0.25-1.34), P < 0.05], see Tables 3 and 4.

[0061] Table 3. Patients with S-LAM and TSC-LAM 18 Comparison of F-FAPI-42PET parameters

[0062]

[0063] Table 4. Patients with S-LAM and TSC-LAM 18 Comparison of F-FDG PET parameters

[0064]

[0065]

[0066] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. 18 Application of F-FAPI-42 in the preparation of products for diagnosing lymphangioleiomyomatosis; The product is a PET / CT imaging agent; The product is designed to identify lesions in lymphangioleiomyomatosis. The lesions were mediastinal lymphangiomyoma, abdominal lymphangiomyoma, and pelvic lymphangiomyoma.

2. The application according to claim 1, characterized in that, The product is based on the above. 18 F-FAPI-42 is an imaging formulation made by adding an active ingredient to an additive and / or carrier that is acceptable for the preparation of an imaging agent.

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