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1.
Mol Pharm ; 21(5): 2606-2621, 2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38606716

RESUMEN

Compounds 8a-j were designed to adjust the mode of interaction and lipophilicity of FTT by scaffold hopping and changing the length of the alkoxy groups. Compounds 8a, 8d, 8g, and BIBD-300 were screened for high-affinity PARP-1 through enzyme inhibition assays and are worthy of further evaluation. PET imaging of MCF-7 subcutaneous tumors with moderate expression of PARP-1 showed that compared to [18F]FTT, [18F]8a, [18F]8d, and [18F]8g exhibited greater nonspecific uptake, a lower target-to-nontarget ratio, and severe defluorination, while [18F]BIBD-300 exhibited lower nonspecific uptake and a greater target-to-nontarget ratio. PET imaging of 22Rv1 subcutaneous tumors, which highly express PARP-1, confirmed that the uptake of [18F]BIBD-300 in normal organs, such as the liver, muscle, and bone, was lower than that of [18F]FTT, and the ratio of tumor-to-muscle and tumor-to-liver [18F]BIBD-300 was greater than that of [18F]FTT. The biodistribution results in mice with MCF-7 and 22Rv1 subcutaneous tumors further validated the results of PET imaging. Unlike [18F]FTT, which mainly relies on hepatobiliary clearance, [18F]BIBD-300, which has lower lipophilicity, undergoes a partial shift from hepatobiliary to renal clearance, providing the possibility for [18F]BIBD-300 to indicate liver cancer. The difference in the PET imaging results for [18F]FTT, [18F]BIBD-300, and [18F]8j in 22Rv1 mice and the corresponding molecular docking results further confirmed that subtle structural modifications in lipophilicity greatly optimize the properties of the tracer. Cell uptake experiments also demonstrated that [18F]BIBD-300 has a high affinity for PARP-1. Metabolized and unmetabolized [18F]FTT and [18F]BIBD-300 were detected in the brain, indicating that they could not accurately quantify the amount of PARP-1 in the brain. However, PET imaging of glioma showed that both [18F]FTT and [18F]BIBD-300 could accurately localize both in situ to C6 and U87MG tumors. Based on its potential advantages in the diagnosis of breast cancer, prostate cancer, and glioma, as well as liver cancer, [18F]BIBD-300 is a new option for an excellent PARP-1 tracer.


Asunto(s)
Radioisótopos de Flúor , Poli(ADP-Ribosa) Polimerasa-1 , Tomografía de Emisión de Positrones , Animales , Humanos , Tomografía de Emisión de Positrones/métodos , Ratones , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Femenino , Distribución Tisular , Radiofármacos/farmacocinética , Línea Celular Tumoral , Ratones Desnudos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Diseño de Fármacos , Ratones Endogámicos BALB C , Células MCF-7
2.
Cancer Cell Int ; 23(1): 234, 2023 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-37817120

RESUMEN

BACKGROUND: Drug resistance is a main factor affecting the chemotherapy efficacy of gastric cancer (GC), in which meiosis plays an important role. Therefore, it is urgent to explore the effect of meiosis related genes on chemotherapy resistance. METHODS: The expression of meiotic nuclear divisions 1 (MND1) in GC was detected by using TCGA and clinical specimens. In vitro and in vivo assays were used to investigate the effects of MND1. The molecular mechanism was determined using luciferase reporter assay, CO-IP and mass spectrometry (MS). RESULTS: Through bioinformatics, we found that MND1 was highly expressed in platinum-resistant samples. In vitro experiments showed that interference of MND1 significantly inhibited the progression of GC and increased the sensitivity to oxaliplatin. MND1 was significantly higher in 159 GC tissues in comparison with the matched adjacent normal tissues. In addition, overexpression of MND1 was associated with worse survival, advanced TNM stage, and lower pathological grade in patients with GC. Further investigation revealed that forkhead box protein A1 (FOXA1) directly binds to the promoter of MND1 to inhibit its transcription. CO-IP and MS assays showed that MND1 was coexpressed with transketolase (TKT). In addition,TKT activated the PI3K/AKT signaling axis and enhanced the glucose uptake and lactate production in GC cells. CONCLUSIONS: Our results confirm that FOXA1 inhibits the expression of MND1, which can directly bind to TKT to promote GC progression and reduce oxaliplatin sensitivity through the PI3K/AKT signaling pathway.

3.
Mol Pharm ; 20(10): 5195-5205, 2023 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-37647563

RESUMEN

Glutamine metabolism-related tracers have the potential to visualize numerous tumors because glutamine is the second largest source of energy for tumors. (2S,4S)-4-[18F]FEBGln was designed by introducing [18F]fluoroethoxy benzyl on carbon-4 of glutamine. The aim of this study was to investigate the pharmacokinetic properties and tumor positron emission tomography (PET) imaging characteristics of (2S,4S)-4-[18F]FEBGln in detail. The biodistribution results of nude mice bearing MCF-7 tumor showed that (2S,4S)-4-[18F]FEBGln had high initial tumor uptake, and a fast clearance rate, resulting in a high tumor-to-muscle ratio at 30 min postinjection. There was no obvious defluorination in vivo. The micro-PET-CT imaging results of (2S,4S)-4-[18F]FEBGln orthotopic MCF-7 tumor-bearing nude mice were consistent with the biological distribution results. Compared with (2S,4R)-4-[18F]FGln, (2S,4S)-4-[18F]FEBGln showed poor tumor retention, but its clearance in normal tissues was also fast, so it had better PET image contrast than the former. Unlike poor retention in MCF-7-bearing nude mice, (2S,4S)-4-[18F]FEBGln has good retention in NCI-h1975 and 22Rv1 tumor models. Since (2S,4S)-4-[18F]FEBGln has low uptake in normal lungs and high uptake in the bladder, it is expected to be used in the accurate diagnosis of lung cancer but cannot accurately determine prostate cancer. Consistent with the advantages of radiolabeled amino acids in the application of brain tumors, (2S,4S)-4-[18F]FEBGln accurately diagnoses U87MG glioma with higher contrast than [18F]FET and [18F]FDG, and there is a correlation between (2S,4S)-4-[18F]FEBGln uptake and tumor growth cycle. Further kinetic model analysis showed that (2S,4S)-4-[18F]FEBGln was similar to (2S,4R)-4-[18F]FGln, conforming to the one-compartment model and the Logan graphical model, and was expected to assess the size of the glutamine pool of the tumor. Therefore, (2S,4S)-4-[18F]FEBGln is expected to provide a strong imaging basis for the diagnosis, formulation of personalized plans, and efficacy evaluation of glioma, lung cancer, and breast cancer.


Asunto(s)
Neoplasias Encefálicas , Glioma , Neoplasias Pulmonares , Masculino , Ratones , Animales , Ratones Desnudos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Glutamina/metabolismo , Distribución Tisular , Tomografía de Emisión de Positrones , Línea Celular Tumoral , Radiofármacos
4.
Mol Pharm ; 19(7): 2456-2470, 2022 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-35621695

RESUMEN

The abnormal expression of aromatase is associated with the occurrence and development of a variety of neurological diseases and tumors. A series of 18F-labeled and 68Ga-labeled potential aromatase-binding candidate compounds were designed and synthesized based on the structures of aromatase inhibitors. Competitive inhibition experiments in vitro and molecular docking showed that BIBD-069 and BIBD-071 have high affinity for aromatase. The radiolabeling conditions of [18F]BIBD-069 and [18F]BIBD-071 were simple, and the yields were high. Biodistribution and in vivo inhibition experiments confirmed that [18F]BIBD-069 and [18F]BIBD-071 specifically bind to aromatase. [18F]BIBD-069 and [18F]BIBD-071 selectively imaged the amygdala and nucleus of the stria terminalis, which is similar to the imaging result of [11C]vorozole. Radiometabolites of [18F]BIBD-069 and [18F]BIBD-071 did not bind to aromatase and interfered with brain imaging. MicroPET-CT imaging further confirmed that [18F]BIBD-069 and [18F]BIBD-071 can specifically bind to aromatase and were not defluorinated in vivo. Given that [18F]BIBD-069 and [18F]BIBD-071 exhibit excellent aromatase binding affinities, mild radiolabeling conditions, and good pharmacokinetics, they can be important tools for the diagnosis and treatment of aromatase-related diseases.


Asunto(s)
Aromatasa , Tomografía de Emisión de Positrones , Aromatasa/metabolismo , Inhibidores de la Aromatasa/metabolismo , Inhibidores de la Aromatasa/farmacología , Radioisótopos de Flúor/química , Simulación del Acoplamiento Molecular , Tomografía de Emisión de Positrones/métodos , Distribución Tisular
5.
Mol Pharm ; 19(7): 2351-2366, 2022 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-35671264

RESUMEN

[11C]ER176 has adequate sensitivity to image the human brain translocator protein (TSPO) in all three genotypes by positron emission tomography (PET). However, its clinical application is limited by the short half-life of 11C (20.38 min). To overcome the deficiency of [11C]ER176 and keep the pharmacophore features of ER176 to the maximum extent, we designed four fluorine-labeled ER176 derivatives using the deuterium method. In vitro competition binding confirmed that the designed compounds had high affinity for TSPO. Biodistribution experiments showed that tissues with high expression of TSPO had high uptake of these compounds, as well as that the compound showed high brain penetration and mild defluorination in vivo. Therefore, [18F]BIBD-239 with simple synthesis conditions was selected for further biological evaluation. Theoretical simulations showed that BIBD-239 and ER176 have similar binding modes and sites to Ala147-TSPO and Thr147-TSPO, which indicated that the tracers may have consistent sensitivity to the three affinity genotypes. In vitro autoradiography and in vivo PET studies of the ischemic rat brain showed dramatically higher uptake of [18F]BIBD-239 on the lesion site compared to the contralateral side with good brain kinetics. Additionally, [18F]BIBD-239 provided clear tumor PET images in a GL261 glioma model. Importantly, PET imaging and liquid chromatography-high-resolution mass spectrometry (LC-HRMS) results showed that in vivo defluorination and other metabolites of [18F]BIBD-239 did not interfere with brain imaging. Conclusively, [18F]BIBD-239, similar to ER176 with low polymorphism sensitivity, has simple labeling conditions, high labeling yield, high affinity, and high specificity for TSPO, and it is planned for further evaluation in higher species.


Asunto(s)
Radioisótopos de Flúor , Glioma , Animales , Encéfalo/metabolismo , Proteínas Portadoras/metabolismo , Fluoruros/metabolismo , Radioisótopos de Flúor/química , Glioma/metabolismo , Tomografía de Emisión de Positrones/métodos , Radiofármacos/metabolismo , Ratas , Receptores de GABA/genética , Receptores de GABA/metabolismo , Distribución Tisular
6.
Bioorg Med Chem Lett ; 34: 127776, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33418064

RESUMEN

Estrogen receptor is an attractive target for the diagnosis and treatment of breast cancer. This article reports for the first time a dual-modality imaging agent targeting estrogen receptor that can use PET imaging to diagnose breast cancer and utilize fluorescence imaging to achieve intraoperative navigation. Fluorescence experiments show that [natGa] 1 has typical aggregate induced emission characteristics. Above the critical concentration, [natGa] 1 can form biocompatible nanomicelles. [natGa] 1 can quickly light up estrogen receptor positive MCF-7 cells. Cell uptake experiments show that [68Ga] 1 is mediated by estrogen receptor. Therefore, [nat/68Ga] 1 shows the characteristics of highly sensitive diagnosis and visualization of breast cancer, and can be used as a lead compound for the development of a novel PET-FI bimodal imaging agent targeting the estrogen receptor.


Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Tomografía de Emisión de Positrones , Radiofármacos/química , Receptores de Estrógenos/análisis , Femenino , Germanio/química , Humanos , Marcaje Isotópico , Células MCF-7 , Conformación Molecular , Imagen Óptica , Radiofármacos/síntesis química
7.
Rev Esp Enferm Dig ; 113(12): 856-857, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34538057

RESUMEN

A 26-year-old lactating mother presented with a 3-week history of abdominal pain, constipation, and vomiting. She denied any history of alcohol abuse or other gastrointestinal problems. Contrast-enhanced CT identified a small-bowel obstruction caused by a cecum cancer (Fig. 1A). Therefore, she underwent right hemicolectomy and ileocolic anastomosis. Post-operatively, she gradually developed drowsiness, fainting, and a rapid heart rate at 130 bpm. However, blood tests were all normal.


Asunto(s)
Neoplasias del Ciego , Obstrucción Intestinal , Encefalopatía de Wernicke , Adulto , Neoplasias del Ciego/complicaciones , Neoplasias del Ciego/diagnóstico por imagen , Neoplasias del Ciego/cirugía , Ciego , Femenino , Humanos , Obstrucción Intestinal/diagnóstico por imagen , Obstrucción Intestinal/etiología , Obstrucción Intestinal/cirugía , Lactancia , Encefalopatía de Wernicke/complicaciones , Encefalopatía de Wernicke/etiología
8.
Angew Chem Int Ed Engl ; 60(19): 10833-10841, 2021 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-33624345

RESUMEN

The m-pyridine urea (mPU) oligomer was constructed by using the intramolecular hydrogen bond formed by the pyridine nitrogen atom and the NH of urea and the intermolecular hydrogen bond of the terminal carbonyl group and the NH of urea. Due to the synergistic effect of hydrogen bonds, mPU oligomer folds and exhibits strong self-assembly behaviour. Affected by folding, mPU oligomer generates a twisted plane, and one of its important features is that the carbonyl group of the urea group orientates outwards from the twisted plane, while the NHs tend to direct inward. This feature is beneficial to NH attraction for electron-rich species. Among them, the trimer self-assembles into helical nanotubes, and can efficiently transport chloride ions. This study provides a novel and efficient strategy for constructing self-assembled biomimetic materials for electron-rich species transmission.


Asunto(s)
Materiales Biomiméticos/química , Canales de Cloruro/química , Piridinas/química , Urea/química , Tamaño de la Partícula , Propiedades de Superficie
9.
Mol Pharm ; 17(5): 1674-1684, 2020 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-32251600

RESUMEN

Positron emission tomography (PET) imaging using 68Ga-labeled bisphosphonates to target bone metastasis could be a valuable tool in cancer diagnosis and monitoring therapeutic treatment. A 68Ga labeled ligand, N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) containing one bisphosphonate group (HBED-CC-BP, 1) was prepared and evaluated. The new ligand, 1, reacted rapidly to form [68Ga]Ga-1, via complexing with [68Ga]GaCl3 eluted from a commercially available 68Ge/68Ga generator (in a sodium acetate buffer at pH 4, reaching >95% labeling yield at room temperature in 5 min). The resulting [68Ga]Ga-1 showed excellent stability in vitro and in vivo. [68Ga]Ga-1 displayed high binding affinity to hydroxyapatite and good uptake in the tibia and femur bone of normal mice. Biodistribution and MicroPET imaging studies of [68Ga]Ga-1 in normal mice and rats showed excellent bone uptake and retention comparable to that of Na[18F]F. The results suggested that [68Ga]Ga-1 might be suitable as a bone imaging agent in humans and it could be useful as a convenient alternative to the current bone imaging PET agent, Na[18F]F, without the need of a near-by cyclotron. Also, an automated synthesis module was developed to produce clinical doses of [68Ga]Ga-1 in a consistent and reproducible manner. Currently, the investigation new drug application (IND) for [68Ga]Ga-HBED-CC-BP, [68Ga]Ga-1, has received FDA approval, and it is currently under clinical trial (IND #129870).


Asunto(s)
Difosfonatos , Radioisótopos de Galio , Animales , Ácido Edético/análogos & derivados , Ligandos , Ratones , Tomografía de Emisión de Positrones/métodos , Ratas , Distribución Tisular
10.
BMC Anesthesiol ; 20(1): 185, 2020 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-32738878

RESUMEN

BACKGROUND: Tracheal extubation is commonly performed in the supine position. However, in patients undergoing abdominal surgery, the supine position increases abdominal wall tension, especially during coughing and deep breathing, which may aggravate pain and lead to abdominal wound dehiscence. The semi-Fowler's position may reduce abdominal wall tension, but its safety and comfort in tracheal extubation have not been reported. We aimed to evaluate the safety and comfort of different extubation positions in patients undergoing abdominal surgery. METHODS: We enrolled 141 patients with an American Society of Anesthesiologists grade of I-III who underwent abdominal surgery. All patients were anesthetized with propofol, fentanyl, cisatracurium, and sevoflurane. After surgery, all patients were transferred to the post-anesthesia care unit (PACU). Patients were then randomly put into the semi-Fowler's (n = 70) or supine (n = 71) position while 100% oxygen was administered. The endotracheal tube was removed after the patients opened their eyes and regained consciousness. Vital signs, coughing, and pain and comfort scores before and/or after extubation were recorded until the patients left the PACU. RESULTS: In comparison with the supine position, the semi-Fowler's position significantly decreased the wound pain scores at all intervals after extubation (3.51 ± 2.50 vs. 4.58 ± 2.26, 2.23 ± 1.68 vs. 3.11 ± 2.00, 1.81 ± 1.32 vs. 2.59 ± 1.88, P = 0.009, 0.005 and 0.005, respectively), reduced severe coughing (8[11.43%] vs. 21[29.58%], P = 0.008) and bucking after extubation (3[4.29%] vs. 18[25.35%], P < 0.001), and improved the comfort scores 5 min after extubation (6.11 ± 2.30 vs. 5.17 ± 1.78, P = 0.007) and when leaving from post-anesthesia care unit (7.17 ± 2.27 vs. 6.44 ± 1.79, P = 0.034). The incidences of vomiting, emergence agitation, and respiratory complications were of no significant difference. CONCLUSION: Tracheal extubation in the semi-Fowler's position is associated with less coughing, sputum suction, and pain, and more comfort, without specific adverse effects when compared to the conventional supine position. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900025566 . Registered on 1st September 2019.


Asunto(s)
Abdomen/cirugía , Extubación Traqueal/métodos , Posicionamiento del Paciente/métodos , Posición Supina , Adulto , Extubación Traqueal/efectos adversos , Periodo de Recuperación de la Anestesia , Anestésicos por Inhalación/administración & dosificación , Anestésicos Intravenosos/administración & dosificación , Atracurio/administración & dosificación , Atracurio/análogos & derivados , Femenino , Fentanilo/administración & dosificación , Humanos , Intubación Intratraqueal , Masculino , Persona de Mediana Edad , Propofol/administración & dosificación , Estudios Prospectivos , Sevoflurano/administración & dosificación , Método Simple Ciego
11.
J Labelled Comp Radiopharm ; 63(3): 108-118, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31697847

RESUMEN

Amyvid (florbetapir f18, [18 F]AV-45, [18 F]5) was the first FDA-approved positron emission tomography imaging agent targeting ß-amyloid (Aß) plaques for assisting the diagnosis of Alzheimer disease. This work aimed to improve the [18 F]AV-45 ([18 F]5) preparation by using solid-phase extraction (SPE) purification. [18 F]AV-45 ([18 F]5) was synthesized by direct nucleophilic radiofluorination of O-tosylated precursor (1 mg) at 120°C in anhydrous dimethyl sulfoxide (DMSO), followed by acid hydrolysis of the N-Boc protecting group. Purification was accomplished by loading the crude reaction mixture to a cartridge (Oasis HLB 3 cc) and eluting with different combinations of solvents. This method removed the chemical impurity while leaving [18 F]AV-45 ([18 F]5) on the cartridge. The final dose was eluted by ethanol. [18 F]AV-45 ([18 F]5) was produced within 51 minutes (radiochemical yield 42.7 ± 5.9%, decay corrected, n = 3), and the radiochemical purity was greater than 95%. Total chemical impurity per batch (24.1 ± 2.7 µg per batch) was below the limit described in the package insert of Amyvid, florbetapir f18 (chemical mass: less than 50 µg/dose). In summary, [18 F]AV-45 ([18 F]5) was produced efficiently and reproducibly using a cartridge-based SPE purification. This method brings the process closer for routine preparation, similar to the commercially used [18 F]FDG.


Asunto(s)
Compuestos de Anilina/química , Compuestos de Anilina/aislamiento & purificación , Glicoles de Etileno/química , Glicoles de Etileno/aislamiento & purificación , Extracción en Fase Sólida , Tomografía de Emisión de Positrones , Radioquímica
12.
Bioorg Med Chem Lett ; 29(9): 1047-1050, 2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-30871772

RESUMEN

We report the preparation of a novel glutamine derivative, (2S,4S)-2,5-diamino-4-(4-(2-fluoroethoxy)benzyl)-5-oxopentanoic acid, (2S, 4S)4-[18F]FEBGln ([18F]4), through efficient organic and radiosyntheses. In vitro assays of [18F]4 using MCF-7 cells showed that it entered cells via multiple amino acid transporter systems including system L and ASC2 transporters but not through the system A transporter. [18F]4 showed promising properties for tumor imaging and may serve as a lead compound for further optimizing and targeting the system L transporter associated with enhanced glutamine metabolism in cancer cells.


Asunto(s)
Glutamina/análogos & derivados , Radiofármacos/síntesis química , Proteínas Reguladoras de la Apoptosis/química , Proteínas Reguladoras de la Apoptosis/metabolismo , Línea Celular Tumoral , Éteres Corona/química , Radioisótopos de Flúor/química , Glutamina/síntesis química , Glutamina/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Radiofármacos/química , Radiofármacos/metabolismo , Ribonucleoproteínas/química , Ribonucleoproteínas/metabolismo
13.
J Labelled Comp Radiopharm ; 62(5): 209-214, 2019 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-30861162

RESUMEN

We report initial experience in synthesis of (2S,4R)-4-[18 F]fluoroglutamine, [18 F]FGln, which has been used as a tool for monitoring glutamine metabolism in cancer patients. [18 F]FGln was prepared by a fully automated PET-MF-2V-IT-I synthesizer under GMP-compliant conditions for routine clinical studies. The total radiosynthesis time was about 65 minutes, the decay-corrected radiochemical yield was 18.0 ± 4.2% (n = 59; failure n = 15), and the radiochemical purity was greater than 90%. In some situations, the yields were low (less than 5%), and the most likely cause of this problem is the initial fluorination step; the fluoride ion might not have been fully activated. In other occasions, low final radiochemical purity was often associated with the failure of the second step-removal of protection groups by anhydrous trifluoroacetic acid. A trace amount of water led to production of undesired 4-[18 F]fluoroglutamic acid. Knowledge learned from the successes and failures of synthesis may be helpful to identify critical steps and pitfalls for preparation of this clinically useful metabolic probe, [18 F]FGln, for imaging glutamine utilization in tumor of cancer patients.


Asunto(s)
Glutamina/análogos & derivados , Técnicas de Química Sintética , Ciclotrones , Glutamina/síntesis química , Glutamina/química , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/instrumentación , Control de Calidad , Radioquímica
15.
Bioconjug Chem ; 27(5): 1314-23, 2016 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-27045547

RESUMEN

Aß plaques deposited on blood vessels are associated with cerebral amyloid angiopathy (CAA). In an effort to selectively map these Aß plaques, we are reporting a new series of (68)Ga labeled styrylpyridine derivatives with high molecular weights. In vitro binding to Aß plaques in post-mortem Alzheimer's disease (AD) brain tissue showed that these (68)Ga labeled bivalent styrylpyridines displayed good affinities and specificity (Ki < 30 nM). In vitro autoradiography using post-mortem AD brain sections showed specific binding of these (68)Ga complexes to Aß plaques. Biodistribution studies in normal mice showed very low initial brain uptakes (<0.3% dose/g) indicating a low blood-brain barrier (BBB) penetration. The preliminary results suggest that (68)Ga labeled bivalent styrylpyridines may be promising candidates as PET imaging radiotracers for detecting CAA.


Asunto(s)
Angiopatía Amiloide Cerebral/complicaciones , Radioisótopos de Galio , Placa Amiloide/complicaciones , Placa Amiloide/diagnóstico por imagen , Polietilenglicoles/química , Tomografía de Emisión de Positrones/métodos , Piridinas/química , Estirenos/química , Animales , Barrera Hematoencefálica/metabolismo , Ratones , Piridinas/metabolismo , Piridinas/farmacocinética , Estirenos/metabolismo , Estirenos/farmacocinética , Distribución Tisular
17.
Mol Pharm ; 11(11): 3852-66, 2014 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-25095908

RESUMEN

Although the growth and proliferation of most tumors is fueled by glucose, some tumors are more likely to metabolize glutamine. In particular, tumor cells with the upregulated c-Myc gene are generally reprogrammed to utilize glutamine. We have developed new 3-fluoropropyl analogs of glutamine, namely [(18)F](2S,4R)- and [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 3 and 4, to be used as probes for studying glutamine metabolism in these tumor cells. Optically pure isomers labeled with (18)F and (19)F (2S,4S) and (2S,4R)-4-(3-fluoropropyl)glutamine were synthesized via different routes and isolated in high radiochemical purity (≥95%). Cell uptake studies of both isomers showed that they were taken up efficiently by 9L tumor cells with a steady increase over a time frame of 120 min. At 120 min, their uptake was approximately two times higher than that of l-[(3)H]glutamine ([(3)H]Gln). These in vitro cell uptake studies suggested that the new probes are potential tumor imaging agents. Yet, the lower chemical yield of the precursor for 3, as well as the low radiochemical yield for 3, limits the availability of [(18)F](2S,4R)-4-(3-fluoropropyl)glutamine, 3. We, therefore, focused on [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4. The in vitro cell uptake studies suggested that the new probe, [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, is most sensitive to the LAT transport system, followed by System N and ASC transporters. A dual-isotope experiment using l-[(3)H]glutamine and the new probe showed that the uptake of [(3)H]Gln into 9L cells was highly associated with macromolecules (>90%), whereas the [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, was not (<10%). This suggests a different mechanism of retention. In vivo PET imaging studies demonstrated tumor-specific uptake in rats bearing 9L xenographs with an excellent tumor to muscle ratio (maximum of ∼8 at 40 min). [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, may be useful for testing tumors that may metabolize glutamine related amino acids.


Asunto(s)
Glutamina/análogos & derivados , Glutamina/farmacocinética , Tomografía de Emisión de Positrones , Animales , Línea Celular , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Glutamina/química , Glucólisis , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Trasplante de Neoplasias , Proteínas Proto-Oncogénicas c-myc/metabolismo , Ratas , Ratas Endogámicas F344 , Temperatura
19.
Quant Imaging Med Surg ; 14(2): 1417-1428, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38415162

RESUMEN

Background: Deep medullary vein (DMV) hypo-visibility is correlated with white matter hyperintensity (WMH), but the underlying causes remain unclear. This study aimed to explore the relationship between deep vein diameters and perivascular space (PVS) scores, and DMV hypo-visibility in the presence of WMH. Methods: This cross-sectional study prospectively analyzed the clinical and imaging data of 190 cerebral small vessel disease patients with WMH and 40 healthy controls from the Lishui Hospital of Traditional Chinese Medicine affiliated with Zhejiang Chinese Medical University. PVS scores ranging from 0 to 4 were determined according to the PVS counts in the basal ganglia area on T2-weighted magnetic resonance images; high-grade PVS was defined as a PVS score >1. The diameters of the deep cerebral veins, including the bilateral septal veins (SVs), thalamostriate veins (TSVs), lateral ventricular veins (LVVs), and internal cerebral veins, were measured using susceptibility weighted imaging (SWI). Left and right DMV scores, ranging from 0 to 9, were calculated based on the visibility of the DMV on SWI in the ipsilateral frontal, parietal, and occipital lobes. Results: The deep cerebral vein diameters, left and right DMV scores, and high-grade PVS differed between the healthy controls and WMH patients (P<0.05). Left DMV scores were independently associated with age {ß [95% confidence interval (CI)]: 0.050 (0.018, 0.082)}, high-grade PVS [ß (95% CI): 0.998 (0.262, 1.737)], and the diameters of the ipsilateral SVs [ß (95% CI): -1.114 (-1.754, -0.475)], SVs [ß (95% CI): -0.734 (-1.191, -0.277)], and LVVs [ß (95% CI): -0.921 (-1.567, -0.275)] [all false discovery rate (FDR)-corrected P<0.05]. Right DMV scores were independently associated with age [ß (95% CI): 0.071 (0.037, 0.105)], high-grade PVS [ß (95% CI): 0.873 (0.111, 1.635)], and the diameters of the ipsilateral SVs [ß (95% CI): -0.837 (-1.386, -0.289)], TSVs [ß (95% CI): -0.875 (-1.331, -0.419)], and LVVs [ß (95% CI): -1.813 (-2.484, -1.142)] (all FDR-corrected P<0.05). Conclusions: Decreased hypo-visibility of DMVs on SWI was associated with a higher age, the presence of high-grade PVS, and smaller diameters of the ipsilateral deep cerebral veins in individuals with WMH. Our findings provide novel insights into the probable mechanisms leading to high DMV scores.

20.
Technol Health Care ; 2024 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-39240600

RESUMEN

BACKGROUND: Advancements in laparoscopic technology have popularized laparoscopic total gastrectomy over traditional open surgery, yet postoperative complications like anastomotic leakage and stenosis persist, particularly in esophagojejunostomy. To address this, since 2017, the authors have introduced the "Pant-Shaped" esophagojejunostomy as an improvement over the classic Roux-en-Y method, especially beneficial for patients with small intestinal diameters or those with gastric body cancer or Siewert III. OBJECTIVE: To assess the viability and safety of employing 'Pant-Shaped' anastomosis following laparoscopic-assisted total gastrectomy. METHODS: A method of descriptive case study was used. In our department of the First Affiliated Hospital of Wannan Medical College, records of 210 patients who underwent laparoscopic-assisted total gastrectomy for gastric body cancer or adenocarcinoma at the junction of esophagus and jejunum with "Pant-Shaped" anastomosis between January 2017 and December 2022 were examined. Clinicopathological features and postoperative conditions were also examined and assessed. RESULTS: The mean age of the 164 male and 46 female research participants was 69.2 ± 8.3 years. There was a mean estimated blood loss of 63.4 ± 29.7 ml, an anastomosis time of 25.9 ± 3.0 minutes, an operation time of 208.2 ± 40.4 minutes, and a postoperative hospital stay of 12.2 ± 8.0 days. Nine patients (4.3%) experienced postoperative problems (Clavien-Dindo > grade II), including two episodes of anastomotic leakage that were resolved with irrigation and drainage, anti-infection therapy, and nutritional assistance. After an unforeseen reoperation, two cases of duodenal stump leaking were resolved. Anastamotic hemorrhage was treated with hemostasis and blood transfusion, and the patient made a full recovery. Due to a Peterson's hernia, one patient required emergent open surgery. three months subsequent to LATG. CONCLUSIONS: The "Pant-Shaped" anastomosis method after laparoscopic-assisted total gastrectomy is simple, easy to promote, and has fewer complications. It is a safe and feasible modified method for esophagojejunostomy, especially suitable for patients with poor intestinal dilation and contraction ability and small jejunal diameter.

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