The synergy of 177Lu-FAPI-46 with tyrosine kinase inhibitor in a sarcoma patient-derived xenograft mouse model.

BACKGROUND: Given the heterogeneity and high mortality associated with metastatic soft tissue sarcoma, this study aims to evaluate the therapeutic efficacy of combining 177Lu-FAPI-46 with Pazopanib against this malignancy. METHODS: Patient-derived xenograft (PDX)-bearing mice were randomly divided into three groups: the control group, the 177Lu-FAPI-46 monotherapy group, and the 177Lu-FAPI-46 combined with Pazopanib therapy group. Therapeutic efficacy was regularly monitored. RESULTS: The microPET imaging showed a 0.84-fold decrease in the T/M ratio of 68Ga-FAPI-46 on day 7/8 post combination therapy, while the control group exhibited a 1.23-fold increase. Combination therapy significantly inhibited tumor proliferation, as evidenced by reduced Ki-67 and increased caspase 3 expressions. Notably, there was no significant body weight loss observed in any group. CONCLUSION: This study successfully demonstrated the reduction in FAP expression and suppression of tumor volume in sarcoma PDX following the combination therapy of 177Lu-FAPI-46 with Pazopanib.

In vivo SPECT imaging of Tc-99 m radiolabeled exosomes from human umbilical-cord derived mesenchymal stem cells in small animals.

Extracellular vesicles derived from human umbilical cord-derived mesenchymal stem cells (UCMSC-EVs) have been postulated to have therapeutic potential for various diseases. However, the biodistribution and pharmacokinetics of these vesicles are still unclear. For a better understanding of the in vivo properties of UCMSC-EVs, in the present study, these vesicles were first radiolabeled with Technetium-99 m (99mTc-UCMSC-EVs) and evaluated using in vivo single photon emission computed tomography (SPECT) imaging and biodistribution experiments. SPECT images demonstrated that the liver and spleen tissues mainly took up the 99mTc-UCMSC-EVs. The biodistribution study observed slight uptake in the thyroid and stomach, indicating that 99mTc-UCMSC-EVs was stable at 24 h in vivo. The pharmacokinetic analyses of the blood half-life demonstrated the quick distribution phase (0.85 ±â€¯0.28 min) and elimination phase (25.22 ±â€¯20.76 min) in mice. This study provides a convenient and efficient method for 99mTc-UCMSC-EVs preparation without disturbing their properties. In conclusion, the biodistribution, quick elimination, and suitable stability in vivo of 99mTc-UCMSC-EVs were quantified by the noninvasive imaging and pharmacokinetic analyses, which provides useful information for indication selection, dosage protocol design, and toxicity assessment in future applications.

Imaging diabetic cardiomyopathy in a type 1 diabetic rat model using 18F-FEPPA PET.

OBJECTIVE: Diabetic patients often experience chronic inflammation and fibrosis in their cardiac tissues, highlighting the pressing need for the development of sensitive diagnostic methods for longitudinal assessment of diabetic cardiomyopathy. This study aims to evaluate the significance of an inflammatory marker known as translocator protein (TSPO) in a positron emission tomography (PET) protocol for longitudinally monitoring cardiac dysfunction in a diabetic animal model. Additionally, we compared the commonly used radiotracer, 18F-fluoro-2-deoxy-d-glucose (18F-FDG). METHODS: Fourteen 7-week-old female Sprague-Dawley rats were used in this study. Longitudinal PET experiments were conducted using 18F-N-2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide (18F-FEPPA) (n = 3), the TSPO radiotracer, and 18F-FDG (n = 3), both before and after the onset of diabetes. Histological and immunohistochemical staining assays were also conducted in both the control (n = 4) and diabetes (n = 4) groups. RESULTS: Results indicated a significant increase in cardiac tissue uptake of 18F-FEPPA after the onset of diabetes (P < 0.05), aligning with elevated TSPO levels observed in diabetic animals according to histological data. Conversely, the uptake of 18F-FDG in cardiac tissue significantly decreased after the onset of diabetes (P < 0.05). CONCLUSION: These findings suggest that 18F-FEPPA can function as a sensitive probe for detecting chronic inflammation and fibrosis in the cardiac tissues of diabetic animals.

The effect of estrogen therapy on cerebral metabolism in diabetic female rats.

The impact of estrogen on brain function, especially in individuals with diabetes, remains uncertain. This study aims to compare cerebral glucose metabolism levels in intact rats, ovariectomized (OVX) rats, and 17ß-estradiol (E2)-treated OVX diabetic female rats. Sixteen rats were administered a single intraperitoneal injection of 70 mg/kg streptozotocin (STZ) to induce diabetes (intact, n = 6; OVX, n = 6; OVX+E2-treated, n = 4). Additionally, 18 rats received an equivalent solvent dose via intraperitoneal injection (intact, n = 6; OVX, n = 6; OVX+E2-treated, n = 6). After 4 weeks of STZ or solvent administration, positron emission tomography scans with 18F-fluorodeoxyglucose (18F-FDG) injection were employed to assess cerebral glucose metabolism. The diabetic rats exhibited substantial reductions in 18F-FDG uptake across all brain regions (all P < 0.01), in contrast to the control rats. Moreover, intact and OVX + E2-treated diabetic female rats displayed more pronounced decreases in cerebral glucose metabolism in the amygdala and hippocampus compared to OVX diabetic female rats (P < 0.05). These findings suggest that diabetes creates an environment wherein estrogen exacerbates neuropathology and intensifies neuronal activity.

Environmentally friendly Nafion-catalyzed synthesis of 3-substituted isoquinoline by using hexamethyldisilazane as a nitrogen source under microwave irradiation.

This study developed an eco-friendly method to synthesize 3-arylisoquinoline from 2-alkynylbenzaldehydes using Nafion® NR50 as an acidic catalyst and hexamethyldisilazane (HMDS) as a nitrogen source. The reaction proceeded via a 6-exo-dig cyclization under microwave irradiation, giving the corresponding isoquinolines in excellent yields. The advantages of this protocol include: (1) the use of recyclable acid catalysts, (2) transition-metal-free catalysis, and (3) the effective formation of the target product. These features make this methodology a promising approach for the sustainable and efficient synthesis of 3-arylisoquinoline. Some structures were also confirmed by single-crystal X-ray diffraction analysis.

Drugs to Treat Neuroinflammation in Neurodegenerative Disorders.

Neuroinflammation is associated with disorders of the nervous system, and it is induced in response to many factors, including pathogen infection, brain injury, toxic substances, and autoimmune diseases. Astrocytes and microglia have critical roles in neuroinflammation. Microglia are innate immune cells in the central nervous system (CNS), which are activated in reaction to neuroinflammation-inducing factors. Astrocytes can have pro- or anti-inflammatory responses, which depend on the type of stimuli presented by the inflamed milieu. Microglia respond and propagate peripheral inflammatory signals within the CNS that cause low-grade inflammation in the brain. The resulting alteration in neuronal activities leads to physiological and behavioral impairment. Consequently, activation, synthesis, and discharge of various pro-inflammatory cytokines and growth factors occur. These events lead to many neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis discussed in this study. After understanding neuroinflammation mechanisms and the involvement of neurotransmitters, this study covers various drugs used to treat and manage these neurodegenerative illnesses. The study can be helpful in discovering new drug molecules for treating neurodegenerative disorders.

Glycolytic Plasticity of Metastatic Lung Cancer Captured by Noninvasive 18F-FDG PET/CT and Serum 1H-NMR Analysis: An Orthotopic Murine Model Study.

We aim to establish a noninvasive diagnostic platform to capture early phenotypic transformation for metastasis using 18F-FDG PET and 1H-NMR-based serum metabolomics. Mice with implantation of NCI-H460 cells grew only primary lung tumors in the localized group and had both primary and metastatic lung tumors in the metastatic group. The serum metabolites were analyzed using 1H-NMR at the time of PET/CT scan. The glycolysis status and cell proliferation were validated by Western blotting and staining. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic accuracy of SUVmean and serum metabolites in metastasis. In the metastatic mice, the SUVmean of metastatic tumors was significantly higher than that of primary lung tumors in PET images, which was supported by elevated glycolytic protein expression of HK2 and PKM2. The serum pyruvate level in the metastatic group was significantly lower than that in the localized group, corresponding to increased pyruvate-catalyzed enzyme and proliferation rates in metastatic tumors. In diagnosing localized or metastatic tumors, the areas under the ROC curves of SUVmean and pyruvate were 0.92 and 0.91, respectively, with p < 0.05. In conclusion, the combination of 18F-FDG PET and 1H-NMR-based serum metabolomics demonstrated the feasibility of a glycolytic platform for diagnosing metastatic lung cancers.

Acid-controlled multicomponent selective synthesis of 2,4,6-triaryl pyridines and pyrimidines by using hexamethyldisilazane as a nitrogen source under microwave irradiation.

An efficient and general protocol for the synthesis of functionalized 2,4,6-triaryl pyridines and pyrimidines was developed from commercially available aromatic ketones, aldehydes and hexamethyldisilazane (HMDS) as a nitrogen source under microwave irradiation. In this multicomponent synthetic route, Lewis acids play an important role in selectively synthesizing six-membered heterocycles, including pyridines (1N) and pyrimidines (2N), by involving [2 + 1 + 2 + 1] or [2 + 1 + 1 + 1 + 1] annulated processes.

TMSOTf-mediated Kröhnke pyridine synthesis using HMDS as the nitrogen source under microwave irradiation.

An efficient protocol for the preparation of pyridine skeletons has been successfully developed involving the TMSOTf/HMDS (trifluoromethanesulfonic acid/hexamethyldisilane) system for the intermolecular cyclization of chalcones under MW (microwave) irradiation conditions. This method provides a facile approach to synthesize 2,4,6-triaryl or 3-benzyl-2,4,6-triarylpyridines in good to excellent yields. Interestingly, the 2,6-diazabicyclo[2.2.2]oct-2-ene core was obtained by changing the acid additive to Sn(OTf)2, and the desired product was also confirmed using X-ray single-crystal diffraction analysis.

Globo H Is a Promising Theranostic Marker for Intrahepatic Cholangiocarcinoma.

Recent studies support the development of cancer therapeutics to target Globo H-ceramide, the most prevalent tumor-associated carbohydrate antigen in epithelial cancers. Herein, we evaluated the expression of Globo H and its prognostic significance in intrahepatic cholangiocarcinoma (ICC) and conducted preclinical studies to assess the antitumor activity of Globo H-specific antibody in thioacetamide (TAA)-induced ICC in rats. Globo H-ceramide in tumor specimens was detected by immunohistochemistry (IHC) and mass spectrometry. Antitumor efficacy of anti-Globo H mAbVK9 was evaluated in TAA-induced ICC in rat. Natural killer (NK) cells and their related genes were analyzed by IHC and quantitative real-time polymerase chain reaction. Data mining revealed that B3GALT5 and FUT2, the key enzymes for Globo H biosynthesis, were significantly up-regulated in human ICC. In addition, Globo H expression was detected in 41% (63 of 155) of ICC tumor specimens by IHC staining, and validated by mass spectrometric analysis of two IHC-positive tumors. Patients with Globo H positive tumors had significantly shorter relapse-free survival (RFS) and overall survival (P = 0.0003 and P = 0.002, respectively). Multivariable Cox regression analysis identified Globo H expression as an independent unfavorable predictor for RFS (hazard ratio: 1.66, 95% confidence interval: 1.08-2.36, P = 0.02) in ICC. Furthermore, gradual emergence of Globo H in liver tissues over 6 months in TAA-treated rats recapitulated the multistage progression of ICC in vivo. Importantly, administration of anti-Globo H mAbVK9 in rats bearing TAA-induced ICC significantly suppressed tumor growth with increased NK cells in the tumor microenvironment. Conclusion: Globo H is a theranostic marker in ICC.

Radiation-Induced Metabolic Shifts in the Hepatic Parenchyma: Findings from 18F-FDG PET Imaging and Tissue NMR Metabolomics in a Mouse Model for Hepatocellular Carcinoma.

PURPOSE: By taking advantage of 18F-FDG PET imaging and tissue nuclear magnetic resonance (NMR) metabolomics, we examined the dynamic metabolic alterations induced by liver irradiation in a mouse model for hepatocellular carcinoma (HCC). METHODS: After orthotopic implantation with the mouse liver cancer BNL cells in the right hepatic lobe, animals were divided into two experimental groups. The first received irradiation (RT) at 15 Gy, while the second (no-RT) did not. Intergroup comparisons over time were performed, in terms of 18F-FDG PET findings, NMR metabolomics results, and the expression of genes involved in inflammation and glucose metabolism. RESULTS: As of day one post-irradiation, mice in the RT group showed an increased 18F-FDG uptake in the right liver parenchyma compared with the no-RT group. However, the difference reached statistical significance only on the third post-irradiation day. NMR metabolomics revealed that glucose concentrations peaked on day one post-irradiation both, in the right and left lobes-the latter reflecting a bystander effect. Increased pyruvate and glutamate levels were also evident in the right liver on the third post-irradiation day. The expression levels of the glucose-6-phosphatase (G6PC) and fructose-1, 6-bisphosphatase 1 (FBP1) genes were down-regulated on the first and third post-irradiation days, respectively. Therefore, liver irradiation was associated with a metabolic shift from an impaired gluconeogenesis to an enhanced glycolysis from the first to the third post-irradiation day. CONCLUSION: Radiation-induced metabolic alterations in the liver parenchyma occur as early as the first post-irradiation day and show dynamic changes over time.

Irisin, an exercise myokine, potently suppresses tumor proliferation, invasion, and growth in glioma.

Glioblastoma multiforme is the most common and aggressive glial tumor with poor prognosis. Importantly, effective treatment options for glioblastoma are unmet needs. Obesity and low physical activity have been linked with a high risk of cancer, and exercise is related to delayed cancer development and progression. Epidemiological studies have revealed a correlation between exercise and the survival rate of patients with glioblastoma. Nevertheless, the mechanisms by which exercise exerts its anticancer effects in glioblastoma remain unclear. Here, we found that irisin, an exercise-induced myokine, induced G2 /M cell cycle arrest and increased p21 levels in glioblastoma cells, leading to the inhibition of cell proliferation. In addition, irisin inhibited glioblastoma cell invasion by upregulating TFPI-2 and even reversed the aggressive tumor phenotype promoted by co-cultivation with cancer-associated adipocytes. Furthermore, irisin retarded xenograft glioblastoma tumor growth, and radiolabeled irisin demonstrated specific tumor-targeting capability in vivo. Therefore, this study identified one potential molecular mechanism by which exercise prevents cancer progression via irisin. Intriguingly, irisin has the potential to be developed as a molecular imaging and therapeutic anticancer agent.

SOX4 activates CXCL12 in hepatocellular carcinoma cells to modulate endothelial cell migration and angiogenesis in vivo.

The overexpression of SOX4 in various kinds of cancer cells was associated with poor prognosis for patients. The role of SOX4 in angiogenesis and tumor microenvironment modulation was recently documented in breast cancer but remains unclear in hepatocellular carcinoma (HCC). In our study, the clinical relevance of SOX4 overexpression in HCC and its role in the tumor microenvironment were investigated. The overexpression of SOX4 (SOX4high) in tumor lesions was associated with higher microvessel density (P = 0.012), tumor thrombosis formation (P = 0.012), distant metastasis (P < 0.001), and an independent prognostic factor for disease-free survival in HCC patients (P = 0.048). Endogenous SOX4 knockout in Hep3B cells by the CRISPR/cas9 system reduced the expression of CXCL12, which, in turn, attenuated chemotaxis in human umbilical vein endothelial cells, tube formation in vitro, reduced tumor growth, reticular fiber production, and angiogenesis in vivo in a xenograft mouse model. Treatment with an antagonist targeting CXCR4 (AMD3100), a receptor of CXCL12, inhibited chemotaxis and tube formation in endothelial cells in vitro. The CXCL12 promoter was activated by ectopic expression of a Flag-tagged SOX4 plasmid, endogenous SOX4 knockdown abolished promoter activity of CXCL12 as shown by luciferase assays, and an association with the CXCL12 promoter was identified via chromatin immunoprecipitation in HCC cells. In conclusion, SOX4 modulates the CXCL12 promoter in HCC cells. The secretory CXCL12, in turn, modulates CXCR4 in endothelial cells, reticular fibers to regulate the tumor microenvironment and modulate neovascularization, which might contribute to the distant metastasis of tumors.

Diffusion-weighted MRI and 18F-FDG PET correlation with immunity in early radiotherapy response in BNL hepatocellular carcinoma mouse model: timeline validation.

PURPOSE: Imaging probes/biomarkers that are correlated with molecular or microenvironmental alterations in tumors have been used not only in diagnosing cancer but also in assessing the efficacy of cancer treatment. We evaluated the early response of hepatocellular carcinoma (HCC) to radiation treatment using T2-weighted magnetic resonance imaging (MRI), diffusion-weighted (DW) MRI, and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET). METHODS: Orthotopic HCC tumors were established in the right liver lobe of Balb/c mice. Mice were longitudinally scanned using T2-weighted/DW MRI and 18F-FDG PET 1 day before and on days 1, 3, 6, 9 and 13 after irradiation with 15 Gy to the right liver lobe to determine tumor size, apparent diffusion coefficient (ADC) value, and maximum standardized uptake value. Immunohistochemical (IHC) staining was performed to validate the tumor microenvironment. RESULTS: Irradiation markedly retarded tumor growth in the orthotopic HCC model and led to increaes in ADC values as early as on day 1 after irradiation. Irradiation also resulted in increases in 18F-FDG uptake on day 1 that were sustained until the end of the observation period. IHC staining revealed a decrease in the number of proliferative cells and a continuous macrophage influx into irradiated tumors, which dramatically altered the tumor microenvironment. Lastly, in vitro coculture of HCC cells and macrophages led to interaction between the cells and enhanced the cellular uptake of 18F-FDG. CONCLUSION: ADC values and 18F-FDG uptake measured using DW MRI and 18F-FDG PET serve as potential biomarkers for early assessment of HCC tumor responses to radiation therapy.

The effect of caffeine on cerebral metabolism during alpha-chloralose anesthesia differs from isoflurane anesthesia in the rat brain.

RATIONALE: Caffeine is a widely studied psychostimulant, even though its exact effect on brain activity remains to be elucidated. Positron emission tomography (PET) allows studying mechanisms underlying cerebral metabolic responses to caffeine in caffeine-naïve rats. Rodent studies are typically performed under anesthesia. However, the anesthesia may affect neurotransmitter systems targeted by tested drugs. OBJECTIVES: The scope of the present study was to address the impairing or enhancing effect of two common anesthetics, alpha-chloralose and isoflurane, on the kinetics of caffeine. METHODS: The first group of rats (n = 15) were anesthetized under 1.5% isoflurane anesthesia. The second group of rats (n = 15) were anesthetized under alpha-chloralose (80 mg/kg). These rats received an intravenous injection of saline (n = 5) or of 2.5 mg/kg (n = 5) or 40 mg/kg (n = 5) caffeine for both groups. RESULTS: With 2.5 mg/kg or 40 mg/kg caffeine, whole-brain cerebral metabolism was significantly reduced by 17.2% and 17% (both P < 0.01), respectively, under alpha-chloralose anesthesia. However, the lower dose of caffeine (2.5 mg/kg) had a limited effect on brain metabolism, whereas its higher dose (40 mg/kg) produced enhancements in brain metabolism in the striatum, hippocampus, and thalamus (all P < 0.05) under isoflurane anesthesia. CONCLUSION: These findings demonstrate significant differences in brain responses to caffeine on the basic of the anesthesia regimen used, which highlights the importance of attention to the anesthetic used when interpreting findings from animal pharmacological studies because of possible interactions between the anesthetic and the drug under study.

Early Imaging Biomarker of Myocardial Glucose Adaptations in High-Fat-Diet-Induced Insulin Resistance Model by Using 18F-FDG PET and [U-13C]glucose Nuclear Magnetic Resonance Tracer.

Background: High-fat diet (HFD) induces systemic insulin resistance leading to myocardial dysfunction. We aim to characterize the early adaptations of myocardial glucose utility to HFD-induced insulin resistance. Methods: Male Sprague-Dawley rats were assigned into two groups, fed a regular chow diet or HFD ad libitum for 10 weeks. We used in vivo imaging of cardiac magnetic resonance (CMR), 18F-FDG PET, and ex vivo nuclear magnetic resonance (NMR) metabolomic analysis for the carbon-13-labeled glucose ([U-13C]Glc) perfused myocardium. Results: As compared with controls, HFD rats had a higher ejection fraction and a smaller left ventricular end-systolic volume (P < 0.05), with SUVmax of myocardium on 18F-FDG PET significantly increased in 4 weeks (P < 0.005). The [U-13C]Glc probed the increased glucose uptake being metabolized into pyruvate and acetyl-CoA, undergoing oxidative phosphorylation via the tricarboxylic acid (TCA) cycle, and then synthesized into glutamic acid and glutamine, associated with overexpressed LC3B (P < 0.05). Conclusions: HFD-induced IR associated with increased glucose utility undergoing oxidative phosphorylation via the TCA cycle in the myocardium is supported by overexpression of glucose transporter, acetyl-CoA synthase. Noninvasive imaging biomarker has potentials in detecting the metabolic perturbations prior to the decline of the left ventricular function.

Focused Ultrasound-Induced Blood-Brain Barrier Opening Enhances GSK-3 Inhibitor Delivery for Amyloid-Beta Plaque Reduction.

Alzheimer's disease (AD) is a neurodegenerative disease that is the leading cause of age-related dementia. Currently, therapeutic agent delivery to the CNS is a valued approach for AD therapy. Unfortunately, the CNS penetration is greatly hampered by the blood-brain barrier (BBB). Focused-ultrasound (FUS) has been demonstrated to temporally open the BBB, thus promoting therapeutic agent delivery to the CNS. Recently, the BBB opening procedure was further reported to clear the deposited Aß plaque due to microglia activation. In this study, we aimed to evaluate whether the use of FUS-induced BBB opening to enhance GSK-3 inhibitor delivery, which would bring additive effect of Aß plaque clearance by FUS with the reduction of Aß plaque synthesis by GSK-3 inhibitor in an AD mice model. FUS-induced BBB opening on APPswe/PSEN1-dE9 transgenic mice was performed unilaterally, with the contralateral hemisphere serving as a reference. GSK-3 level was confirmed by immunohistochemistry (IHC) and autoradiography (ARG) was also conducted to quantitatively confirm the Aß plaque reduction. Results from IHC showed GSK-3 inhibitor effectively reduced GSK-3 activity up to 61.3% with the addition of FUS-BBB opening and confirming the proposed therapeutic route. ARG also showed significant Aß-plaque reduction up to 31.5%. This study reveals the therapeutic potentials of ultrasound to AD treatment, and may provide a useful strategy for neurodegenerative disease treatment.

Nab-paclitaxel is effective against intrahepatic cholangiocarcinoma via disruption of desmoplastic stroma.

Intrahepatic cholangiocarcinoma (IH-CCA) is the second predominant hepatic malignancy worldwide. However, effective treatment strategies for IH-CCA have not yet been developed. Nab-paclitaxel may be an effective drug against IH-CCA, a type of desmoid-like tumor, and its antitumor effects may be attributable to its ability to disrupt the cancer-associated fibroblasts. In the present study, MTT and Annexin-V apoptosis detection kits were used to evaluate the efficacy of paclitaxel and nab-paclitaxel against human cholangiocarcinoma KKU-100 and KKU-213 cell lines. A rat model of thioacetamide-induced spontaneous desmoplastic IH-CCA was used to compare the treatment response of four different drug regimens: Control, paclitaxel, nab-paclitaxel and gemcitabine/oxaliplatin. Positron emission tomography and immunofluorescence analysis were used to measure the tumor volume and to study the resected tumor, respectively. In vitro, paclitaxel and nab-paclitaxel induced anti-proliferative effects in KKU-100 and KKU-M213 cells. With regards to the treatment regimes, only nab-paclitaxel and gemcitabine/oxaliplatin induced antitumor effects in the rat model of thioacetamide-induced IH-CCA. The immunofluorescence study indicated that nab-paclitaxel was more efficient in disrupting cancer-associated fibroblasts than paclitaxel. In conclusion, nab-paclitaxel is effective against IH-CCA owing to its ability to markedly disrupt the desmoplastic stroma.

Synthesis and evaluation of ortho-[18F] fluorocelecoxib for COX-2 cholangiocarcinoma imaging.

BACKGROUND: An 18F-tagged NSAID analog was prepared for use as a probe for COX-2 expression, which is associated with tumor development. METHODS: The in vivo uptake of celecoxib was monitored with ortho-[18F]fluorocelecoxib using positron emission tomography (PET). The binding affinity of ortho-[18F]fluorocelecoxib to COX-1 and COX-2 enzymes were assessed using the competitor celecoxib. RESULTS: The IC50 values were 0.039 µM and 0.024 µM, respectively. A selectivity index of 1.63 was obtained (COX-2 vs COX-1). COX-2 overexpressed cholangiocarcinoma (CCA) murine cells took up more ortho-[18F]fluorocelecoxib than that by usual CCA cells from 10 to 60 minutes post incubation. Competitive inhibition (blocking) of the tracer uptake of ortho-[18F]fluorocelecoxib in the presence of celecoxib by the COX-2 overexpressed CCA cells and the usual CCA cells gave the IC50 values of 0.5 µM and 46.5 µM, respectively. Based on the in vitro accumulation data and in vivo metabolism half-life (30 min), PET scanning was performed 30-60 min after the administration of ortho-[18F]fluorocelecoxib through the tail vein. Study of ortho-[18F]F-celecoxib in the CCA rats showed a tumor to normal ratio (T/N) of 1.38±0.23 and uptake dose of 1.14±0.25 (%ID/g). CONCLUSION: The inferior in vivo blocking results of 1.48±0.20 (T/N) and 1.18±0.22 (%ID/g) suggests that the nonspecificity is associated with the complex role of peroxidase or the binding to carbonic anhydrase.

Early Response Monitoring Following Radiation Therapy by Using [18F]FDG and [11C]Acetate PET in Prostate Cancer Xenograft Model with Metabolomics Corroboration.

We aim to characterize the metabolic changes associated with early response to radiation therapy in a prostate cancer mouse model by 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) and [11C]acetate ([11C]ACT) positron emission tomography, with nuclear magnetic resonance (NMR) metabolomics corroboration. [18F]FDG and [11C]ACT PET were performed before and following irradiation (RT, 15Gy) for transgenic adenocarcinoma of mouse prostate xenografts. The underlying metabolomics alterations of tumor tissues were analyzed by using ex vivo NMR. The [18F]FDG total lesion glucose (TLG) of the tumor significant increased in the RT group at Days 1 and 3 post-irradiation, compared with the non-RT group (p < 0.05). The [11C]ACT maximum standard uptake value (SUVmax) in RT (0.83 ± 0.02) and non-RT groups (0.85 ± 0.07) were not significantly different (p > 0.05). The ex vivo NMR analysis showed a 1.70-fold increase in glucose and a 1.2-fold increase in acetate in the RT group at Day 3 post-irradiation (p < 0.05). Concordantly, the expressions of cytoplasmic acetyl-CoA synthetase in the irradiated tumors was overexpressed at Day 3 post-irradiation (p < 0.05). Therefore, TLG of [18F]FDG in vivo PET images can map early treatment response following irradiation and be a promising prognostic indicator in a longitudinal preclinical study. The underlying metabolic alterations was not reflected by the [11C]ACT PET.