Molecular Imaging最新文献

Hydrolytic enzymes are a large class of biological catalysts that play a vital role in a plethora of critical biochemical processes required to maintain human health. However, the expression and/or activity of these important enzymes can change in many different diseases and therefore represent exciting targets for the development of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) radiotracers. This review focuses on recently reported radiolabeled substrates, reversible inhibitors, and irreversible inhibitors investigated as PET and SPECT tracers for imaging hydrolytic enzymes. By learning from the most successful examples of tracer development for hydrolytic enzymes, it appears that an early focus on careful enzyme kinetics and cell-based studies are key factors for identifying potentially useful new molecular imaging agents.

Purpose: To assess and quantify by molecular imaging knee osseous metabolic changes serially in an in vivo canine model of posttraumatic osteoarthritis (PTOA) of the knee utilizing sodium fluoride (Na¹⁸F) positron emission tomography (PET)/computed tomography (CT) coregistered with magnetic resonance imaging (MRI).

Materials and methods: Sodium fluoride PET imaging of 5 canines was performed prior to anterior cruciate ligament transection (ACLT) and 2 times post-ACLT (3 and 12 weeks). The PET/CT was coregistered with MRI, enabling serial anatomically guided visual and quantitative three-dimensional (3D) region of interest (ROI) assessment by maximum standardized uptake value.

Results: Prior to ACLT, every 3D ROI assessed in both knees showed no Na¹⁸F uptake above background. The uptake of Na¹⁸F in the bone of the ACLT knees increased exponentially, presenting significantly higher uptake at 12 weeks in every region compared to the ACLT knees at baseline. Furthermore, the uninjured contralateral limb and the ipsilateral distal bones and joints presented Na¹⁸F uptake at 3 and 12 weeks post-ACLT.

Conclusion: This study demonstrated that Na¹⁸F PET/CT coregistered with MRI is a feasible molecular imaging biomarker to assess knee osseous metabolic changes serially in an in vivo canine model of knee PTOA. Moreover, it brings a novel musculoskeletal preclinical imaging methodology that can provide unique insights into PTOA pathophysiology.

The myriad physiological functions of γ-amino butyric acid (GABA) are mediated by the GABA-benzodiazepine receptor complex comprising of the GABA_A, GABA_B, and GABA_C groups. The various GABA_A subunits with region-specific distributions in the brain subserve different functional and physiological roles. For example, the sedative and anticonvulsive effects of classical benzodiazepines are attributed to the α₁ subunit, and the α₂ and α₃ subunits mediate the anxiolytic effect. To optimize pharmacotherapies with improved efficacy and devoid of undesirable side effects for the treatment of anxiety disorders, subtype-selective imaging radiotracers are required to assess target engagement at GABA sites and determine the dose-receptor occupancy relationships. The goal of this work was to characterize, in nonhuman primates, the in vivo binding profile of a novel positron emission tomography (PET) radiotracer, [¹¹C]ADO, which has been indicated to have functional selectivity for the GABA_A α₂/α₃ subunits. High specific activity [¹¹C]ADO was administrated to 3 rhesus monkeys, and PET scans of 120-minute duration were performed on the Focus-220 scanner. In the blood, [¹¹C]ADO metabolized at a fairly rapid rate, with ∼36% of the parent tracer remaining at 30 minutes postinjection. Uptake levels of [¹¹C]ADO in the brain were high (peak standardized uptake value of ∼3.0) and consistent with GABA_A distribution, with highest activity levels in cortical areas, intermediate levels in cerebellum and thalamus, and lowest uptake in striatal regions and amygdala. Tissue kinetics was fast, with peak uptake in all brain regions within 20 minutes of tracer injection. The one-tissue compartment model provided good fits to regional time-activity curves and reliable measurement of kinetic parameters. The absolute test-retest variability of regional distribution volumes ( V_T) was low, ranging from 4.5% to 8.7%. Pretreatment with flumazenil (a subtype nonselective ligand, 0.2 mg/kg, intravenous [IV], n = 1), Ro15-4513 (an α₅-selective ligand, 0.03 mg/kg, IV, n = 2), and zolpidem (an α₁-selective ligand, 1.7 mg/kg, IV, n = 1) led to blockade of [¹¹C]ADO binding by 96.5%, 52.5%, and 76.5%, respectively, indicating the in vivo binding specificity of the radiotracer. Using the nondisplaceable volume of distribution ( V_ND) determined from the blocking studies, specific binding signals, as measured by values of regional binding potential ( BP_ND), ranged from 0.6 to 4.4, which are comparable to those of [¹¹C]flumazenil. In conclusion, [¹¹C]ADO was demonstrated to be a specific radiotracer for the GABA_A receptors with several favorable properties: high brain uptake, fast tissue kinetics, and high levels of specific binding

Using longitudinal micro positron emission tomography (microPET)/computed tomography (CT) studies, we quantified changes in myocardial metabolism and perfusion in spontaneously hypertensive rats (SHRs), a model of left ventricular hypertrophy (LVH). Fatty acid and glucose metabolism were quantified in the hearts of SHRs and Wistar-Kyoto (WKY) normotensive rats using long-chain fatty acid analog ¹⁸F-fluoro-6-thia heptadecanoic acid (¹⁸F-FTHA) and glucose analog ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) under normal or fasting conditions. We also used ¹⁸F-fluorodihydrorotenol (¹⁸F-FDHROL) to investigate perfusion in their hearts without fasting. Rats were imaged at 4 or 5 times over their life cycle. Compartment modeling was used to estimate the rate constants for the radiotracers. Blood samples were obtained and analyzed for glucose and free fatty acid concentrations. SHRs demonstrated no significant difference in ¹⁸F-FDHROL wash-in rate constant ( P = .1) and distribution volume ( P = .1), significantly higher ¹⁸F-FDG myocardial influx rate constant ( P = 4×10^-8), and significantly lower ¹⁸F-FTHA myocardial influx rate constant ( P = .007) than WKYs during the 2009-2010 study without fasting. SHRs demonstrated a significantly higher ¹⁸F-FDHROL wash-in rate constant ( P = 5×10^-6) and distribution volume ( P = 3×10^-8), significantly higher ¹⁸F-FDG myocardial influx rate constant ( P = 3×10^-8), and a higher trend of ¹⁸F-FTHA myocardial influx rate constant (not significant, P = .1) than WKYs during the 2011-2012 study with fasting. Changes in glucose plasma concentrations were generally negatively correlated with corresponding radiotracer influx rate constant changes. The study indicates a switch from preferred fatty acid metabolism to increased glucose metabolism with hypertrophy. Increased perfusion during the 2011-2012 study may be indicative of increased aerobic metabolism in the SHR model of LVH.

Immunotherapy holds great promise in cancer treatment. The challenges in advancing immunotherapies lie in patient stratification and monitoring therapy. Noninvasive detection of immune checkpoint ligand PD-L1 can serve as an important biomarker for guidance and monitoring of immunotherapy. Here in, we provide an overview of our efforts to develop clinically translatable PD-L1-specific imaging agents for quantitative and real-time assessment of PD-L1 expression in tumor microenvironment.

Malignant pleural mesothelioma is a deadly disease. Complete surgical resection provides patients with the best opportunity for long-term survival. Unfortunately, identification of disease during resection can be challenging. In this report, we describe successful intraoperative utilization of the near-infrared imaging agent, indocyanine green, to help the surgeon identify malignant disease in a patient with malignant pleural mesothelioma who had previously received neoadjuvant chemotherapy. This technology may ultimately enhance the thoracic surgeon's ability to identify small disease deposits at the time of resection.

Recent technical advances in positron emission tomography/magnetic resonance imaging (PET/MRI) technology allow much improved time-of-flight (TOF) and regularized iterative PET reconstruction regularized iterative reconstruction (RIR) algorithms. We evaluated the effect of TOF and RIR on standardized uptake values (maximum and peak SUV [SUV_max and SUV_peak]) and their metabolic tumor volume dependencies and visual image quality for ¹⁸F-fluorocholine PET/MRI in patients with newly diagnosed prostate cancer. Fourteen patients were administered with 3 MBq/kg of ¹⁸F-fluorocholine and scanned dynamically for 30 minutes. Positron emission tomography images were divided to early and late time points (1-6 minutes summed and 7-30 minutes summed). The values of the different SUVs were documented for dominant PET-avid lesions, and metabolic tumor volume was estimated using a 50% isocontour and SUV threshold of 2.5. Image quality was assessed via visual acuity scoring (VAS). We found that incorporation of TOF or RIR increased lesion SUVs. The lesion to background ratio was not improved by TOF reconstruction, while RIR improved the lesion to background ratio significantly ( P < .05). The values of the different VAS were all significantly higher ( P < .05) for RIR images over TOF, RIR over non-TOF, and TOF over non-TOF. In conclusion, our data indicate that TOF or RIR should be incorporated into current protocols when available.

Background: Evolving immune-mediated therapeutic strategies for rheumatoid arthritis (RA) may benefit from an improved understanding of the complex role that T-cell activation plays in RA. This study assessed the potential of fluorine-18-labeled 9-β-d-arabinofuranosylguanine ([¹⁸F]F-AraG) positron emission tomography (PET) imaging to report immune activation in vivo in an adjuvant-induced arthritis (AIA) small animal model.

Methods: Using positron emission tomography-computed tomography imaging, uptake of [¹⁸F]F-AraG in the paws of mice affected by arthritis at 6 (acute) and 20 (chronic) days following AIA induction in a single paw was assessed and compared to uptake in contralateral control paws. Fractions of T cells and B cells demonstrating markers of activation at the 2 time points were determined by flow cytometry.

Results: Differential uptake of [¹⁸F]F-AraG was demonstrated on imaging of the affected joint when compared to control at both acute and chronic time points with corresponding changes in markers of T-cell activation observed on flow cytometry.

Conclusion: [¹⁸F]F-AraG may serve as an imaging biomarker of T-cell activation in inflammatory arthritis. Further development of this technique is warranted and could offer a tool to explore the temporal link between activated T cells and RA as well as to monitor immune-mediated therapies for RA in clinical trials.

ß₆-integrin immunohistochemistry analysis of a large number of pancreatic ductal adenocarcinoma (PDAC, 383 primary tumors, 7 lymph node, and 8 distant metastases) and 34 pancreatic intraepithelial neoplasia (PanIN) specimens revealed a high prevalence of α_vß₆-integrin expression in PDAC primaries (88%) and in almost all metastases, as well as in PanIN (57%). These findings underscore the high potential of a novel α_vß₆-integrin targeting positron emission tomography (PET) radiopharmaceutical, Ga-68-Avebehexin, for early diagnosis of pancreatic cancer.

Purpose: We investigated 2-(5-fluoro-pentyl)-2-methyl-malonic acid (¹⁸F-ML-10) positron emission tomography (PET) imaging of apoptosis posttherapy to determine optimal timing for predicting chemotherapy response in a mouse head/neck xenograft cancer model.

Procedures: BALB/c nude mice (4-8 weeks old) were implanted with UM-SCC-22B tumors. The treatment group received 2 doses of doxorubicin (10 mg/kg, days 0, 2). Small animal ¹⁸F-ML-10 PET/computed tomography was performed before and on days 1, 3, and 7 postchemotherapy. Using regions of interest around tumors, ¹⁸F-ML-10 uptake change was measured as %ID/g and uptake relative to liver. Terminal Uridine Nick-End Labeling (TUNEL) immunohistochemistry assay was performed using tumor samples of baseline and on days 1, 3, and 7 posttreatment.

Results: Treated mice demonstrated increased ¹⁸F-ML-10 uptake compared to baseline and controls, and 10 of 13 mice showed tumor volume decreases. All control mice showed tumor volume increases. Tumor-to-liver (T/L) ratios from the control group mice did not show significant change from baseline ( P > .05); however, T/L ratios of the treatment group showed significant ¹⁸F-ML-10 uptake differences from baseline compared to days 3 and 7 posttreatment ( P < .05), but no significant difference at 1 day posttreatment.

Conclusion: 2-(5-Fluoro-pentyl)-2-methyl-malonic acid PET imaging has the potential for early assessment of treatment-induced apoptosis. Timing and image analysis strategies may require optimization, depending on the type of tumor and cancer treatment.