Molecular Imaging最新文献

Positron emission tomography (PET) using the radiotracer [¹⁸F]-FDOPA provides a tool for studying brain dopamine synthesis capacity in animals and humans. We have previously standardised a micro-PET methodology in mice by intravenously administering [¹⁸F]-FDOPA via jugular vein cannulation and assessment of striatal dopamine synthesis capacity, indexed as the influx rate constant K _i ^Mod of [¹⁸F]-FDOPA, using an extended graphical Patlak analysis with the cerebellum as a reference region. This enables a direct comparison between preclinical and clinical output values. However, chronic intravenous catheters are technically difficult to maintain for longitudinal studies. Hence, in this study, intraperitoneal administration of [¹⁸F]-FDOPA was evaluated as a less-invasive alternative that facilitates longitudinal imaging. Our experiments comprised the following assessments: (i) comparison of [¹⁸F]-FDOPA uptake between intravenous and intraperitoneal radiotracer administration and optimisation of the time window used for extended Patlak analysis, (ii) comparison of Ki ^Mod in a within-subject design of both administration routes, (iii) test-retest evaluation of Ki ^Mod in a within-subject design of intraperitoneal radiotracer administration, and (iv) validation of Ki ^Mod estimates by comparing the two administration routes in a mouse model of hyperdopaminergia induced by subchronic ketamine. Our results demonstrate that intraperitoneal [¹⁸F]-FDOPA administration resulted in good brain uptake, with no significant effect of administration route on Ki ^Mod estimates (intraperitoneal: 0.024 ± 0.0047 min^-1, intravenous: 0.022 ± 0.0041 min^-1, p = 0.42) and similar coefficient of variation (intraperitoneal: 19.6%; intravenous: 18.4%). The technique had a moderate test-retest validity (intraclass correlation coefficient (ICC) = 0.52, N = 6) and thus supports longitudinal studies. Following subchronic ketamine administration, elevated K _i ^Mod as compared to control condition was measured with a large effect size for both methods (intraperitoneal: Cohen's d = 1.3; intravenous: Cohen's d = 0.9), providing further evidence that ketamine has lasting effects on the dopamine system, which could contribute to its therapeutic actions and/or abuse liability.

Hepatocellular carcinoma (HCC) is a notoriously difficult cancer to treat. The recent development of immune checkpoint inhibitors has revolutionised HCC therapy; however, successful response is only observed in a small percentage of patients. Biomarkers typically used to predict treatment response in other tumour types are ineffective in HCC, which arises in an immune-suppressive environment. However, imaging markers that measure changes in tumour infiltrating immune cells may supply information that can be used to determine which patients are responding to therapy posttreatment. We have evaluated [¹⁸F]AlF-mNOTA-GZP, a radiolabeled peptide targeting granzyme B, to stratify response to ICIs in a HEPA 1-tumours, a syngeneic model of HCC. Posttherapy, in vivo tumour retention of [¹⁸F]AlF-mNOTA-GZP was correlated to changes in tumour volume and tumour-infiltrating immune cells. [¹⁸F]AlF-mNOTA-GZP successfully stratified response to immune checkpoint inhibition in the syngeneic HEPA 1-6 model. FACS indicated significant changes in the immune environment including a decrease in immune suppressive CD4+ T regulatory cells and increases in tumour-associated GZB+ NK+ cells, which correlated well with tumour radiopharmaceutical uptake. While the immune response to ICI therapies differs in HCC compared to many other cancers, [¹⁸F]AlF-mNOTA-GZP retention is able to stratify response to ICI therapy associated with tumour infiltrating GZB+ NK+ cells in this complex tumour microenvironment.

Objectives: This study is aimed at investigating the impact of frame numbers in preclinical electrocardiogram- (ECG-) gated ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) on systolic and diastolic left ventricular (LV) parameters in rats.

Methods: ¹⁸F-FDG PET imaging using a dedicated small animal PET system with list mode data acquisition and continuous ECG recording was performed in diabetic and control rats. The list-mode data was sorted and reconstructed with different numbers of frames (4, 8, 12, and 16) per cardiac cycle into tomographic images. Using an automatic ventricular edge detection software, left ventricular (LV) functional parameters, including ejection fraction (EF), end-diastolic (EDV), and end-systolic volume (ESV), were calculated. Diastolic variables (time to peak filling (TPF), first third mean filling rate (1/3 FR), and peak filling rate (PFR)) were also assessed.

Results: Significant differences in multiple parameters were observed among the reconstructions with different frames per cardiac cycle. EDV significantly increased by numbers of frames (353.8 ± 57.7 μl^∗, 380.8 ± 57.2 μl^∗, 398.0 ± 63.1 μl^∗, and 444.8 ± 75.3 μl at 4, 8, 12, and 16 frames, respectively; ^∗ P < 0.0001 vs. 16 frames), while systolic (EF) and diastolic (TPF, 1/3 FR and PFR) parameters were not significantly different between 12 and 16 frames. In addition, significant differences between diabetic and control animals in 1/3 FR and PFR in 16 frames per cardiac cycle were observed (P < 0.005), but not for 4, 8, and 12 frames.

Conclusions: Using ECG-gated PET in rats, measurements of cardiac function are significantly affected by the frames per cardiac cycle. Therefore, if you are going to compare those functional parameters, a consistent number of frames should be used.

Developing sensitive diagnostic methods for a longitudinal evaluation of the status of liver fibrosis is a priority. This study is aimed at assessing the significance of longitudinal positron emission tomography (PET) imaging with ¹⁸F-labeling tracers for assessing liver fibrosis in a rat model with bile duct ligation (BDL). Twenty-one 6-week-old Sprague-Dawley male rats were used in this study. Longitudinal PET images using [¹⁸F]N-2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([¹⁸F]FEPPA) (n = 3), [¹⁸F]fluoroacetate ([¹⁸F]FAc) (n = 3), and 18F-fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) (n = 3) were obtained at 0, 1, and 2 weeks after BDL. Biochemical assays, histological assays, immunohistochemical staining assays, and next generation sequencing analyses were also performed at 0 (n = 3), 1 (n = 3), 2 (n = 3), and 3 (n = 3) weeks after BDL, which demonstrated the severe damage in rat livers after BDL. Regarding [¹⁸F]FEPPA and [¹⁸F]FDG, there was a significantly higher uptake in the liver after BDL (both P < 0.05), which lasted until week 2. However, the uptake of [¹⁸F]FAc in the liver was not significantly different before and after BDL (P = 0.28). Collectively, both [¹⁸F]FEPPA and [¹⁸F]FDG can serve as sensitive probes for detecting the liver fibrosis. However, [¹⁸F]FAc is not recommended to diagnose liver fibrosis.

Sphingosine-1-phosphate receptor 1 (S1PR1) plays a crucial role in infectious diseases. Targeting S1PR1 provides protection against pathogens, such as influenza viruses. This study is aimed at investigating S1PR1 in response to bacterial infection by assessing S1PR1 expression in S. aureus-infected mice. A rodent local muscle bacterial infection model was developed by injecting S. aureus to the lower hind limb of Balb/c mice. The changes of S1PR1 expression in response to bacterial infection and blocking treatment were assessed using ex vivo biodistribution and in vivo positron emission tomography (PET) after intravenous injection of an S1PR1-specific radiotracer [¹⁸F]TZ4877. The specificity of [¹⁸F]TZ4877 was assessed using S1PR1-specific antagonist, NIBR-0213, and S1PR1-specific DsiRNA pretreated the animals. Immunohistochemical studies were performed to confirm the increase of S1PR1 expression in response to infection. Ex vivo biodistribution data showed that the uptake of [¹⁸F]TZ4877 was increased 30.6%, 54.3%, 74.3%, and 115.3% in the liver, kidney, pancreas, and thymus of the infected mice, respectively, compared to that in normal control mice, indicating that S1PR1 is involved in the early immune response to bacterial infection. NIBR-0213 or S1PR1-specific DsiRNA pretreatment reduced the tissue uptake of [¹⁸F]TZ4877, suggesting that uptake of [¹⁸F]TZ4877 is specific. Our PET/CT study data also confirmed that infected mice have increased [¹⁸F]TZ4877 uptake in several organs comparing to that in normal control mice. Particularly, compared to control mice, a 39% increase of [¹⁸F]TZ4877 uptake was observed in the infected muscle of S. aureus mice, indicating that S1PR1 expression was directly involved in the inflammatory response to infection. Overall, our study suggested that S1PR1 plays an important role in the early immune response to bacterial infection. The uptake of [¹⁸F]TZ4877 is tightly correlated with the S1R1 expression in response to S. aureus infection. PET with S1PR1-specific radiotracer [¹⁸F]TZ4877 could provide a noninvasive tool for detecting the early S1PR1 immune response to infectious diseases.

Background: Some studies have reported the effectiveness of [¹⁸F]PI-2620 as an effective tau-binding radiotracer; however, few reports have applied semiquantitative analysis to the tracer. Therefore, this study's aim was to perform a semiquantitative analysis of [¹⁸F]PI-2620 in individuals with normal cognition and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD).

Methods: Twenty-six cognitively normal (CN) subjects, 7 patients with AD, and 36 patients with MCI were enrolled. A dynamic positron emission tomography (PET) scan was performed 30-75 min postinjection. PET and T1-weighted magnetic resonance imaging scans were coregistered. The standardized uptake value ratio (SUVr) was used for semiquantitative analysis. The P-Mod software was applied to create volumes of interest. The ANOVA and post hoc Tukey HSD were used for statistical analysis.

Results: In the AD group, the occipital lobe had a significantly higher mean SUVr (1.46 ± 0.57) than in the CN and MCI groups. Compared with the CN group, the AD group showed significantly higher mean SUVr in the fusiform gyrus (1.06 ± 0.09 vs. 1.49 ± 0.86), inferior temporal (1.07 ± 0.07 vs. 1.46 ± 0.08), parietal lobe, lingual gyrus, and precuneus regions. Similarly, the AD group demonstrated a higher mean SUVr than the MCI group in the precuneus, lingual, inferior temporal, fusiform, supramarginal, orbitofrontal, and superior temporal regions. The remaining observed regions, including the striatum, basal ganglia, thalamus, and white matter, showed a low SUVr across all groups with no statistically significant differences.

Conclusion: A significantly higher mean SUVr of [¹⁸F]PI-2620 was observed in the AD group; a significant area of the brain in the AD group demonstrated tau protein deposit in concordance with Braak Stages III-V, providing useful information to differentiate AD from CN and MCI. Moreover, the low SUVr in the deep striatum and thalamus could be useful for excluding primary tauopathies.

Background: Inducible nitric oxide synthase (iNOS) plays a crucial role in neuroinflammation, especially microglial activity, and may potentially represent a useful biomarker of neuroinflammation. In this study, we carefully defined a strategic plan to develop iNOS-targeted molecular PET imaging using (4'-amino-5',8'-difluoro-1'H-spiro[piperidine-4,2'-quinazolin]-1-yl)(4-fluorophenyl)methanone ([¹⁸F]FBAT) as a tracer in a mouse model of lipopolysaccharide- (LPS-) induced brain inflammation.

Methods: An in vitro model, murine microglial BV2 cell line, was used to assess the uptake of [¹⁸F]FBAT in response to iNOS induction at the cellular level. In vivo whole-body dynamic PET/MR imaging was acquired in LPS-treated (5 mg/kg) and control mice. Standard uptake value (SUV), total volume of distribution (V _t), and area under the curve (AUC) based on the [¹⁸F]FBAT PET signals were determined. The expression of iNOS was confirmed by immunohistochemistry (IHC) of brain tissues.

Results: At the end of synthesis, the yield of [¹⁸F]FBAT was 2.2-3.1% (EOS), radiochemical purity was >99%, and molar radioactivity was 125-137 GBq/μmol. In vitro, [¹⁸F]FBAT rapidly and progressively accumulated in murine microglial BV2 cells exposed to LPS; however, [¹⁸F]FBAT accumulation was inhibited by aminoguanidine, a selective iNOS inhibitor. In vivo biodistribution studies of [¹⁸F]FBAT showed a significant increase in the liver and kidney on LPS-treated mice. At 3 h postinjection of LPS, in vivo, the [¹⁸F]FBAT accumulation ratios at 30 min post intravenous (i.v.) radiotracer injection for the whole brain, cortex, cerebellum, and brainstem were 2.16 ± 0.18, 1.53 ± 0.25, 1.41 ± 0.21, and 1.90 ± 0.12, respectively, compared to those of mice not injected with LPS. The mean area under the curve (AUC_0-30min), total volume of distribution (V _t, mL/cm³), and K _i (influx rate) of [¹⁸F]FBAT were 1.9 ± 0.21- and 1.4 ± 0.22-fold higher in the 3 h LPS group, respectively, than in the control group. In the pharmacokinetic two-compartment model, the whole brain K _i of [¹⁸F]FBAT was significantly higher in mice injected with LPS compared to the control group. Aminoguanidine, selective iNOS inhibitor, pretreatment significantly reduced the AUC_0-30min and V _t values in LPS-induced mice. Quantitative analysis of immunohistochemically stained brain sections confirmed iNOS was preferentially upregulated in the cerebellum and cortex of mice injected with LPS.

Conclusion: An automated robotic method was established for radiosynthesis of [¹⁸F]FBAT, and the preliminary in vitro and in vivo results demonstrated the fe

The recently emerging technique of sparse reconstruction has received much attention in the field of photoacoustic imaging (PAI). Compressed sensing (CS) has large potential in efficiently reconstructing high-quality PAI images with sparse sampling signal. In this article, we propose a CS-based error-tolerant regularized smooth L0 (ReSL0) algorithm for PAI image reconstruction, which has the same computational advantages as the SL0 algorithm while having a higher degree of immunity to inaccuracy caused by noise. In order to evaluate the performance of the ReSL0 algorithm, we reconstruct the simulated dataset obtained from three phantoms. In addition, a real experimental dataset from agar phantom is also used to verify the effectiveness of the ReSL0 algorithm. Compared to three L₀ norm, L₁ norm, and TV norm-based CS algorithms for signal recovery and image reconstruction, experiments demonstrated that the ReSL0 algorithm provides a good balance between the quality and efficiency of reconstructions. Furthermore, the PSNR of the reconstructed image calculated by the introduced method was better than the other three methods. In particular, it can notably improve reconstruction quality in the case of noisy measurement.

We investigated the potential use of [¹⁸F]FDG PET as a response biomarker for PI3K pathway targeting therapies in two HER-2-overexpressing cancer models. Methods. CD-1 nude mice were inoculated with HER-2-overexpressing JIMT1 (trastuzumab-resistant) or SKOV3 (trastuzumab-sensitive) human cancer cells. Animals were treated with trastuzumab, everolimus (mTOR inhibitor), PIK90 (PI3K inhibitor), saline, or combination therapy. [¹⁸F]FDG scans were performed at baseline, two, and seven days after the start of the therapy. Tumors were delineated on CT images and relative tumor volumes (RTV) and maximum standardized uptake value (SUV_max) were calculated. Levels of pS6 and pAkt on protein tumor lysates were determined with ELISA. Results. In the SKOV3 xenografts, all treatment schedules resulted in a gradual decrease in RTV and delta SUV_max (ΔSUV_max). For all treatments combined, ΔSUV_max after 2 days was predictive for RTV after 7 days (r = 0.69, p = 0.030). In JIMT1 tumors, monotherapy with everolimus or PIK90 resulted in a decrease in RTV (-30% ± 10% and -20% ± 20%, respectively) and ΔSUV_max (-39% ± 36% and -42% ± 8%, respectively) after 7 days of treatment, but not earlier, while trastuzumab resulted in nonsignificant increases compared to control. Combination therapies resulted in RTV and ΔSUV_max decrease already at day 2, except for trastuzumab+everolimus, where an early flare was observed. For all treatments combined, ΔSUV_max after 2 days was predictive for RTV after 7 days (r = 0.48, p = 0.028), but the correlation could be improved when combination with everolimus (r = 0.59, p = 0.023) or trastuzumab (r = 0.69, p = 0.015) was excluded. Conclusion. Reduction in [¹⁸F]FDG after 2 days correlated with tumor volume changes after 7 days of treatment and confirms the use of [¹⁸F]FDG PET as an early response biomarker. Treatment response can however be underestimated in schedules containing trastuzumab or everolimus due to temporary increased [¹⁸F]FDG uptake secondary to negative feedback loop and crosstalk between different pathways.

Combining standard drugs with low doses of histone deacetylase inhibitors (HDACIs) is a promising strategy to increase the efficacy of chemotherapy. The ability of well-tolerated doses of HDACIs that act as chemosensitizers for platinum-based chemotherapeutics has recently been proven in many types and stages of cancer in vitro and in vivo. Detection of changes in HDAC activity/expression may provide important prognostic and predictive information and influence treatment decision-making. Use of [¹⁸F] FAHA, a HDAC IIa-specific radionuclide, for molecular imaging may enable longitudinal, noninvasive assessment of HDAC activity/expression in metastatic cancer. We evaluated the synergistic anticancer effects of cisplatin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in xenograft models of nonsmall cell lung cancer (NSCLC) using [¹⁸F] FAHA and [¹⁸F] FDG PET/CT imaging. Cisplatin alone significantly increased [¹⁸F] FAHA accumulation and reduced [¹⁸F] FDG accumulation in H441 and PC14 xenografts; coadministration of cisplatin and SAHA resulted in the opposite effects. Immunochemical staining for acetyl-histone H3 confirmed the PET/CT imaging findings. Moreover, SAHA had a more significant effect on the acetylome in PC14 (EGFR exon 19 deletion mutation) xenografts than H441 (wild-type EGFR and KRAS codon 12 mutant) xenografts. In conclusion, [¹⁸F] FAHA enables quantitative visualization of HDAC activity/expression in vivo, thus, may represent a clinically useful, noninvasive tool for the management of patients who may benefit from synergistic anticancer therapy.