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Molecular Imaging is a peer-reviewed journal highlighting the breadth of molecular imaging research from basic science to preclinical studies to human applications. Molecular Imaging covers all imaging modalities.
Chief Editor Henry VanBrocklin is a Professor at the University of California, San Francisco, USA, and Director of its Radiopharmaceutical Research Program. His research interests include short-lived radioisotope production and the creation of fluorine-18 and carbon-11 labeling chemistry strategies
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PET Study of Sphingosine-1-phosphate Receptor 1 Expression in Response to S. aureus Infection
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.
The Evaluation of Tau Deposition with [18F]PI-2620 by Using a Semiquantitative Method in Cognitively Normal Subjects and Patients with Mild Cognitive Impairment and Alzheimer’s Disease
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 () than in the CN and MCI groups. Compared with the CN group, the AD group showed significantly higher mean SUVr in the fusiform gyrus ( vs. ), inferior temporal ( vs. ), 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.
Automated Synthesis and Initial Evaluation of (4-Amino-5,8-difluoro-1H-spiro[piperidine-4,2-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase
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-1H-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 (), 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 , , , and , respectively, compared to those of mice not injected with LPS. The mean area under the curve (AUC0-30min), total volume of distribution (, mL/cm3), and (influx rate) of [18F]FBAT were - and -fold higher in the 3 h LPS group, respectively, than in the control group. In the pharmacokinetic two-compartment model, the whole brain of [18F]FBAT was significantly higher in mice injected with LPS compared to the control group. Aminoguanidine, selective iNOS inhibitor, pretreatment significantly reduced the AUC0-30min and 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 feasibility of detecting iNOS activity/expression in LPS-treated neuroinflammation by noninvasive imaging with [18F]FBAT PET/MRI.
A Photoacoustic Imaging Algorithm Based on Regularized Smoothed L0 Norm Minimization
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.
Early Changes in [18F]FDG Uptake as a Readout for PI3K/Akt/mTOR Targeted Drugs in HER-2-Positive Cancer Xenografts
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 (SUVmax) 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 SUVmax (ΔSUVmax). For all treatments combined, ΔSUVmax after 2 days was predictive for RTV after 7 days (, ). In JIMT1 tumors, monotherapy with everolimus or PIK90 resulted in a decrease in RTV ( and , respectively) and ΔSUVmax ( and , respectively) after 7 days of treatment, but not earlier, while trastuzumab resulted in nonsignificant increases compared to control. Combination therapies resulted in RTV and ΔSUVmax decrease already at day 2, except for trastuzumab+everolimus, where an early flare was observed. For all treatments combined, ΔSUVmax after 2 days was predictive for RTV after 7 days (, ), but the correlation could be improved when combination with everolimus (, ) or trastuzumab (, ) 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.
In Vivo Evaluation of the Combined Anticancer Effects of Cisplatin and SAHA in Nonsmall Cell Lung Carcinoma Using [18F]FAHA and [18F]FDG PET/CT Imaging
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.