Molecular Imaging最新文献

Background: Equipped with two stationary detectors, a large bore collimator for medium-sized animals has been recently introduced for dedicated preclinical single-photon emission computed tomography (SPECT) imaging. We aimed to evaluate the basic performance of the system using phantoms and healthy rabbits.

Methods: A general-purpose medium-sized animal (GP-MSA) collimator with 135 mm bore diameter and thirty-three holes of 2.5 mm diameter was installed on an ultrahigh-resolution scanner equipped with two large stationary detectors (U-SPECT5-E/CT). The sensitivity and uniformity were investigated using a point source and a cylinder phantom containing ^99mTc-pertechnetate, respectively. Uniformity (in %) was derived using volumes of interest (VOIs) on images of the cylinder phantom and calculated as [(maximum count - minimum count)/(maximum count + minimum count) × 100], with lower values of % indicating superior performance. The spatial resolution and contrast-to-noise ratios (CNRs) were evaluated with images of a hot-rod Derenzo phantom using different activity concentrations. Feasibility of in vivo SPECT imaging was finally confirmed by rabbit imaging with the most commonly used clinical myocardial perfusion SPECT agent [^99mTc]Tc-sestamibi (dynamic acquisition with a scan time of 5 min).

Results: In the performance evaluation, a sensitivity of 790 cps/MBq, a spatial resolution with the hot-rod phantom of 2.5 mm, and a uniformity of 39.2% were achieved. The CNRs of the rod size 2.5 mm were 1.37, 1.24, 1.20, and 0.85 for activity concentration of 29.2, 1.0, 0.5, and 0.1 MBq/mL, respectively. Dynamic SPECT imaging in rabbits allowed to visualize most of the thorax and to generate time-activity curves of the left myocardial wall and ventricular cavity.

Conclusion: Preclinical U-SPECT5-E/CT equipped with a large bore collimator demonstrated adequate sensitivity and resolution for in vivo rabbit imaging. Along with its unique features of SPECT molecular functional imaging is a superior collimator technology that is applicable to medium-sized animal models and thus may promote translational research for diagnostic purposes and development of novel therapeutics.

Purpose: Extracellular acidity is a marker of highly aggressive breast cancer (BC). pH-low insertion peptides (pHLIPs) target the acidic tumor microenvironment. This study evaluates the distribution and therapeutic efficacy of radioiodine-labeled pHLIP variant 3 (Var3) in a mouse model of BC.

Methods: The binding of fluorescein isothiocyanate (FITC)- or radioiodine-125 (¹²⁵I) labeled Var3-pHLIP to MDA-MB-231, 4T1, and SK-BR-3 BC cell lines under different pH values was evaluated in vitro. The distribution of ¹²⁵I-labeled Var3-pHLIP and wild-type- (WT-) pHLIP in tumor-bearing mice was analyzed in vivo using micro-SPECT/CT imaging. The therapeutic efficacy of radioiodine-131 (¹³¹I)-labeled Var3-pHLIP in MDA-MB-231 xenografts was evaluated by relative tumor volume measurement and immunohistochemical analysis.

Results: The binding ability of FITC- or ¹²⁵I-labeled Var3-pHLIP to tumor cells increased with the decrease in pH. The tumor-to-background ratio of ¹²⁵I-Var3-pHLIP in BC xenografts showed the best imaging contrast at 24 h or 48 h postinjection. The uptake of ¹²⁵I-Var3-pHLIP in MDA-MB-231 xenografts at 2 h postinjection was significantly higher than that of ¹²⁵I-WT-pHLIP (3.76 ± 0.37 vs. 2.87 ± 0.60%ID/g, p = 0.046). The relative tumor volume in MDA-MB-231 xenografts was significantly lower in the ¹³¹I-Var3-pHLIP-treated group than in the groups treated with Var3-pHLIP (p = 0.027), ¹³¹I (p = 0.001), and saline (p < 0.001). The ¹³¹I-Var 3-pHLIP group presented a lower expression of Ki67 and a higher expression of caspase 3.

Conclusion: Radioiodine-labeled Var3-pHLIP effectively targeted BC cells in an acidic environment and inhibited the growth of MDA-MB-231 xenografts by ionizing radiation.

It has been a big challenge to distinguish synchronous multiple primary lung cancer (sMPLC) from primary lung cancer with intrapulmonary metastases (IPM). We aimed to assess the clinical application of dynamic ¹⁸F-FDG PET/CT in patients with multiple lung cancer nodules. We enrolled patients with multiple pulmonary nodules who had undergone dynamic ¹⁸F-FDG PET/CT and divided them into sMPLC and IPM groups based on comprehensive features. The SUV_max, fitted K _i value based on dynamic scanning, and corresponding maximum diameter (D _max) from the two largest tumors were determined in each patient. We determined the absolute between-tumor difference of SUV_max/D _max and K _i /D _max (ΔSUV_max/D _max; ΔK _i /D _max) and assessed the between-group differences. Further, the diagnostic accuracy was evaluated by ROC analysis and the correlation between ΔSUV_max/D _max and ΔK _i /D_max from all groups was determined. There was no significant difference for ΔSUV_max/D _max between the IPM and sMPLC groups, while the IPM group had a significantly higher ΔK _i /D_max than the sMPLC group. The AUC of ΔK _i /D _max for differentiating sMPLC from IPM was 0.80 (cut-off value of K _i = 0.0059, sensitivity 79%, specificity 75%, p < 0.001). There was a good correlation (Pearson r = 0.91, 95% CI: 0.79-0.96, p < 0.0001) between ΔSUV_max/D _max and ΔK _i /D _max in the IPM group but not in the sMPLC group (Pearson r = 0.45, p > 0.05). Dynamic ¹⁸F-FDG PET/CT could be a useful tool for distinguishing sMPLC from IPM. K _i calculation based on Patlak graphic analysis could be more sensitive than SUV_max in discriminating IPM from sMPLC in patients with multiple lung cancer nodules.

Purpose: This study is aimed at investigating the feasibility of cetuximab (Cet) F(ab')₂ fragment- (Cet-F(ab')₂-) based single photon emission tomography/computed tomography (SPECT/CT) for assessing the epidermal growth factor receptor (EGFR) expression in digestive tumor mouse models.

Methods: Cet-F(ab')₂ was synthesized using immunoglobulin G-degrading enzyme of Streptococcus pyogenes (IdeS) protease and purified with protein A beads. The product and its in vitro stability in normal saline and 1% bovine serum albumin were analyzed with sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The EGFR expression in the human colon tumor cell line HT29 and the human stomach tumor cell line MGC803 were verified using western blotting and immunocytochemistry. Cet-F(ab')₂ was conjugated with 5(6)-carboxytetramethylrhodamine succinimidyl ester to demonstrate its binding ability to the MGC803 and HT29 cells. Cet-F(ab')₂ was conjugated with NHS-MAG₃ for ^99mTc radiolabeling. The best imaging time was determined using a biodistribution assay at 1, 4, 16, and 24 h after injection of the ^99mTc-MAG₃-Cet-F(ab')₂ tracer. Furthermore, ^99mTc-MAG₃-Cet-F(ab')₂ SPECT/CT was performed on MGC803 and HT29 tumor-bearing nude mice.

Results: HT29 cells had low EGFR expression while MGC803 cell exhibited the high EGFR expression. Cet-F(ab')₂ and intact cetuximab showed similar high binding ability to MGC803 cells but not to HT29 cells. Cet-F(ab')₂ and ^99mTc-MAG₃-Cet-F(ab')₂ showed excellent in vitro stability. The biodistribution assay showed that the target to nontarget ratio was the highest at 16 h (17.29 ± 5.72, n = 4) after tracer injection. The ^99mTc-MAG₃-Cet-F(ab')₂-based SPECT/CT imaging revealed rapid and sustained tracer uptake in MGC803 tumors rather than in HT29 tumors with high image contrast, which was consistent with the results in vitro.

Conclusion: SPECT/CT imaging using ^99mTc-MAG₃-Cet-F(ab')₂ enables the evaluation of the EGFR expression in murine EGFR-positive tumors, indicating the potential utility for noninvasive evaluation of the EGFR expression in tumors.

Background: Mediating glucose absorption in the small intestine and renal clearance, sodium glucose cotransporters (SGLTs) have emerged as an attractive therapeutic target in diabetic patients. A substantial fraction of patients, however, only achieve inadequate glycemic control. Thus, we aimed to assess the potential of the SGLT-targeting PET radiotracer alpha-methyl-4-deoxy-4-[¹⁸F]fluoro-D-glucopyranoside ([¹⁸F]Me4FDG) as a noninvasive intestinal and renal biomarker of SGLT-mediated glucose transport.

Methods: We investigated healthy rats using a dedicated small animal PET system. Dynamic imaging was conducted after administration of the reference radiotracer 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG), or the SGLT-targeting agent, [¹⁸F]Me4FDG either directly into the digestive tract (for assessing intestinal absorption) or via the tail vein (for evaluating kidney excretion). To confirm the specificity of [¹⁸F]Me4FDG and responsiveness to treatment, a subset of animals was also pretreated with the SGLT inhibitor phlorizin. In this regard, an intraintestinal route of administration was used to assess tracer absorption in the digestive tract, while for renal assessment, phlorizin was injected intravenously (IV).

Results: Serving as reference, intestinal administration of [¹⁸F]FDG led to slow absorption with retention of 89.2 ± 3.5% of administered radioactivity at 15 min. [¹⁸F]Me4FDG, however, was rapidly absorbed into the blood and cleared from the intestine within 15 min, leading to markedly lower tracer retention of 18.5 ± 1.2% (P < 0.0001). Intraintestinal phlorizin led to marked increase of [¹⁸F]Me4FDG uptake (15 min, 99.9 ± 4.7%; P < 0.0001 vs. untreated controls), supporting the notion that this PET agent can measure adequate SGLT inhibition in the digestive tract. In the kidneys, radiotracer was also sensitive to SGLT inhibition. After IV injection, [¹⁸F]Me4FDG reabsorption in the renal cortex was significantly suppressed by phlorizin when compared to untreated animals (%ID/g at 60 min, 0.42 ± 0.10 vs. untreated controls, 1.20 ± 0.03; P < 0.0001).

Conclusion: As a noninvasive read-out of the concurrent SGLT expression in both the digestive tract and the renal cortex, [¹⁸F]Me4FDG PET may serve as a surrogate marker for treatment response to SGLT inhibition. As such, [¹⁸F]Me4FDG may enable improvement in glycemic control in diabetes by PET-based monitoring strategies.

Background: [¹⁸F]FEPPA is a potent TSPO imaging agent that has been found to be a potential tracer for imaging neuroinflammation. In order to fulfill the demand of this tracer for preclinical and clinical studies, we have developed a one-pot automated synthesis with simplified HPLC purification of this tracer, which was then used for PET imaging of neuroinflammation in fine particulate matter- (PM2.5-) exposed rats.

Results: Using this automated synthesis method, the RCY of the [¹⁸F]FEPPA was 38 ± 4% (n = 17, EOB) in a synthesis time of 83 ± 8 min from EOB. The radiochemical purity and molar activities were greater than 99% and 209 ± 138 GBq/μmol (EOS, n = 15), respectively. The quality of the [¹⁸F]FEPPA synthesized by this method met the U.S. Pharmacopoeia (USP) criteria. The stability test showed that the [¹⁸F]FEPPA was stable at 21 ± 2°C for up to 4 hr after the end of synthesis (EOS). Moreover, microPET imaging showed that increased tracer activity of [¹⁸F]FEPPA in the brain of PM2.5-exposed rats (n = 6) were higher than that of normal controls (n = 6) and regional-specific.

Conclusions: Using the improved semipreparative HPLC purification, [¹⁸F]FEPPA has been produced in high quantity, high quality, and high reproducibility and, for the first time, used for PET imaging the effects of PM2.5 in the rat brain. It is ready to be used for imaging inflammation in various clinical or preclinical studies, especially for nearby PET centers without cyclotrons.

We developed an immuno-PET technique that monitors modulation of tumor CD133 expression, which is required for the success of CD133-targeted therapies. Methods. Anti-CD133 antibodies were subjected to sulfhydryl moiety-specific ⁸⁹Zr conjugation. ⁸⁹Zr-CD133 IgG was evaluated for specific activity and radiolabel stability. Colon cancer cells underwent binding assays and Western blotting. Biodistribution and PET studies were performed in mice. Results. ⁸⁹Zr-CD133 IgG showed excellent target specificity with 97.2 ± 0.7% blocking of HT29 cell binding by an excess antibody. Intravenous ⁸⁹Zr-CD133 IgG followed biexponential blood clearance and showed CD133-specific uptake in HT29 tumors. ⁸⁹Zr-CD133 IgG PET/CT and biodistribution studies confirmed high HT29 tumor uptake with lower activities in the blood and normal organs. In HT29 cells, celecoxib dose-dependently decreased CD133 expression and ⁸⁹Zr-CD133 IgG binding that reached 19.9 ± 2.1% (P < 0.005) and 50.3 ± 10.9% (P < 0.001) of baseline levels by 50 μM, respectively. Celecoxib treatment of mice significantly suppressed tumor CD133 expression to 67.5 ± 7.8% of controls (P < 0.005) and reduced tumor ⁸⁹Zr-CD133 IgG uptake from 15.5 ± 1.4% at baseline to 12.3 ± 2.0%ID/g (P < 0.01). Celecoxib-induced CD133 reduction in HT29 cells and tumors was associated with substantial suppression of AKT activation. There were also reduced HIF-1α accumulation and IκBα/NFκB phosphorylation. Conclusion. ⁸⁹Zr-CD133 IgG PET provides high-contrast tumor imaging and monitors celecoxib treatment-induced modulation of tumor CD133 expression, which was found to occur through AKT inhibition. This technique may thus be useful for screening drugs that can effectively suppress colon cancer stem cells.

Photoacoustic imaging involves reconstructing an estimation of the absorbed energy density distribution from measured ultrasound data. The reconstruction task based on incomplete and noisy experimental data is usually an ill-posed problem that requires regularization to obtain meaningful solutions. The purpose of the work is to propose an elastic network (EN) model to improve the quality of reconstructed photoacoustic images. To evaluate the performance of the proposed method, a series of numerical simulations and tissue-mimicking phantom experiments are performed. The experiment results indicate that, compared with the L ₁-norm and L ₂-normbased regularization methods with different numerical phantoms, Gaussian noise of 10-50 dB, and different regularization parameters, the EN method with α = 0.5 has better image quality, calculation speed, and antinoise ability.

Background: Early detection and complete resection are important prognostic factors for esophageal cancer (EC). Intraoperative molecular imaging (IMI) using tumor-targeted tracers is effective in many cancer types. However, there are no EC-specific IMI tracers. We sought to test a cathepsin activity-based tracer (VGT-309) for EC resection.

Methods: Murine (AKR, HNM007) and human (OE19) EC cell lines were screened for cathepsin expression by western blotting. In vitro binding affinity of VGT-309 was evaluated by fluorescence microscopy. Flank tumor models were developed by injecting EC cells into the flanks of BALB/c or athymic nude mice. Mice pretreated with a cathepsin inhibitor (JPM-OEt) were used to confirm on target binding. Animals were injected with 2 mg/kg VGT-309, underwent IMI, and were sacrificed 24 hours after injection.

Results: Cathepsins B, L, S, and X were expressed by EC cell lines, and all cell lines were labeled in vitro with VGT-309. Fluorescent signal was eliminated when cells were pretreated with JPM-OEt. On biodistribution analysis, VGT-309 accumulated in the liver, kidneys, and spleen without other organ involvement. VGT-309 selectively accumulated in flank allografts and xenografts, with mean signal-to-background ratio of 5.21 (IQR: 4.18-6.73) for flank allografts and 4.34 (IQR: 3.75-5.02) for flank xenografts. Fluorescence microscopy and histopathological analysis confirmed the selective accumulation of the tracer in tumors compared to background normal tissues.

Conclusions: VGT-309 is an effective tracer for IMI of esophageal cancer. There is potential for clinical translation both as an adjunct to endoscopic detection and for complete removal of disease during esophagectomy.

Purpose: [¹⁸F]F-AraG is a radiolabeled nucleoside analog that shows relative specificity for activated T cells. The aim of this study was to investigate the biodistribution of [¹⁸F]F-AraG in healthy volunteers and assess the preliminary safety and radiation dosimetry.

Methods: Six healthy subjects (three female and three male) between the ages of 24 and 60 participated in the study. Each subject received a bolus venous injection of [¹⁸F]F-AraG (dose range: 244.2-329.3 MBq) prior to four consecutive PET/MR whole-body scans. Blood samples were collected at regular intervals and vital signs monitored before and after tracer administration. Regions of interest were delineated for multiple organs, and the area under the time-activity curves was calculated for each organ and used to derive time-integrated activity coefficient (TIAC). TIACs were input for absorbed dose and effective dose calculations using OLINDA.

Results: PET/MR examination was well tolerated, and no adverse effects to the administration of [¹⁸F]F-AraG were noted by the study participants. The biodistribution was generally reflective of the expression and activity profiles of the enzymes involved in [¹⁸F]F-AraG's cellular accumulation, mitochondrial kinase dGK, and SAMHD1. The highest uptake was observed in the kidneys and liver, while the brain, lung, bone marrow, and muscle showed low tracer uptake. The estimated effective dose for [¹⁸F]F-AraG was 0.0162 mSv/MBq (0.0167 mSv/MBq for females and 0.0157 mSv/MBq for males).

Conclusion: Biodistribution of [¹⁸F]F-AraG in healthy volunteers was consistent with its association with mitochondrial metabolism. PET/MR [¹⁸F]F-AraG imaging was well tolerated, with a radiation dosimetry profile similar to other commonly used [¹⁸F]-labeled tracers. [¹⁸F]F-AraG's connection with mitochondrial biogenesis and favorable biodistribution characteristics make it an attractive tracer with a variety of potential applications.