Molecular Imaging and Biology最新文献

Purpose: The sphingosine-1-phosphate receptor-1 (S1PR₁) is involved in regulating responses to neuroimmune stimuli. There is a need for S1PR₁-specific radioligands with clinically suitable brain pharmcokinetic properties to complement existing radiotracers. This work evaluated a promising S1PR₁ radiotracer, [¹⁸F]TZ4877, in nonhuman primates.

Procedures: [¹⁸F]TZ4877 was produced via nucleophilic substitution of tosylate precursor with K[¹⁸F]/F^- followed by deprotection. Brain PET imaging data were acquired with a Focus220 scanner in two Macaca mulatta (6, 13 years old) for 120-180 min following bolus injection of 118-163 MBq [¹⁸F]TZ4877, with arterial blood sampling and metabolite analysis to measure the parent input function and plasma free fraction (f_P). Each animal was scanned at baseline, 15-18 min after 0.047-0.063 mg/kg of the S1PR₁ inhibitor ponesimod, 33 min after 0.4-0.8 mg/kg of the S1PR₁-specific compound TZ82112, and 167-195 min after 1 ng/kg of the immune stimulus endotoxin. Kinetic analysis with metabolite-corrected input function was performed to estimate the free fraction corrected total distribution volume (V_T/f_P). Whole-body dosimetry scans were acquired in 2 animals (1M, 1F) with a Biograph Vision PET/CT System, and absorbed radiation dose estimates were calculated with OLINDA.

Results: [¹⁸F]TZ4877 exhibited fast kinetics that were described by the reversible 2-tissue compartment model. Baseline [¹⁸F]TZ4877 f_P was low (<1%), and [¹⁸F]TZ4877 V_T/f_P values were 233-866 mL/cm³. TZ82112 dose-dependently reduced [¹⁸F]TZ4877 V_T/f_P, while ponesimod and endotoxin exhibited negligible effects on V_T/f_P, possibly due to scan timing relative to dosing. Dosimetry studies identified the critical organs of gallbladder (0.42 (M) and 0.31 (F) mSv/MBq) for anesthetized nonhuman primate.

Conclusions: [¹⁸F]TZ4877 exhibits reversible kinetic properties, but the low f_P value limits reproducible quantification with this radiotracer. S1PR₁ is a compelling PET imaging target, and these data support pursuing alternative F-18 labeled radiotracers for potential future human studies.

Purpose: This preclinical study explored the feasibility of assessing P-glycoprotein (P-gp) function in both brain and gastrointestinal (GI) tract of rats using positron emission tomography (PET) following oral administration of [¹⁸F]MC225. Different oral administration protocols were evaluated, and radioactivity uptake was compared with uptake following intravenous administration.

Procedures: Twelve male Wistar rats were divided into four groups and subjected to intravenous or oral [¹⁸F]MC225 administration protocols: G₁ (intravenous route), G₂ (oral administration without fasting), G₃ (oral administration with fasting), and G₄ (oral administration with fasting following administration of the P-gp inhibitor tariquidar). Dynamic brain imaging, late abdominal imaging, ex vivo biodistribution, and metabolite analysis were conducted to assess tracer distribution.

Results: In the brain, oral administration yielded lower values compared with intravenous administration, resulting in a reduction in the tissue-to-plasma ratio by approximately 51% for the cortex and 45% for the midbrain and cerebellum. Fasting improved radioactivity uptake, aiding brain visualization. Unexpectedly, administration of the P-gp inhibitor tariquidar did not increase brain concentration, suggesting a signal that was dominated by non-specific uptake, possibly due to instability of [¹⁸F]MC225 in the GI tract. Metabolite analysis in G₄ indicated a significant presence of polar metabolites.

Conclusions: Oral administration of [¹⁸F]MC225 faces challenges and, at this stage, cannot be used to quantify P-gp function. Further research to assess tracer stability and metabolism in the stomach and intestine will be essential for advancing the feasibility of oral tracer administration.

Purpose: Clinical adoption of NK cell immunotherapy is underway for medulloblastoma and osteosarcoma, however there is currently little feedback on cell fate after administration. We propose magnetic particle imaging (MPI) may have applications for the quantitative detection of NK cells.

Procedures: Human-derived NK-92 cells were labeled by co-incubation with iron oxide nanoparticles (VivoTrax™) for 24 h then excess nanoparticles were washed with centrifugation. Cytolytic activity of labeled versus unlabeled NK-92 cells was assessed after 4 h of co-incubation with medulloblastoma cells (DAOY) or osteosarcoma cells (LM7 or OS17). Labeled NK-92 cells at two different doses (0.5 or 1 × 10⁶) were administered to excised mouse brains (cerebellum), fibulas, and lungs then imaged by 3D preclinical MPI (MOMENTUM™) for detection relative to fiducial markers. NK-92 cells were also imaged by clinical-scale MPI under development at Magnetic Insight Inc.

Results: NK-92 cells were labeled with an average of 3.17 pg Fe/cell with no measurable effects on cell viability or cytolytic activity against 3 tumor cell lines. MPI signal was directly quantitative with the number of labeled NK-92 cells, with preclinical limit of detection of 3.1 × 10⁴ cells on MOMENTUM imager. Labeled NK-92 cells could be accurately localized in mouse brains, fibulas, and lungs within < 1 mm of stereotactic injection coordinates with preclinical scanner. Feasibility for detection on a clinical-scale MPI scanner was demonstrated using 4 × 10⁷ labeled NK-92 cells, which is in the range of NK cell doses administered in our previous clinical trial.

Conclusion: MPI can provide sensitive, quantitative, and accurate spatial information on NK cells soon after delivery, showing initial promise to address a significant unmet clinical need to track NK cell fate in patients.

Purpose: Proton exchange rate (K_ex) is a valuable biophysical metric. K_ex MRI may augment conventional structural MRI by revealing brain impairments at the molecular level. This study aimed to investigate the feasibility of K_ex MRI in evaluating brain injuries at multiple epilepsy stages.

Procedures: Six adult rats with epilepsy induced by intra-amygdalae administration of kainic acid (KA) underwent MRI experiment at 11.7 T. Two MRI scans, including T₁ mapping and CEST imaging under three B₁ amplitudes of 0.75, 1.0, and 1.5 μT, were conducted before and 2, 7, and 28 days after KA injection. Quasi-steady-state analysis was performed to reconstruct equilibrium Z spectra. Direct saturation was resolved using a multi-pool Lorentzian model and removed from Z spectra. The residual spectral signal (ΔZ) was used to construct the omega plot of (1-ΔZ)/ΔZ as a linear function of 1/ ${\omega }_1^2$ , from which K_ex was quantified from the X-axis intercept. One-way ANOVA or two-tailed paired student's t-test was employed with P < 0.05 as statistically significant.

Results: All animals exhibited repetitive status epilepticus with IV to V seizure stages after KA injection. At day 28, K_ex values in the hippocampus and cerebral cortex at the surgical hemisphere with KA injection were significantly higher than that at the time points of control and/or day 2 in the same regions (P < 0.01). Moreover, the values were significantly higher than that in respective contralateral regions at day 28 (P < 0.02). No substantial changes of K_ex were seen in bilateral thalamus or contralateral hemisphere among time points (all P > 0.05).

Conclusions: K_ex increase significantly in the cerebral cortex and hippocampus at the surgical hemisphere, especially at day 28, likely due to substantial alterations at chronic epilepsy stage. K_ex MRI is promising to evaluate brain impairment, facilitating the diagnosis and evaluation of neurological disorders.

Purpose: Radionuclide-labeled fibroblast activation protein inhibitor (FAPI) is an emerging tumor tracer. We sought to assess the uptake and diagnostic performance of ¹⁸F-FAPI-42 PET/CT compared with simultaneous 2-deoxy-2[¹⁸F]fluoro-D-glucose (¹⁸F-FDG) PET/CT in primary and metastatic lesions in patients with malignant digestive system neoplasms and to determine the potential clinical benefit.

Procedures: Forty-two patients (men = 30, women = 12, mean age = 56.71 ± 13.26 years) who underwent ¹⁸F-FDG PET/CT and ¹⁸F-FAPI-42 PET/CT simultaneously for diagnosis, staging, and restaging were enrolled. Quantitative data, including standardized uptake value (SUV), tumor-to-liver ratio (TLR), and tumor-to-blood pool ratio (TBR), were analyzed. Two independent readers performed a visual assessment of lesion number and location on PET/CT images. Interobserver agreement between two examinations was calculated using Cohen's kappa (κ).

Results: Primary tumor locations included the liver (n = 20), stomach (n = 9), pancreas (n = 5), and intestine (n = 10). More intense ¹⁸F-FAPI-42 uptake and higher tumor-to-background contrast were detected in most primary and metastatic lesions compared with ¹⁸F-FDG, contributing to improved diagnostic accuracy ranging from 95.24% to 100%. Moreover, additional lesions showing ¹⁸F-FAPI-42 uptake in primary, locoregional and distant metastatic lesions were visualized, especially in multiple liver and peritoneal metastases. Patient-based interobserver agreement varied from moderate to strong, with suboptimal outcomes observed in primary tumors (κ = 0.441, P = 0.01) and preferable results derived from metastatic liver and bone lesions (κ = 1 and 0.896, both P < 0.01). ¹⁸F-FAPI-42 PET/CT resulted in modified treatment strategies for 40.48% (17/42) of patients, while ¹⁸F-FDG PET/CT led to altered therapeutic regimens in only 4.8% (2/42) of patients.

Conclusions: In selected patients with malignant digestive system neoplasms, our study shows that ¹⁸F-FAPI-42 PET/CT is a promising alternative for assessing primary tumors and metastases and aiding staging, restaging, and decision-making, with higher uptake and better lesion visualization compared with ¹⁸F-FDG. Additionally, it may shed light into the treatment selection and response assessment for FAP-targeted therapy or immunotherapy.

Purpose: The accurate assessment of inflammatory activity of the extraocular muscles (EOMs) in thyroid associated ophthalmopathy (TAO) is crucial for formulating subsequent treatment strategies and prognostic judgments. This study aims to explore the efficacy of using [⁶⁸Ga]DOTATATE PET/CT to assess the inflammatory activity of EOMs in TAO patients.

Procedures: This study enrolled 22 TAO patients and 6 healthy volunteers, all of whom underwent orbital [⁶⁸Ga]DOTATATE PET/CT. Among these, 18 patients underwent orbital [^99mTc]DTPA SPECT/CT within one week, and the other 4 patients received orbital MRI. All imaging data were independently assessed, followed by comparative data analysis. The patients then received different treatment schemes, and their prognosis was followed up.

Results: [⁶⁸Ga]DOTATATE PET/CT could effectively evaluate the inflammatory activity of the EOMs in TAO patients and demonstrate good consistency with [^99mTc]DTPA SPECT/CT and orbital MRI, but show a better resolution to distinguish EOMs and surrounding structure. The receiver operating characteristic (ROC) curves for each EOM, treated as individual research units, exhibited an area under the curve (AUC) exceeding 0.9. The medial rectus demonstrated the highest involvement and diagnostic accuracy(AUC = 0.976, P < 0.001). Patients treated with glucocorticoids showed significantly higher SUVmax in EOMs compared to those receiving symptomatic treatment (P < 0.01).

Conclusions: [⁶⁸Ga]DOTATATE PET/CT is a reliable method for assessing the inflammatory activity of EOMs in TAO patients, providing strong objective evidence for the precise diagnosis and treatment.

Purpose: Treatment of pediatric cancers with doxorubicin is a common and predictable cause of cardiomyopathy. Early diagnosis of treatment-induced cardiotoxicity and intervention are major determinants for the prevention of advanced disease. The onset of cardiomyopathies is often accompanied by profound changes in lipid metabolism, including an enhanced uptake of short-chain fatty acids (SCFA). Therefore, we explored the utility of 2-[¹⁸F]fluoropropionic acid ([¹⁸F]FPA), an SCFA analog, as an imaging biomarker of cardiac injury in mice exposed to doxorubicin.

Procedures: Cardiotoxicity and cardiac dysfunction were induced in mice by an 8-dose regimen of doxorubicin (cumulative dose 24 mg/kg) administered over 14 days. The effects of doxorubicin exposure were assessed by measurement of heart weights, left ventricular ejection fractions, and blood cardiac troponin levels. Whole body and cardiac [¹⁸F]FPA uptakes were determined by PET and tissue gamma counting in the presence or absence of AZD3965, a pharmacological inhibitor of monocarboxylate transporter 1 (MCT1). Radiation absorbed doses were estimated using tissue time-activity concentrations.

Results: Significantly higher cardiac [¹⁸F]FPA uptake was observed in doxorubicin-treated animals. This uptake remained constant from 30 to 120 min post-injection. Pharmacological inhibition of MCT1-mediated transport by AZD3965 selectively decreased the uptake of [¹⁸F]FPA in tissues other than the heart. Co-administration of [¹⁸F]FPA and AZD3965 enhanced the imaging contrast of the diseased heart while reducing overall exposure to radioactivity.

Conclusions: [¹⁸F]FPA, especially when co-administered with AZD3965, is a new tool for imaging changes in fatty acid metabolism occurring in response to doxorubicin-induced cardiomyopathy by PET.

The imposter phenomenon (IP) is a destructive set of beliefs, traits, and experiences in which high-achieving individuals fail to internalize their accomplishments and falsely perceive themselves as frauds. IP is a function of underrepresentation and contributes to and perpetuates a cycle of low self-worth, perfectionism, and anxiety, all of which negatively affect job performance and reinforce the IP cycle. Mitigating the deleterious effects of IP requires first naming this phenomenon and recognizing the patterns of IP. In this article, we summarize pertinent social science literature on this topic and share experiences of IP as told by the authors and anonymous contributors. We highlight the potential destructive effects of IP, as well as strategies that mentors and trainees can utilize to counter this phenomenon.

Purpose: We aim to perform radiogenomic profiling of breast cancer tumors using dynamic contrast magnetic resonance imaging (MRI) for the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) genes.

Methods: The dataset used in the current study consists of imaging data of 922 biopsy-confirmed invasive breast cancer patients with ER, PR, and HER2 gene mutation status. Breast MR images, including a T1-weighted pre-contrast sequence and three post-contrast sequences, were enrolled for analysis. All images were corrected using N4 bias correction algorithms. Based on all images and tumor masks, a bounding box of 128 × 128 × 68 was chosen to include all tumor regions. All networks were implemented in 3D fashion with input sizes of 128 × 128 × 68, and four images were input to each network for multi-channel analysis. Data were randomly split into train/validation (80%) and test set (20%) with stratification in class (patient-wise), and all metrics were reported in 20% of the untouched test dataset.

Results: For ER prediction, SEResNet50 achieved an AUC mean of 0.695 (CI95%: 0.610-0.775), a sensitivity of 0.564, and a specificity of 0.787. For PR prediction, ResNet34 achieved an AUC mean of 0.658 (95% CI: 0.573-0.741), a sensitivity of 0.593, and a specificity of 0.734. For HER2 prediction, SEResNext101 achieved an AUC mean of 0.698 (95% CI: 0.560-0.822), a sensitivity of 0.750, and a specificity of 0.625.

Conclusion: The current study demonstrated the feasibility of imaging gene-phenotype decoding in breast tumors using MR images and deep learning algorithms with moderate performance.