Molecular Imaging and Biology最新文献

Purpose: This study aims to integrate CT (Computed Tomography) radiomic features, gene expression profiles, and clinical data to identify radiogenomic biomarkers and improve overall survival prediction in gastric cancer (GC) patients.

Procedures: Quantitative radiomic analysis was performed on 37 GC CT images, alongside gene expression and clinical data, to identify biomarkers associated with overall survival. Tumor segmentation and radiomic feature extraction were followed by Pearson correlation for feature selection. Gene Set Enrichment Analysis (GSEA) identified pathways linking gene expression changes with radiomic features. Regression models were applied to explore the relationships between these pathways, radiomic features, and clinical data in survival prediction.

Results: A total of 107 radiomic features were extracted, with 46 radiomic features, 1,032 genes, and one clinical feature (age) selected for further analysis. GSEA identified 29 significant KEGG pathways, mainly involving immune, signal transduction, and catabolism pathways. In survival analysis, the SVM model performed best, identifying age, genes CSF1R and CXCL12, and image features ShortRunHighGrayLevelEmphasis and Idn (Inverse Difference Normalized) as independent predictors.

Conclusion: This study highlights the potential of integrating imaging, genomics, and clinical data for prognosis in GC patients, with identified genes suggesting new radiogenomic biomarker candidates for future evaluation.

Background: This study explored the relationship between mRNA expression profiles obtained through next-generation sequencing (NGS) and ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) texture analysis in patients with treatment-resistant oral squamous cell carcinoma (OSCC) who were treated with molecular-targeted drugs. We analyzed the correlation between ¹⁸F-FDG PET texture features and NGS data in a small cohort of five patients with recurrent or metastatic OSCC who received molecular-targeted drugs after surgery. Patients were categorized into two groups based on treatment response: responders (n = 3) and non-responders (n = 2). To validate our findings, we examined transcriptomic data from 292 OSCC patients in The Cancer Genome Atlas (TCGA) database.

Results: The gene ankyrin repeat and SOCS box containing two (ASB2) was significantly overexpressed in non-responders and strongly correlated with specific PET radiomic features, including GLRLM_GLNU, GLRLM_RLNU, and GLZLM_GLNU (p < 0.05). High ASB2 expression was also associated with poor prognosis in OSCC patients (p < 0.05) and decreased overall survival, as shown by Kaplan-Meier analysis of the TCGA database (p = 0.017).

Conclusions: Integrating ASB2 expression data with ¹⁸F-FDG PET texture features could potentially improve the prediction of treatment outcomes in treatment-resistant OSCC patients undergoing molecular-targeted therapy.

Purpose: Dopamine transporter (DAT) in the central nervous system is an attractive biomarker for the diagnosis and study of various neurodegenerative diseases. To develop in vivo metabolically stable positron emission tomography (PET) probes for DAT imaging with a high target/background ratio, two ¹⁸F-labeled tropane derivatives with deuteration on both the N-fluoropropyl and 2β-carbomethoxy groups of the tropane scaffold were synthesized and evaluated.

Methods: Radioligands [¹⁸F]6 and [¹⁸F]10 were synthesized from anhydroecgonine and radiolabeled with ¹⁸F through a "two-step one-pot" method. Lipophilicity, in vitro binding assay and microPET imaging in rats were performed. [¹⁸F]10 showed a higher standardized uptake value ratio (SUVr) and was selected for further evaluations by in vivo metabolism and biodistribution.

Results: The radioligands [¹⁸F]6 and [¹⁸F]10 were obtained in radiochemical purities > 98% and molar activity of about 30 GBq/μmol. [¹⁸F]6 or [¹⁸F]10 demonstrated high specificity and binding affinity to DAT in vitro, with IC₅₀ values between 2 ~ 3 nM. MicroPET imaging in wild type Sprague-Dawley rats revealed that [¹⁸F]10 has a higher SUVr than [¹⁸F]6. Blocking experiments demonstrated the selectivity and reversibility of [¹⁸F]10 for DAT binding in microPET imaging. The diagnostic efficacy of [¹⁸F]10 for DAT-related disorders was verified in semi-PD model rats with microPET. In vivo metabolic studies in rats indicated that [¹⁸F]10 exhibited enhanced stability. Biodistribution experiments further confirmed that [¹⁸F]10 accumulated in the DAT-rich region of the striatum.

Conclusion: [¹⁸F]10 is a highly promising metabolically stable ¹⁸F-labeled PET probe for DAT imaging, with potential clinical applications in detecting and monitoring DAT-related neurological disorders.

Purpose: Targeted radioligand therapy of metastatic castration-resistant prostate cancer (mCRPC) with ¹⁷⁷Lu-PSMA (RLT) requires sufficient dose monitoring of the kidneys. Currently, dosimetry using SPECT/CT-imaging is the most preferred method. However, SPECT/CT is a time-consuming procedure and comprises additional radiation exposure to the patient. Moreover, not every therapeutic nuclear medicine facility has access to SPECT/CT. Therefore, the aim of this study was to develop a new procedure of kidney dosimetry without the use of SPECT/CT and evaluate this method in a large cohort of patients with mCRPC undergoing RLT.

Procedures: A dedicated torso phantom with kidneys filled with a solution of ¹⁷⁷Lu-PSMA was used for quantitative calibration of a SPECT-camera. The calculated sensitivity was adapted according to the individual attenuation of the patient in four directions from the kidney surface to the body surface (ventral, dorsal, left and right) obtained from a previously performed CT. A total of 196 patients undergoing 926 cycles of ¹⁷⁷Lu-PSMA therapy were retrospectively analyzed. Abdominal SPECT was performed 24, 48 and 72 h after administration of ¹⁷⁷Lu-PSMA including scatter and dead-time correction in every patient. Kidney dose was calculated using an individual attenuation-based procedure and compared to values from international literature.

Results: Volumes of interest of the kidneys were drawn in the three sequential SPECT-images to calculate intra-renal effective half-life. Absolute quantification of activity in the kidneys was accomplished obtaining a patient individual sensitivity based on the individual attenuation in the patient. Kidney dose was then calculated applying a bi-exponential time activity curve in Microsoft EXCEL. Mean kidney dose per administered activity was 0.54 (± 0.26) Gy/GBq.

Conclusions: With the presented procedure a reliable kidney dosimetry is possible without the use of SPECT/CT. Facilities without SPECT/CT are therefore able to perform an adequate kidney dosimetry without additional radiation exposure for the patient.

Purpose: Positron Emission Tomography (PET) scans with radioligands targeting tau neurofibrillary tangles (NFT) have accelerated our understanding of the role of misfolded tau in neurodegeneration. While intended for human research, applying these radioligands to small animals establishes a vital translational link. Transgenic animal models of dementia, such as the tau rat SHR24, play a crucial role in enhancing our understanding of these disorders. This study aims to evaluate the utility of SHR24 rat model for PET studies.

Procedures: Dynamic PET scans were conducted in male SHR24 rats and their wild-type SHR (SHRwt) littermates using [¹⁸F]AV1451. Rapid blood sampling and metabolite analysis were performed to acquire input curves. Time activity curves were obtained from various brain regions over 60 min. Blood-based, 2-Tissue Compartment Model (2-TCM) and Logan graphical analysis were used to obtain kinetic modelling parameters. The ability of reference tissue models to predict the binding potential (BP_ND) were assessed. Autoradiography studies were performed to corroborate the scan data.

Results: Total distribution volume (V_T) was the best predicted parameter which revealed significantly higher uptake of [¹⁸F]AV1451 in the cortex (5.8 ± 1.1 vs 4.6 ± 0.7, P < 0.05) of SHR24 rats compared to SHRwt rats. Binding potential obtained from 2-TCM was variable, however BP_ND from reference tissue models detected significantly higher binding in cortex (0.28 ± 0.07 vs 0.20 ± 0.04, P < 0.01 by SRTM) and brainstem (0.14 ± 0.04 vs 0.08 ± 0.02, P < 0.01, by SRTM).

Conclusions: With the ability to detect binding of established radioligand [¹⁸F]AV1451 in these rats, we have demonstrated the utility of this model for assessing aggregated tau neurobiology by PET, with reference tissue models providing potential for longitudinal studies.

Purpose: We evaluate the role of radiomics, dosiomics, and dose-volume constraints (DVCs) in predicting the response of hepatocellular carcinoma to selective internal radiation therapy with ⁹⁰Y with glass microspheres.

Methods: ^99mTc-macroagregated albumin (^99mTc-MAA) and ⁹⁰Y SPECT/CT images of 17 patients were included. Tumor responses at three months were evaluated using modified response evaluation criteria in solid tumors criteria and patients were categorized as responders or non-responders. Dosimetry was conducted using the local deposition method (Dose) and biologically effective dosimetry. A total of 264 DVCs, 321 radiomic features, and 321 dosiomic features were extracted from the tumor, normal perfused liver (NPL), and whole normal liver (WNL). Five different feature selection methods in combination with eight machine learning algorithms were employed. Model performance was evaluated using area under the AUC, accuracy, sensitivity, and specificity.

Results: No statistically significant differences were observed between neither the dose metrics nor radiomicas or dosiomics features of responders and non-responder groups. ⁹⁰Y-dosiomics models with any given set of inputs outperformed other models. This was also true for ⁹⁰Y-radiomics from SPECT and SPECT-clinical features, achieving an AUC, accuracy, sensitivity, and specificity of 1. Among MAA-dosiomic and radiomic models, two models showed AUC ≥ 0.91. While the performance of MAA-dose volume histogram (DVH)-based models were less promising, the ⁹⁰Y-DVH-based models showed strong performance (AUC ≥ 0.91) when considered independently of clinical features.

Conclusion: This study demonstrated the potential of ^99mTc-MAA and ⁹⁰Y SPECT-derived radiomics, dosiomics, and dosimetry metrics in establishing predictive models for tumor response.

Purpose: Hepatic organic anion transporting polypeptides (OATPs) transport off-the-shelf, FDA-approved, hepatospecific Gd-based MRI contrast agents into cells that express the transporters enhancing signal on T1-weighted MRI. Studies have used MRI to identify OATP-overexpressing tumors and metastases transplanted in mice following the delivery of Gd-EOB-DTPA at 27-67-fold higher than clinical doses. With safety and regulatory concerns over Gd-based contrast agents, translating OATPs as an MRI reporter protein to humans for regenerative medicine will require substantially lower doses of agent.

Procedures: We engineered the MyC-CaP mouse tumor cell line to express rat OATP1B2, which influxes both Gd-EOB-DTPA and Gd-BOPTA, resulting in signal enhancement on T1-weighted MRI. We then inoculated mice with rat OATP1B2 and non-expressing cells bilaterally to generate tumors. 3-4 weeks after inoculation, when tumors had formed, in-vivo MRI imaging was performed with delivery of 0.025 mmol/kg or 0.25 mmol/kg of the Gd-based contrast agents. We complemented static T1-weighted MRI and T1-mapping with dynamic contrast enhanced (DCE)-MRI and performed area under the curve (AUC) analysis to discriminate the two tumor types.

Results: While all OATP1B2-expressing tumors were easily visible at the high dose of 0.25 mmol/kg on T1-weighted MRI and easy to distinguish from control tumors, OATP1B2-expressing tumors were hard to identify and distinguish from non-expressing tumors at the lower, clinical dose of 0.025 mmol/kg with standard T1-weighted MRI or T1-mapping. However, AUC analyses of the DCE-MRI curves could identify and distinguish these tumors, needing 30 (Gd-EOB-DTPA) or 45 (Gd-BOPTA) minutes acquisition time.

Conclusions: By performing AUC analyses of DCE-MRI curves following delivery of clinical concentration of MRI contrast agents, OATP1B2-expressing tumors could be identified and distinguished from control tumors, suggesting this imaging approach as a path to substantially reducing the amount of contrast agent needed to use OATPs as a clinically viable reporter protein for imaging regenerative medicine.

Purpose: Colony-stimulating factor 1 receptor (CSF1R) signaling plays a pivotal role in neuroinflammation, driving microglia proliferation and activation. CSF1R is considered a hallmark of inflammation in many neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Our study aims to evaluate the potential value of 5-cyano-N-(4-(4-(2-([¹⁸F]fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([¹⁸F]JNJ-CSF1R-1) as a positron emission tomography (PET) ligand targeting CSF1R in preclinical models of neuroinflammation.

Procedures: A cell-based MSD assay was used to measure the IC₅₀ of 5-cyano-N-(4-(4-(2-(fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide (JNJ-CSF1R-1). JNJ-CSF1R-1 was radiolabeled with fluorine-18. PET imaging was used to evaluate brain uptake, and target engagement of [¹⁸F]JNJ-CSF1R-1 in two neuroinflammation mouse models, including systemic lipopolysaccharide (LPS) and App^SAA knock in (KI). CSF1R protein levels in brain tissue were determined by western blot and ELISA assays. [¹⁸F]JNJ-CSF1R-1 brain uptake was also measured in a non-human primate (NHP) PET study.

Results: JNJ-CSF1R-1 is a 12 nM (IC₅₀) inhibitor of CSF1R. ​[¹⁸F]JNJ-CSF1R-1 demonstrated significantly higher brain uptake in both LPS and AD mouse models as measured by the area under the time activity curves (AUC) compared to control animals. In the App^SAA KI model, CSF1R levels increased near amyloid plaques as detected by IHC. ​[¹⁸F]JNJ-CSF1R-1 PET imaging signal showed a good correlation with CSF1R expression levels measured by western blot and ELISA. In an NHP study, ​[¹⁸F]JNJ-CSF1R-1 readily entered the brain and demonstrated reversible kinetics.

Conclusion: ​[¹⁸F]JNJ-CSF1R-1 is a potent and promising CSF1R PET tracer with translational potential for measuring microglia-based neuroinflammatory processes and for tracking the impact of anti-inflammatory therapies.

Purpose: Early diagnosis and complete resection of cancer are pivotal for enhancing patient survival rates and prognosis. However, a significant current challenge lies in the lack of specific imaging probes for the identifying various tumor types. The expression levels of neuropilin-1 (NRP1) and glucose transporter 1 (GLUT1) in most tumors, including breast cancer, are closely linked to tumor proliferation and metastasis. This study seeks to develop a novel near-infrared fluorescence (NIRF) probe aimed at precise tumor detection by targeting NRP1 and GLUT1.

Procedures: G₀ was conjugated with N₃-PEG₄-ALKADK and 2-Azido-2-deoxy-D-glucose to synthesize the NGF probe. The spectral properties (fluorescence and absorbance spectra) of NGF were studied in both methanol and water. The targeting specificity of NGF towards NRP1 and GLUT1 was evaluated using confocal fluorescence microscopy imaging, flow cytometry assays and in vivo IVIS spectrum imaging.

Results: A dual-targeting fluorescent probe named NGF was successfully synthesized to bind to both NRP1 and GLUT1 receptors. NGF exhibited greater hydrophilicity (Log P = -0.95 ± 0.07) and superior optical properties compared to its precursor, G₀. Confocal fluorescence imaging, flow cytometry assays, and blocking studies revealed that the cellular uptake of NGF correlated with the NRP1 and GLUT1 expression levels across cell lines. Moreover, a strong linear relationship (R² = 0.98) was observed between fluorescence intensity and increasing NGF concentrations in MDA-MB-231 cells. In vivo IVIS imaging in animal models demonstrated specific binding of NGF to breast cancer (MDA-MB-231) and colorectal cancer (HCT116), with prolonged retention observed up to 72 h.

Conclusions: This study highlighted the efficient targeting and sustained retention of the dual-target heterodimeric fluorescent probe NGF, binding to NRP1 and GLUT1 receptors. These findings suggest significant potential for clinical applications in early cancer detection and fluorescence image-guided surgery.

Purpose: Peptide-based probes targeting integrin α_vβ₆ have shown promise in clinical trials for cancer imaging based on the high over-expression of this epithelial-specific cell surface receptor in many cancerous tissues. Recently, the α_vβ₆-targeting gallium-68 labeled DOTA-5G peptide, [⁶⁸Ga]Ga DOTA-5G, demonstrated diagnostic value in patients with metastatic pancreatic cancer. To facilitate adoption at sites without access to gallium-68 and take advantage of the characteristics of fluorine-18 through convenient [¹⁸F]fluoride chelation chemistry, this study evaluated the fluorine-18 labeled analog, [¹⁸F]AlF NOTA-5G, in vitro and in vivo in a tumor mouse model, and compared it to [⁶⁸Ga]Ga DOTA-5G.

Procedures: NOTA-5G was synthesized on solid phase and radiolabeled with aluminum [¹⁸F]fluoride to generate [¹⁸F]AlF NOTA-5G. Cell binding and internalization of [¹⁸F]AlF NOTA-5G were evaluated in paired DX3puroβ6 (α_vβ₆ +) and DX3puro (α_vβ₆ -), and pancreatic BxPC-3 (α_vβ₆ +) cells. Imaging (1-6 h) and biodistribution were performed in BxPC-3 tumor-bearing mice.

Results: [¹⁸F]AlF NOTA-5G was obtained in > 93% radiochemical purity. Cell binding was α_vβ₆-targeted (1 h: 66% bound to DX3puroβ6, vs 2% to DX3puro), and ≥ 50% of bound activity was internalized; analogous to [⁶⁸Ga]Ga DOTA-5G, PET imaging showed clearly delineated tumors. Excretion remained primarily renal (1 to 4 h: 18.6 to 12.5% ID/g). Tumor uptake remained relatively steady (1 to 4 h: 2.3 ± 0.4 to 1.8 ± 0.6% ID/g - closely matching [⁶⁸Ga]Ga DOTA-5G with 2.6 ± 0.8 and 2.0 ± 0.6% ID/g at 1 and 2 h), resulting in tumor/pancreas, tumor/liver, and tumor/blood ratios of 18/1, 24/1, and 162/1, respectively (4 h); by comparison, for [⁶⁸Ga]Ga DOTA-5G the values were 21/1, 20/1, and 22/1 (2 h).

Conclusions: [¹⁸F]AlF NOTA-5G demonstrated selective α_vβ₆-targeting and tumor uptake similar to [⁶⁸Ga]Ga DOTA-5G. The tumor-to-background ratio resulted high-contrast PET images, with an extended imaging window compared to [⁶⁸Ga]Ga DOTA-5G. The synthesis of [¹⁸F]AlF NOTA-5G is currently being optimized for clinical production.