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Positron emission tomography (PET) constitutes a functional imaging technique that is harnessed to probe biological processes in vivo. PET imaging has been used to diagnose and monitor the progression of diseases, as well as to facilitate drug development efforts at both preclinical and clinical stages. The wide applications and rapid development of PET have ultimately led to an increasing demand for new methods in radiochemistry, with the aim to expand the scope of synthons amenable for radiolabeling. In this work, we provide an overview of commonly used chemical transformations for the syntheses of PET tracers in all aspects of radiochemistry, thereby highlighting recent breakthrough discoveries and contemporary challenges in the field. We discuss the use of biologicals for PET imaging and highlight general examples of successful probe discoveries for molecular imaging with PET - with a particular focus on translational and scalable radiochemistry concepts that have been entered to clinical use.
There is increasing evidence for genetic heterogeneity in Alzheimer disease. A longitudinal clinical and imaging study had been established in order to determine whether specific phenotypic profiles are present in aetiologically distinct familial Alzheimer disease (FAD) pedigrees. [18F]fluorodeoxyglucose positron emission tomography has been used in conjunction with statistical parametric mapping to determine the relative distribution of hypometabolism. A parietotemporal deficit has been observed in individuals from both amyloid precursor protein mutation and chromosome 14 linked FAD families. Preliminary data from asymptomatic individuals at risk of FAD shows similar, although a less extensive pattern of deficit.
We evaluated the potential differences of a digital positron-emission tomography (PET) prototype equipped with photon-counting detectors (D-PET, Philips Healthcare, Cleveland, Ohio, USA) in tumor volume delineation compared with the analog Gemini TF PET system (A-PET, Philips). Eleven oncologic patients first underwent clinical fluorodeoxyglucose (FDG) PET/computed tomography (CT) on A-PET. The D-PET ring was then inserted between the PET and CT scanner of A-PET and the patient was scanned for the second time. Two interpreters reviewed the two sets of PET/CT images for image quality and diagnostic confidence. FDG avid lesions were evaluated for volume measured at 35% and 50% of maximum standard uptake value (SUV) thresholds (35% SUV, 50% SUV), and for SUV gradient as a measure of lesion sharpness. Bland-Altman plots were used to assess the agreement between the two PET scans. Qualitative lesion conspicuity, sharpness, and diagnostic confidence were greater at D-PET than that of A-PET with favorable inter-rater agreements. Median lesion size of the 24 measured lesions was 1.6 cm. The lesion volume at D-PET was smaller at both 35% SUV and 50% SUV thresholds compared with that of A-PET, with a mean difference of - 3680.0 mm3 at 35% SUV and - 835.3 mm3 at 50% SUV. SUV gradient was greater at D-PET than at A-PET by 49.2% (95% confidence interval: 34.1%-60.8%). Given the smaller volume definition, coupled with improved conspicuity and sharpness, digital PET may be more robust and accurate in tumor rendering compared with analog PET not only for radiotherapy planning but also in prognostication and systemic treatment monitoring.
The efficacy of preoperative 18F-fluoro-D-glucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) in endometrium cancer is controversial. We examined the efficacy of PET-CT and the association between maximum standardized uptake value (SUVmax) and prognostic factors in endometrial cancer.
We aimed to determine the sensitivity and specificity of fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) for the spread of disease to inguinal lymph nodes in vulvar cancer. A retrospective review of vulvar cancer patients who underwent both inguinal nodal sampling and dissection as well as FDG PET-CT was performed, with 21 patients meeting criteria. The sensitivity and specificity of the FDG PET-CT imaging was performed using a combination of maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Using an SUVmaxcutoff of 4.5 or of two times the average liver uptake, we had a 100% sensitivity and 89% specificity for positive inguinal nodes. MTV and TLG did not add to sensitivity or specificity. We conclude that FDG PET-CT has good sensitivity for inguinal nodal spread in vulvar cancer, and either a quantitative or semiquantitative approach is effective.
Neuroimaging has transformed neuro-oncology and the way that glioblastoma is diagnosed and treated. Magnetic Resonance Imaging (MRI) is the most widely used non-invasive technique in the primary diagnosis of glioblastoma. Although MRI provides very powerful anatomical information, it has proven to be of limited value for diagnosing glioblastomas in some situations. The final diagnosis requires a brain biopsy that may not depict the high intratumoral heterogeneity present in this tumor type. The revolution in "cancer-omics" is transforming the molecular classification of gliomas. However, many of the clinically relevant alterations revealed by these studies have not yet been integrated into the clinical management of patients, in part due to the lack of non-invasive biomarker-based imaging tools. An innovative option for biomarker identification in vivo is termed "immunotargeted imaging". By merging the high target specificity of antibodies with the high spatial resolution, sensitivity, and quantitative capabilities of positron emission tomography (PET), "Immuno-PET" allows us to conduct the non-invasive diagnosis and monitoring of patients over time using antibody-based probes as an in vivo, integrated, quantifiable, 3D, full-body "immunohistochemistry" in patients. This review provides the state of the art of immuno-PET applications and future perspectives on this imaging approach for glioblastoma.
We present a novel gamma-ray-detector design based on total internal reflection (TIR) of scintillation photons within a crystal that addresses many limitations of traditional PET detectors. Our approach has appealing features, including submillimeter lateral resolution, DOI positioning from layer thickness, and excellent energy resolution. The design places light sensors on the edges of a stack of scintillator slabs separated by small air gaps and exploits the phenomenon that more than 80% of scintillation light emitted during a gamma-ray event reaches the edges of a thin crystal with polished faces due to TIR. Gamma-ray stopping power is achieved by stacking multiple layers, and DOI is determined by which layer the gamma ray interacts in.
Pulmonary actinomycosis frequently mimics lung malignancy on radiologic imaging studies. Positron emission tomography-computed tomography (PET-CT) is a useful diagnostic modality for differentiating lung malignancy from benign diseases. However, few studies evaluated PET-CT findings of pulmonary actinomycosis. Therefore, it is unclear whether PET-CT is helpful to distinguish lung malignancy from benign lung disease when pulmonary actinomycosis is clinically suspected. We investigated PET-CT findings in 11 patients with pathologically confirmed pulmonary actinomycosis. The median maximal standardized uptake value (SUV) on PET-CT of pulmonary actinomycosis was increased to 5.5 (interquartile range, 4.2-8.8), which was higher than the threshold value of 2.5 indicating malignancy. Pulmonary actinomycosis without central necrosis demonstrated higher maximal SUV of 7.5 (4.9-12.2) compared to 4.8 (3.2-5.6) of ones with central necrosis. PET-CT might be not helpful in differentiating lung malignancy from benign lesions when pulmonary actinomycosis is clinically suspected.
Metabolic images from Positron Emission Tomography (PET) are used routinely for diagnosis, follow-up or treatment planning purposes of cancer patients. In this study we aimed at determining if radiomic features extracted from 18F-Fluoro Deoxy Glucose (FDG) PET images could mirror tumor transcriptomics. In this study we analyzed 45 patients with locally advanced head and neck cancer (H&N) that underwent FDG-PET scans at the time of diagnosis and transcriptome analysis using RNAs from both cancer and healthy tissues on microarrays. Association between PET radiomics and transcriptomics was carried out with the Genomica software and a functional annotation was used to associate PET radiomics, gene expression and altered biological pathways. We identified relationships between PET radiomics and genes involved in cell-cycle, disease, DNA repair, extracellular matrix organization, immune system, metabolism or signal transduction pathways, according to the Reactome classification. Our results suggest that these FDG PET radiomic features could be used to infer tissue gene expression and cellular pathway activity in H&N cancers. These observations strengthen the value of radiomics as a promising approach to personalize treatments through targeting tumor-specific molecular processes.
The water-soluble vitamin biotin is essential for cellular growth, development, and well-being, but its absorption, distribution, metabolism, and excretion are poorly understood. This paper describes the radiolabeling of biotin with the positron emission tomography (PET) radionuclide carbon-11 ([11C]biotin) to enable the quantitative study of biotin trafficking in vivo. We show that intravenously administered [11C]biotin is quickly distributed to the liver, kidneys, retina, heart, and brain in rodents-consistent with the known expression of the biotin transporter-and there is a surprising accumulation in the brown adipose tissue (BAT). Orally administered [11C]biotin was rapidly absorbed in the small intestine and swiftly distributed to the same organs. Preadministration of nonradioactive biotin inhibited organ uptake and increased excretion. [11C]Biotin PET imaging therefore provides a dynamic in vivo map of transporter-mediated biotin trafficking in healthy rodents. This technique will enable the exploration of biotin trafficking in humans and its use as a research tool for diagnostic imaging of obesity/diabetes, bacterial infection, and cancer.
Non-ST-elevation myocardial infarction (NSTEMI) and unstable angina (UA) are caused often by destabilization of non-flow limiting inflamed coronary artery plaques. 18F-fluorodeoxyglucose (FDG) uptake with positron emission tomography/computed tomography (PET/CT) reveals plaque inflammation, while intracoronary optical coherence tomography (OCT) reliably identifies morphological features of coronary instability, such as plaque rupture or erosion. We aimed to prospectively compare these two innovative biotechnologies in the characterization of coronary artery inflammation, which has never been attempted before.
Positron emission tomography (PET) is not a standard recommendation in most of the major guidelines for the evaluation of renal cell carcinoma (RCC). Earlier studies evaluating PET scan in patients with RCC have provided discordant results. However, with the advent of newer hybrid PET/computed tomography (CT) scanning systems, this modality has shown increased efficacy in the evaluation of primary renal masses along with the detection of extrarenal metastases, restaging recurrent RCC, and also in monitoring response to targeted therapy. We performed a systematic review of the existing literature on the role of PET scan in the evaluation of RCC.
Inverted papilloma (IP) is a benign but locally aggressive sinonasal tumour. Aggressive surgical treatment has thus been traditionally recommended because of the risk of transformation in squamous carcinoma. CT and MRI are used to evaluate bone destruction and soft-tissue extension before surgery but may be ineffective to differentiate an inverted papilloma from squamous cell carcinoma. In recent years, F-18 Fluorodeoxyglucose positron emission tomography ((18)FDG-PET) is widely used as diffuse imaging procedure for diagnosis and followup of malignancy affecting the head and neck district. To evaluate the utility of (18)FDG-PET/CT in the diagnosis of patients with suspicious lesions for IP, twelve patients with suspicious sinonasal inverted papilloma were selected for this study. (18)FDG-PET/CT imaging was performed, and standard uptake value (SUV) was calculated for each patient. SUV(max) was considered as the maximum value measured in the visualized lesions. Seven of the twelve cases exhibited uptake of (18)FFDG with an SUV(max) ranging from 1 to 8.1. Histopathologic diagnosis after surgery confirmed the diagnosis of IP in five cases; all these cases had an SUV(max) > 3. The five cases, which exhibited absence of (18)FDG uptake, had a histological diagnosis of absence of IP.
The optimal method of tumor burden evaluation in newly diagnosed multiple myeloma (NDMM) is yet to be determined. This study aimed to compare the value of 11C-acetate positron-emission tomography (PET)/computed tomography (CT) (AC-PET and 18F-fluorodeoxyglucose PET/CT (FDG-PET) in the assessment of tumor burden in NDMM. This study evaluated 64 NDMM patients between February 2015 and July 2018. AC-PET and FDG-PET were used to assess myeloma lesions. The clinical data, imaging results, and their correlations were analyzed. Diffuse bone marrow uptake in AC-PET was significantly correlated with biomarkers for tumor burden, including serum hemoglobin (P = 0.020), M protein (P = 0.054), the percentage of bone marrow plasma cells (P < 0.001), and the Durie-Salmon stage of the disease (P = 0.007). The maximum standard uptake value (SUVmax) of focal lesions and high diffuse bone marrow uptake in AC-PET showed stronger correlations with high-risk disease (P = 0.017, P = 0.013) than those in FDG-PET. Moreover, the presence of diffuse bone marrow uptake, more than ten focal lesions, and an SUVmax of focal lesions of > 6.0 in AC-PET, but not in FDG-PET, predicted a higher probability of disease progression and shorter progression-free survival (P < 0.05). AC-PET outperformed FDG-PET in tumor burden evaluation and disease progression prediction in NDMM.
The orexin receptor (OX) is critically involved in motivation and sleep-wake regulation and holds promising therapeutic potential in various mood disorders. To further investigate the role of orexin receptors (OXRs) in the living human brain and to evaluate the treatment potential of orexin-targeting therapeutics, we herein report a novel PET probe ([11C]CW24) for OXRs in the brain. CW24 has moderate binding affinity for OXRs (IC50 = 0.253 μM and 1.406 μM for OX1R and OX2R, respectively) and shows good selectivity to OXRs over 40 other central nervous system (CNS) targets. [11C]CW24 has high brain uptake in rodents and nonhuman primates, suitable metabolic stability, and appropriate distribution and pharmacokinetics for brain positron emission tomography (PET) imaging. [11C]CW24 warrants further evaluation as a PET imaging probe of OXRs in the brain.
This study aimed to develop a PET imaging agent of angiomotin (AMOT) expression, a potential biomarker of functional tissue regeneration in post-ischaemic conditions. Methods: Hindlimb ischaemia was induced by ligature and resection of the right femoral artery in mice, and clinical score and limb perfusion were evaluated up to 30 days after surgery. AMOT expression was evaluated by histology and Western blot analysis. NODAGA-conjugates of AMOT ligand, sCD146, were designed, synthesised and radiolabelled with gallium-68. 68Ga-sCD146 microPET/CT imaging was performed from day 1 to day 30 after ischaemia. 68Ga-sCD146 specificity for AMOT was evaluated by autoradiography. Results: Immunohistochemistry showed a significant endothelial overexpression of AMOT from day 5 up to day 10 in the ischaemic hindlimb. 68Ga-sCD146 PET signal intensity correlated significantly with AMOT immunohistochemistry evaluation. 68Ga-sCD146 PET imaging showed a significant uptake in the ischaemic hindlimb from day 2 to day 15, peaking on day 5 (ipsi/contralateral ratio = 2.4 ± 1.3, P = 0.0005) and significantly decreased after pharmacological blocking (62.57 ± 11% decrease in PET signal P = 0.032). Finally, we observed a significant correlation between day 5 68Ga-sCD146 PET signal intensity and clinical recovery (day 28) or hindlimb perfusion recovery (day 30). Conclusions: This work reports for the first time an early and sustained increase in AMOT expression after hindlimb ischaemia in mice. We therefore developed an AMOT-targeting imaging agent, 68Ga-sCD146, and showed its specific uptake up to 21 days after ischaemic hindlimb using microPET imaging. Correlation of early post-ischaemic PET signal with both delayed perfusion recovery and clinical outcome allows us to postulate that 68Ga-sCD146 represents a promising radiotracer for tissue angiogenesis assessment.
In vivo molecular imaging can measure the average kinetics and movement routes of injected cells through the body. However, owing to non-specific accumulation of the contrast agent and its efflux from the cells, most of these imaging methods inaccurately estimate the distribution of the cells. Here, we show that single human breast cancer cells loaded with mesoporous silica nanoparticles concentrating the 68Ga radioisotope and injected into immunodeficient mice can be tracked in real time from the pattern of annihilation photons detected using positron emission tomography, with respect to anatomical landmarks derived from X-ray computed tomography. The cells travelled at an average velocity of 50 mm s-1 and arrested in the lungs 2-3 s after tail-vein injection into the mice, which is consistent with the blood-flow rate. Single-cell tracking could be used to determine the kinetics of cell trafficking and arrest during the earliest phase of the metastatic cascade, the trafficking of immune cells during cancer immunotherapy and the distribution of cells after transplantation.
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