The metabolic brain network in patients with Parkinson's disease based on ^(18)F-FDG PET imaging: evaluation of neuronal injury and regeneration

Over the past two decades, the development of functional imaging methods has greatly promoted our understanding on the changes of neurons following neurodegenerative disorders, such as Parkin- son＇s disease （PD）. The application of a spatial covariance analysis on 18F-FDG PET imaging has led to the identification of a distinc- tive disease-related metabolic pattern. This pattern has proven to be useful in clinical diagnosis, disease progression monitoring as well as assessment of the neuronal changes before and after clinical treatment. It may potentially serve as an objective biomarker on disease progression monitoring, assessment, histological and func- tional evaluation of related diseases.

Microglia activation in the offspring of prenatal Poly I:C exposed rats:a PET imaging and immunohistochemistry study

Background The well-known ‘pyrotherapy’ of Julius Wagner-Jauregg might be the beginning of the study on the immunological concepts of schizophrenia. As the primary immune effector cells in the brain, microglia play a pivotal role in neuroinfammatory processes. Maternal viral infection during pregnancy is associated with an increased risk for psychiatric disorders with presumed neurodevelopmental origin, including autism spectrum disorders and schizophrenia. The present study was to quantify microglia activation in vivo in the mature offspring of rats exposed to polyriboinosinic–polyribocytidilicacid （Poly I：C） during pregnancy using ^11C-PK11195 positron emission tomography （PET） and immunohistochemistry.Objective The study aimed to quantify microglia activation in vivo in the prefrontal cortex and hippocampus in mature offspring of prenatal Poly I：C exposed rats.Methods Offspring of Poly I：C-treated dams were the model group, offspring of saline-treated dams were the control group. Behavioural test for two groups was taken by spontaneous activity, prepulse inhibition （PPI） and latent inhibition （LI） test （including active avoidance conditioning task and passive avoidance conditioning task）. Randomly selected successful model rats were assessed by behavioural test in the model group and control group rats. 11C-PK11195 micro-PET/CT and immunohistochemistry were performed on the selected rats to measure microglia activation.Results The treatment group showed hyperlocomotion and defcits in PPI and LI compared with the control group. The treatment group also showed an increased 11C-PK11195 uptake ratio in the prefrontal cortex （t=-3.990, p=0.003） and hippocampus （t=-4.462, p=0.001）. The number of activated microglia cells was signifcantly higher in the treatment group than in the control group （hippocampus： t=8.204, p〈0.001; prefrontal： t=6.995, p〈0.001）. Within the treatment group, there were signifcant correlations between the behavioural parameters and the activation of microglia as measured by PET and immunohistochemistry.Conclusions The present study demonstrated microglia activation in vivo in the prefrontal cortex and hippocampus in mature offspring of prenatal Poly I：C exposed rats. This study suggests that microglia activation may play a possible or potential role in the pathogenesis of schizophrenia.

Head-to-head comparison of plasma and PET imaging ATN markers in subjects with cognitive complaints

Background Gaining more information about the reciprocal associations between different biomarkers within the ATN(Amyloid/Tau/Neurodegeneration)framework across the Alzheimer’s disease(AD)spectrum is clinically relevant.We aimed to conduct a comprehensive head-to-head comparison of plasma and positron emission tomography(PET)ATN biomarkers in subjects with cognitive complaints.Methods A hospital-based cohort of subjects with cognitive complaints with a concurrent blood draw and ATN PET imaging(18F-florbetapir for A,18F-Florzolotau for T,and 18F-fluorodeoxyglucose[18F-FDG]for N)was enrolled(n=137).Theβ-amyloid(Aβ)status(positive versus negative)and the severity of cognitive impairment served as the main outcome measures for assessing biomarker performances.Results Plasma phosphorylated tau 181(p-tau181)level was found to be associated with PET imaging of ATN biomarkers in the entire cohort.Plasma p-tau181 level and PET standardized uptake value ratios of AT biomarkers showed a similarly excellent diagnostic performance for distinguishing between Aβ+and Aβ−subjects.An increased tau burden and glucose hypometabolism were significantly associated with the severity of cognitive impairment in Aβ+subjects.Additionally,glucose hypometabolism-along with elevated plasma neurofilament light chain level-was related to more severe cognitive impairment in Aβ−subjects.Conclusion Plasma p-tau181,as well as 18F-florbetapir and 18F-Florzolotau PET imaging can be considered as interchangeable biomarkers in the assessment of Aβstatus in symptomatic stages of AD.18F-Florzolotau and 18F-FDG PET imaging could serve as biomarkers for the severity of cognitive impairment.Our findings have implications for establishing a roadmap to identifying the most suitable ATN biomarkers for clinical use.

A PET probe targeting polyamine transport system for precise tumor diagnosis and therapy

Polyamine metabolism dysregulation is a hallmark of many cancers,offering a promising avenue for early tumor theranostics.This study presents the development of a nuclear probe derived from spermidine(SPM)for dual-purpose tumor PET imaging and internal radiation therapy.The probe,radiolabeled with either[68Ga]Ga for diagnostic applications or[177Lu]Lu for therapeutic use,was synthesized with exceptional purity,stability,and specific activity.Extensive testing involving 12 different tumor cell lines revealed remarkable specificity towards B16 melanoma cells,showcasing outstanding tumor localization and target-to-non-target ratio.Mechanistic investigations employing polyamines,non-labeled precursor,and polyamine transport system(PTS)inhibitor,consistently affirmed the probe?s targetability through recognition of the PTS.Notably,while previous reports indicated PTS upregulation in various tumor types for targeted therapy,this study observed no positive signals,highlighting a concentration-dependent discrepancy between targeting for therapy and diagnosis.Furthermore,when labeled with[177Lu],the probe demonstrated its therapeutic potential by effectively controlling tumor growth and extending mouse survival.Investigations into biodistribution,excretion,and biosafety in healthy humans laid a robust foundation for clinical translation.This study introduces a versatile SPM-based nuclear probe with applications in precise tumor theranostics,offering promising prospects for clinical implementation.

MCIF-Transformer Mask RCNN:Multi-Branch Cross-Scale Interactive Feature Fusion Transformer Model for PET/CT Lung Tumor Instance Segmentation

The precise detection and segmentation of tumor lesions are very important for lung cancer computer-aided diagnosis.However,in PET/CT(Positron Emission Tomography/Computed Tomography)lung images,the lesion shapes are complex,the edges are blurred,and the sample numbers are unbalanced.To solve these problems,this paper proposes a Multi-branch Cross-scale Interactive Feature fusion Transformer model(MCIF-Transformer Mask RCNN)for PET/CT lung tumor instance segmentation,The main innovative works of this paper are as follows:Firstly,the ResNet-Transformer backbone network is used to extract global feature and local feature in lung images.The pixel dependence relationship is established in local and non-local fields to improve the model perception ability.Secondly,the Cross-scale Interactive Feature Enhancement auxiliary network is designed to provide the shallow features to the deep features,and the cross-scale interactive feature enhancement module(CIFEM)is used to enhance the attention ability of the fine-grained features.Thirdly,the Cross-scale Interactive Feature fusion FPN network(CIF-FPN)is constructed to realize bidirectional interactive fusion between deep features and shallow features,and the low-level features are enhanced in deep semantic features.Finally,4 ablation experiments,3 comparison experiments of detection,3 comparison experiments of segmentation and 6 comparison experiments with two-stage and single-stage instance segmentation networks are done on PET/CT lung medical image datasets.The results showed that APdet,APseg,ARdet and ARseg indexes are improved by 5.5%,5.15%,3.11%and 6.79%compared with Mask RCNN(resnet50).Based on the above research,the precise detection and segmentation of the lesion region are realized in this paper.This method has positive significance for the detection of lung tumors.

Recent development in selective Tau tracers for PET imaging in the brain

Abnormal Tau deposition is a crucial pathological hallmark of various neurodegenerative disorders defined as tauopathies,of which Alzheimer’s disease is the most prominent one.To date,a large number of chemical entities with different structures have been developed as Tau imaging tracers for the early diagnosis of tauopathies.Several of them with excellent bio-properties are currently being assessed in clinical trials,and more recently,the Tauvid^(TM)([^(18)F]Flortaucipir,also known as[^(18)F]AV1451 or[^(18)F]T807)as the first Tau tracer was approved by the U.S.Food and Drug Administration in 2020.This review summarized the latest development of Tau tracers and analyzed their chemical structures,with particular attention to the effects of chemical structures on biological properties.In addition,we also discuss the limitations of current Tau imaging tracers,issues that need attention in the development of new tracers,and possible future directions.

Synthesis and Radiation Dosimetry of [⁶⁸Ga]-Ga-Lys¹, Lys³-DOTA-Bombesin (1,14) Antagonist for PET-Imaging, as a Potential Theragnostic Tracer in Oncology

This Bombesin (BBN), a tetradecapeptide analog of human gastrin-releasing peptide (GRP) with a high binding affinity for GRP receptors (GRPR), is over- expressed in early stages of androgen-dependent prostate carcinomas, but not in advanced stages. Therefore, there is a need to develop effective tracers for the accurate and specific detection of this disease. The objective of this study was to evaluate Lys1, Lys3-DOTA-BBN (1,14) analog with the radiolabeled positron emitter [68Ga]-Ga-BBN for receptor imaging with PET, and to determine its biodistribution and radiation dosimetry using whole-body (WB) PET scans in healthy volunteers. The highest uptake was in the pancreas, followed by urinary bladder. The critical organ was pancreas with a mean absorbed dose of 206 ± 0.7, 210 ± 0.7, 120 ± 0.9, 390.23 ± 0.6 μGy/MBq and the effective doses were estimated as 73.2 ± 0.6, 49.8 ± 0.3 μGy/MBq (women and men, respectively).

Application of ^(18) F-FDG PET/CT Imaging in Diagnosing Bladder Tumor Metastasis Lesions

Bladder tumor is the most common malignant tumor in urinary system and always com- panied with lymph node metastasis. The accurate staging plays a significant role in treatment for bladder tumor and prognostic evaluation, and the distant metastasis predicts worse prognosis. The objective of this study was to assess the clinical significance of 18F-FDG PET/CT imaging in diagnosing bladder tumor metastasis lesions. A retrospective analysis of 60 patients with bladder tumor from October 2008 to May 2010 was done. The patients were stratified based on the imaging technique. Among all 60 cases, besides the primary lesion, 81 suspected lesions were spotted and 73 confirmed as metastasis, including 50 lymph node metastases, 22 distant metastases, and 1 bone metastasis. For PET/CT imaging, its sensitivity was 94.5%, specificity 87.5%, positive predictive value 98.6%, negative predictive value 63.6% and accuracy 93.8% respectively. For CT, its sensitivity was 82.2%, specificity 50%, positive predictive value 93.8%, negative predictive value 23.5% and accuracy 79% respectively. PET/CT im- aging was superior to CT in sensitivity, specificity and accuracy. In conclusion, 18F-FDG PET/CT imaging is more significant in diagnosing bladder tumor metastasis lesions.

Development of a Ready-to-Use PSMA-11 Kit Formulation and Biological Evaluation of Binding Affinity

Introduction: 68Ga-PSMA-11 is considered the gold standard in detection of micro and oligometastases in advanced prostate cancer, being used for therapeutic planning, as well as, potentially, for evaluating response to treatment. The development of ready-to-use lyophilized kit of PSMA-11 adds quality and safety to the routine use of this radiopharmaceutical and represents a pharmacotechnical challenge as it must preserve the integrity and specificity of the ligand. Methods: PSMA-11 kit formulation was proposed, considering radiolabeling parameters and the preservation of the peptide during the lyophilization process, using mannitol as an excipient. Critical temperature characterization studies were carried out using DSC equipment and the freeze-drying process was developed. The direct radiolabeling conditions were evaluated and standardized using 68Ge/68Ga generator eluate from two different manufacturers (ITG and Eckert & Ziegler). The radiochemical purity was evaluated by TLC and HPLC. Biological evaluation was carried out with lyophilized PSMA-11 to demonstrate the integrity of the peptide and preservation of biological activity after the lyophilization process. Results: Based on critical temperature characterization studies, the freeze-drying cycle was designed to reach a freezing temperature of around −40˚C and primary drying at 2˚C. Using 20 mg of mannitol, an intact and elegant lyophilized cake was obtained. PSMA-11 lyophilized kit was directly labeled with 68Ga eluate from 68Ge/68Ga GMP generators (ITG and Eckert & Ziegler) resulting in % RP > 95% at pH 4.0 to 4.5. The results obtained from in vitro and in vivo biological competition studies confirmed the preservation of PSMA-11 affinity for the receptor after lyophilization. Conclusion: A lyophilized formulation (Kit) of PSMA-11 was successfully obtained, which preserved the integrity and biological activity of the peptide and guaranteed radiolabeling efficiency.

Segmentation of Head and Neck Tumors Using Dual PET/CT Imaging:Comparative Analysis of 2D,2.5D,and 3D Approaches Using UNet Transformer

The segmentation of head and neck(H&N)tumors in dual Positron Emission Tomography/Computed Tomogra-phy(PET/CT)imaging is a critical task in medical imaging,providing essential information for diagnosis,treatment planning,and outcome prediction.Motivated by the need for more accurate and robust segmentation methods,this study addresses key research gaps in the application of deep learning techniques to multimodal medical images.Specifically,it investigates the limitations of existing 2D and 3D models in capturing complex tumor structures and proposes an innovative 2.5D UNet Transformer model as a solution.The primary research questions guiding this study are:(1)How can the integration of convolutional neural networks(CNNs)and transformer networks enhance segmentation accuracy in dual PET/CT imaging?(2)What are the comparative advantages of 2D,2.5D,and 3D model configurations in this context?To answer these questions,we aimed to develop and evaluate advanced deep-learning models that leverage the strengths of both CNNs and transformers.Our proposed methodology involved a comprehensive preprocessing pipeline,including normalization,contrast enhancement,and resampling,followed by segmentation using 2D,2.5D,and 3D UNet Transformer models.The models were trained and tested on three diverse datasets:HeckTor2022,AutoPET2023,and SegRap2023.Performance was assessed using metrics such as Dice Similarity Coefficient,Jaccard Index,Average Surface Distance(ASD),and Relative Absolute Volume Difference(RAVD).The findings demonstrate that the 2.5D UNet Transformer model consistently outperformed the 2D and 3D models across most metrics,achieving the highest Dice and Jaccard values,indicating superior segmentation accuracy.For instance,on the HeckTor2022 dataset,the 2.5D model achieved a Dice score of 81.777 and a Jaccard index of 0.705,surpassing other model configurations.The 3D model showed strong boundary delineation performance but exhibited variability across datasets,while the 2D model,although effective,generally underperformed compared to its 2.5D and 3D counterparts.Compared to related literature,our study confirms the advantages of incorporating additional spatial context,as seen in the improved performance of the 2.5D model.This research fills a significant gap by providing a detailed comparative analysis of different model dimensions and their impact on H&N segmentation accuracy in dual PET/CT imaging.

Discovery and evaluation of a novel ^(18)F-labeled vasopressin 1a receptor PET ligand with peripheral binding specificity

The arginine-vasopressin(AVP)hormone plays a pivotal role in regulating various physiological processes,such as hormone secretion,cardiovascular modulation,and social behavior.Recent studies have highlighted the V1a receptor as a promising therapeutic target.In-depth insights into V1a receptor-related pathologies,attained through in vivo imaging and quantification in both peripheral organs and the central nervous system(CNS),could significantly advance the development of effective V1a inhibitors.To address this need,we develop a novel V1a-targeted positron emission tomography(PET)ligand,[^(18)F]V1A-2303([^(18)F]8),which demonstrates favorable in vitro binding affinity and selectivity for the V1a receptor.Specific tracer binding in peripheral tissues was also confirmed through rigorous cell uptake studies,autoradiography,biodistribution assessments.Furthermore,[^(18)F]8 was employed in PET imaging and arterial blood sampling studies in healthy rhesus monkeys to assess its brain permeability and specificity,whole-body distribution,and kinetic properties.Our research indicated[^(18)F]8 as a valuable tool for noninvasively studying V1a receptors in peripheral organs,and as a foundational element for the development of next-generation,brain-penetrant ligands specifically designed for the CNS.

Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease

Although the epigenetic regulatory protein histone deacetylase 6(HDAC6)has been recently implicated in the etiology of Alzheimer’s disease(AD),little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD.Here,we performed positron emission tomography(PET)imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD.We first developed[^(18)F]PB118 which was demonstrated as a valid HDAC6 radioligand with excellent brain penetration and high specificity to HDAC6.PET studies of[^(18)F]PB118 in 5xFAD mice showed significantly increased radioactivity in the brain compared to WT animals,with more pronounced changes identified in the cortex and hippocampus.The translatability of this radiotracer for AD in a potential human use was supported by additional studies,including similar uptake profiles in non-human primates,an increase of HDAC6 in ADrelated human postmortem hippocampal tissues by Western blotting protein analysis,and our ex vivo histopathological analysis of HDAC6 in postmortem brain tissues of our animals.Collectively,our findings show that HDAC6 may lead to AD by mechanisms that tend to affect brain regions particularly susceptible to AD through an association with amyloid pathology.

^(11)C-PK11195 plasma metabolization has the same rate in multiple sclerosis patients and healthy controls:a cross-sectional study

^(11)C-PK11195 is a positron emitter tracer used for Positron Emission Tomography(PET)imaging of innate immune cell activation in studies of neuroinflammatory diseases.For the image quantitative analysis,it is necessary to quantify the intact fraction of this tracer in the arterial plasma during imaging acquisition(plasma intact fraction).Due to the complexity and costs involved in this analysis it is important to evaluate the real necessity of individual analysis in each 11C-PK11195 PET imaging acquisition.The purpose of this study is to compare 11CPK11195 plasma metabolization rate between healthy controls and multiple sclerosis(MS)patients and evaluate the interference of sex,age,treatment,and disease phenotype in the tracer intact fraction measured in arterial plasma samples.11C-PK11195 metabolization rate in arterial plasma was quantified by high performance liquid chromatography in samples from MS patients(n=50)and healthy controls(n=23)at 20,45,and 60 minutes after 11C-PK11195 injection.Analyses were also stratified by sex,age,treatment type,and MS phenotype.The results showed no significant differences in the metabolization rate of healthy controls and MS patients,or in the stratified samples.In conclusion,11C-PK11195 metabolization has the same rate in patients with MS and healthy controls,which is not affected by sex,age,treatment,and disease phenotype.Thus,these findings could contribute to exempting the necessity for tracer metabolization determination in all 11C-PK11195 PET imaging acquisition,by using a population metabolization rate average.The study procedures were approved by the Ethics Committee for Research Projects Analysis of the Hospital das Clinicas of the University of Sao Paulo Medical School(approval No.624.065)on April 23,2014.

Novel STING-targeted PET radiotracer for alert and therapeutic evaluation of acute lung injury

Acute lung injury(ALI),as a common clinical emergency,is pulmonary edema and diffuse lung infiltration caused by inflammation.The lack of non-invasive alert strategy,resulting in failure to carry out preventive treatment,means high mortality and poor prognosis.Stimulator of interferon genes(STING)is a key molecular biomarker of innate immunity in response to inflammation,but there is still a lack of STING-targeted strategy.In this study,a novel STING-targeted PET tracer,[~(18)F]FBTA,was labeled with high radiochemical yield(79.7±4.3%)and molar activity(32.5±2.9 GBq/μmol).We confirmed that[~(18)F]FBTA has a strong STING binding affinity(K_d=26.86±6.79 nmol/L)and can be used for PET imaging in ALI mice to alert early lung inflammation and to assess the efficacy of drug therapy.Our STING-targeted strategy also reveals that[~(18)F]FBTA can trace ALI before reaching the computed tomography(CT)diagnostic criteria,and demonstrates its better specificity and distribution than[~(18)F]fluorodeoxyglucose([~(18)F]FDG).

Synthesis and Preliminary Evaluation of 1-[^18F]Fluoro-1-deoxy-2,5-anhydro-D-mannitol as a PET Radiotracer for Breast Cancer Imaging

1-[^18F]Fluoro-l-deoxy-2,5-anhydro-D-mannitol （3, ^18F-FDAM） has been synthesized in 6 steps starting from 2,5-anhydro-D-mannitol （2,5-AM） and evaluated as a new radiotracer for PET imaging of MCF-7 breast tumor. The result of PET imaging study showed that 3 displayed a slightly higher uptake by breast tumor in comparison with the normal breast tissue, implying the possibility of development of PET radiotraeers based on targeting fructose transporters.

Hybrid Segmentation Approach for Different Medical Image Modalities

The segmentation process requires separating the image region into sub-regions of similar properties.Each sub-region has a group of pixels having the same characteristics,such as texture or intensity.This paper suggests an efficient hybrid segmentation approach for different medical image modalities based on particle swarm optimization(PSO)and improved fast fuzzy C-means clustering(IFFCM)algorithms.An extensive comparative study on different medical images is presented between the proposed approach and other different previous segmentation techniques.The existing medical image segmentation techniques incorporate clustering,thresholding,graph-based,edge-based,active contour,region-based,and watershed algorithms.This paper extensively analyzes and summarizes the comparative investigation of these techniques.Finally,a prediction of the improvement involves the combination of these techniques is suggested.The obtained results demonstrate that the proposed hybrid medical image segmentation approach provides superior outcomes in terms of the examined evaluation metrics compared to the preceding segmentation techniques.

^(18)F-FDG PET/MR Imaging for Evaluating of Obstructive Jaundice:Chinese Expert Consensus

The cause of obstructive jaundice is usually complex which renders its differential diagnosis and lesion localization challenging in clinical practice.Integrated Positron Emission tomography/Magnetic Resonance(PET/MR)offers complementary information from PET and MR in the diagnosis of obstructive jaundice and is becoming widely adopted in clinical setting.While preserving its diagnostic accuracy,it is important to standardize and streamline the clinical scan protocol of PET/MR in evaluating obstructive jaundice.Based on literature review and experience of large number of clinical cases from the author group,this article reports an expert consensus on imaging protocol optimization and case interpretation template standardization.

Whole-body PET tracking of a D-dodecapeptide and its radiotheranostic potential for PD-L1 overexpressing tumors

Peptides that are composed of dextrorotary(D)-amino acids have gained increasing attention as a potential therapeutic class.However,our understanding of the in vivo fate of D-peptides is limited.This highlights the need for whole-body,quantitative tracking of D-peptides to better understand how they interact with the living body.Here,we used mouse models to track the movement of a programmed death-ligand 1(PD-L1)-targeting D-dodecapeptide antagonist(DPA)using positron emission tomography(PET).More specifically,we profiled the metabolic routes of[^(64)Cu]DPA and investigated the tumor engagement of[^(64)Cu/^(68)Ga]DPA in mouse models.Our results revealed that intact[^(64)Cu/^(68)Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors.Moreover,a single dose of[^(64)Cu]DPA effectively delayed tumor growth and improved the survival of mice.Collectively,these results not only deepen our knowledge of the in vivo fate of D-peptides,but also underscore the utility of D-peptides as radiopharmaceuticals.

Highly variable biodistribution of ^(68)Ga labeled somatostatin analogues ^(68)Ga-DOTA-NOC and ^(68)Ga-DOTA-TATE in neuroendocrine tumors: clinical implications for somatostatin receptor directed PET/CT

Background:Somatostatin receptor(SSTR)-targeted positron emission tomography/computed tomography(PET/CT)imaging has risen to the forefront for neuroendocrine tumor(NET)detection and management,yet the variability of significant uptake variability(SUV)as a semiquantitative measure of disease detection and tumor response to treatment has not been fully explored.Methods:We assess the reproducibility and interscan variability of SUV metrics of normal tissue and NET in serial^(68)Ga-DOTA-NOC and^(68)Ga-DOTA-TATE PET imaging to clinically monitor disease state.Eighty-one patients were enrolled in this retrospective study.Results:Both primary and metastatic hepatic lesions demonstrated SUV(SUVmean 16.5±8.0).The median SUVmean was 16 for the spleen,9.7 for the pituitary,12.6 for the adrenal glands,and 4.8 for the liver.The normal pituitary gland demonstrates focal homogenous uptake with SUVmax range of 4.5–23.The adrenal gland showed uptake with SUVmax range of 4.1–29.4,which is more than two times greater than liver uptake(SUVmean range,2.3–12.4).Highest physiological uptake seen in the spleen(average SUVmean of 17.3,range of 5.4–34.4).Conclusions:The highly variable nature of regional SUVmean and SUVmax in both physiologic tissue and lesions suggests the need for incorporation of more reliable quantitative measures for clinical decision making.

[^(18)F]MAGL-4-11 positron emission tomography molecular imaging of monoacylglycerol lipase changes in preclinical liver fibrosis models

Monoacylglycerol lipase(MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol(2-AG) into the proinflammatory eicosanoid precursor arachidonic acid(AA). MAGL and other endogenous cannabinoid(EC) degrading enzymes are involved in the fibrogenic signaling pathways that induce hepatic stellate cell(HSC) activation and ECM accumulation during chronic liver disease. Our group recently developed an;F-labeled MAGL inhibitor([18F]MAGL-4-11)for PET imaging and demonstrated highly specific binding in vitro and in vivo. In this study, we determined [18F]MAGL-4-11 PET enabled imaging MAGL levels in the bile duct ligation(BDL) and carbon tetrachloride(CCl_(4)) models of liver cirrhosis;we also assessed the hepatic gene expression of the enzymes involved with EC system including MAGL, NAPE-PLD, FAAH and DAGL that as a function of disease severity in these models;[18F]MAGL-4-11 autoradiography was performed to assess tracer binding in frozen liver sections both in animal and human. [18F]MAGL-4-11 demonstrated reduced PET signals in early stages of fibrosis and further significantly decreased with disease progression compared with control mice. We confirmed MAGL and FAAH expression decreases with fibrosisseverity, while its levels in normal liver tissue are high;in contrast, the EC synthetic enzymes NAPE-PLD and DAGL are enhanced in these different fibrosis models. In vitro autoradiography further supported that[18F]MAGL-4-11 bound specifically to MAGL in both animal and human fibrotic liver tissues. Our PET ligand [18F]MAGL-4-11 shows excellent sensitivity and specificity for MAGL visualization in vivo and accurately reflects the histological stages of liver fibrosis in preclinical models and human liver tissues.