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Gli36dEGFR cells were implanted. Thereafter, two imaging sequences were conducted: In sequence 1, T2w MRI and PET with [18F]DPA-714 was performed, while [18F]BR-351 PET and [18F]FET PET were conducted at day 13 and 14, respectively. In imaging sequence 2, T2w MRI and [18F]FET PET were conducted at day 12, followed by [18F]BR-351 and [18F]DPA-714 at day 13 and 14, respectively. After the last imaging experiment, mice were sacrificed and the brains immediately harvested for further analysis.

PET and CT images were co-registered using three CT-detectable, molecular sieve spheres (# 1-3) rinsed in radiotracer solution. After segmentation of spheres in the CT image (arrows), PET and CT images were superimposed by using the automated "Landmark tool" provided by the Vinci software. The "Magic tool" was applied for minor corrections of co-registrations. The resulting resliced PET image was saved for further processing. In a second step, MR and CT images were superimposed using the "Fusion- and Magic tool". For illustration MR is pseudocolored in red, while the CT was inverted in color (black). The CT contour was further superimposed to demonstrate co-registration accuracy. Selected bone structures were used as additional quality measures of image registration. The resliced CT image was saved with the new transformation matrix. In a last step, the before mentioned transformation of the CT (CTMR) was transferred to the PET, resulting in co-registration of PET/MR/CT. This workflow was repeated for every PET scan per mouse.

(A) T/B ratios, (B-D) tracer volumes, (E-J) areas of unique tracer uptake and overlapping regions. No significant effect on volumetric data was observed based on the order of imaging experiments.

Supplementary Figure Legends 1-5

(A) An elliptical VOI (yellow) was drawn in the striatum. (B) Another elliptical VOI (green) was placed over the affected hemisphere. (C) After application of a thresholding based on the control VOI. The same original VOIs (left and middle) were used for all animals for individual thresholding.

The tumor microenvironment is highly heterogeneous. For gliomas, the tumor-associated inflammatory response is pivotal to support growth and invasion. Factors of glioma growth, inflammation, and invasion, such as the translocator protein (TSPO) and matrix metalloproteinases (MMP), may serve as specific imaging biomarkers of the glioma microenvironment. In this study, noninvasive imaging by PET with [18F]DPA-714 (TSPO) and [18F]BR-351 (MMP) was used for the assessment of localization and quantification of the expression of TSPO and MMP. Imaging was performed in addition to established clinical imaging biomarker of active tumor volume ([18F]FET) in conjunction with MRI. We hypothesized that each imaging biomarker revealed distinct areas of the heterogeneous glioma tissue in a mouse model of human glioma. Tracers were found to be increased 1.4- to 1.7-fold, with [18F]FET showing the biggest volume as depicted by a thresholding-based, volumes of interest analysis. Tumor areas, which could not be detected by a single tracer and/or MRI parameter alone, were measured. Specific compartments of [18F]DPA-714 (14%) and [18F]BR-351 (11%) volumes along the tumor rim could be identified. [18F]DPA-714 (TSPO) and [18F]BR-351 (MMP) matched with histology. Glioma-associated microglia/macrophages (GAM) were identified as TSPO and MMP sources. Multitracer and multimodal molecular imaging approaches may allow us to gain important insights into glioma-associated inflammation (GAM, MMP). Moreover, this noninvasive technique enables characterization of the glioma microenvironment with respect to the disease-driving cellular compartments at the various disease stages. Cancer Res; 77(8); 1831–41. ©2017 AACR.

An exemplary subset of n=6 mice were randomly assessed for intra-rater reproducibility. (A-E) [18F]DPA-714 and [18F]FET images were on two consecutive days repeatedly co-registered. Volumetry was performed twice (coreg 2 and coreg 3) and compared to the data reported in the main text (coreg 1). Dotted lines represent the overall mean for all n=20 animals reported in the main text. No significant changes for all parameters, except for the "percentage of [18F]DPA-714 only" between coreg 1 and 3, was found over the three different time points of co-registration.

Rationale: The heterogeneous nature of gliomas makes the development and application of novel treatments challenging. In particular, infiltrating myeloid cells play a role in tumor progression and therapy resistance. Hence, a detailed understanding of the dynamic interplay of tumor cells and immune cells in vivo is necessary. To investigate the complex interaction between tumor progression and therapy-induced changes in the myeloid immune component of the tumor microenvironment, we used a combination of [18F]FET (amino acid metabolism) and [18F]DPA-714 (TSPO, GAMMs, tumor cells, astrocytes, endothelial cells) PET/MRI together with immune-phenotyping. The aim of the study was to monitor temozolomide (TMZ) treatment response and therapy-induced changes in the inflammatory tumor microenvironment (TME). Methods: Eighteen NMRInu/nu mice orthotopically implanted with Gli36dEGFR cells underwent MRI and PET/CT scans before and after treatment with TMZ or DMSO (vehicle). Tumor-to-background (striatum) uptake ratios were calculated and areas of unique tracer uptake (FET vs. DPA) were determined using an atlas-based volumetric approach. Results: TMZ therapy significantly modified the spatial distribution and uptake of both tracers. [18F]FET uptake was significantly reduced after therapy (-53 ± 84%) accompanied by a significant decrease of tumor volume (-17 ± 6%). In contrast, a significant increase (61 ± 33%) of [18F]DPA-714 uptake was detected by TSPO imaging in specific areas of the tumor. Immunohistochemistry (IHC) validated the reduction in tumor volumes and further revealed the presence of reactive TSPO-expressing glioma-associated microglia/macrophages (GAMMs) in the TME. Conclusion: We confirm the efficiency of [18F]FET-PET for monitoring TMZ-treatment response and demonstrate that in vivo TSPO-PET performed with [18F]DPA-714 can be used to identify specific reactive areas of myeloid cell infiltration in the TME.

International audience; Epidermal growth factor receptor (EGFR), involved in cell proliferation and migration, is overexpressed in ~50% of glioblastomas. Anti-EGFR based strategies using monoclonal antibodies (mAb) such as cetuximab (CTX) have been proposed for central nervous system (CNS) cancer therapy. However, the blood-brain barrier (BBB) drastically restricts their brain penetration which limits their efficacy for the treatment of glioblastomas. Herein, a longitudinal PET imaging study was performed to assess the relevance and the impact of focused ultrasound (FUS)-mediated BBB permeabilization on the brain exposure to the anti-EGFR mAb CTX over time. For this purpose, FUS permeabilization process with microbubbles was applied on intact BBB mouse brain before the injection of 89 Zr-labeled CTX for longitudinal imaging monitoring. FUS induced a dramatic increase in mAb penetration to the brain, 2 times higher compared to the intact BBB. The transfer of 89 Zr-CTX from blood to the brain was rendered significant by FUS (k uptake = 1.3 ± 0.23 min −1 with FUS versus k uptake = 0 ± 0.006 min −1 without FUS). FUS allowed significant and prolonged exposure to mAb in the brain parenchyma. This study confirms the potential of FUS as a target delivery method for mAb in CNS.

Translational methods are needed to monitor the impact of the Alzheimer's disease (AD) and therapies on brain function in animal models and patients. The formation of amyloid plaques was investigated using [

Focused ultrasound in combination with microbubbles (FUS) provides an effective means to locally enhance the delivery of therapeutics to the brain. Translational and quantitative imaging techniques are needed to noninvasively monitor and optimize the impact of FUS on blood–brain barrier (BBB) permeability in vivo. Positron-emission tomography (PET) imaging using [18F]2-fluoro-2-deoxy-sorbitol ([18F]FDS) was evaluated as a small-molecule (paracellular) marker of blood–brain barrier (BBB) integrity. [18F]FDS was straightforwardly produced from chemical reduction of commercial [18F]2-deoxy-2-fluoro-D-glucose. [18F]FDS and the invasive BBB integrity marker Evan’s blue (EB) were i.v. injected in mice after an optimized FUS protocol designed to generate controlled hemispheric BBB disruption. Quantitative determination of the impact of FUS on the BBB permeability was determined using kinetic modeling. A 2.2 ± 0.5-fold higher PET signal (n = 5, p &lt, 0.01) was obtained in the sonicated hemisphere and colocalized with EB staining observed post mortem. FUS significantly increased the blood-to-brain distribution of [18F]FDS by 2.4 ± 0.8-fold (VT, 0.01). Low variability (=10.1%) of VT values in the sonicated hemisphere suggests reproducibility of the estimation of BBB permeability and FUS method. [18F]FDS PET provides a readily available, sensitive and reproducible marker of BBB permeability to noninvasively monitor the extent of BBB disruption induced by FUS in vivo.

Purpose The non-transported and non-metabolized sorbitol derivative [18F]2-fluoro-2-deoxy-sorbitol ([18F]FDS) can be straightforwardly obtained from chemical reduction of commercial [18F]2-deoxy-2-fluoro-D-glucose. [18F]FDS was evaluated as a small-molecule (paracellular) marker of blood-brain barrier (BBB) integrity for PET. Methods Five mice underwent focused ultrasound (FUS) to generate spatially controlled BBB disruption in the right hemisphere. PET kinetics of [18F]FDS in each brain hemisphere were described by a 1-tissue compartment model using an image-derived input function. Results BBB disruption resulted in a 2.4±0.8-fold increase in the brain distribution (VT, p18F]FDS. Enhanced brain uptake was associated with an increase in the influx transfer rate K1 (+1.4±0.7-fold, pk2 (-1.7±0.4-fold, pConclusion Thanks to the quantitative performance of PET compared with other neuroimaging techniques, [18F]FDS PET and kinetic modelling provides a readily available and sensitive method for non-invasive determination of different levels of BBB permeability in vivo.

Recent studies in neurodegenerative conditions have increasingly highlighted that the same neuropathology can trigger different clinical phenotypes or, vice-versa, that similar phenotypes can be triggered by different neuropathologies. This evidence has called for the adoption of a pathology spectrum-based approach to study neurodegenerative proteinopathies. These conditions share brain deposition of abnormal protein aggregates, leading to aberrant biochemical, metabolic, functional, and structural changes. Positron emission tomography (PET) is a well-recognized and unique tool for the in vivo assessment of brain neuropathology, and novel PET techniques are emerging for the study of specific protein species. Today, key applications of PET range from early research and clinical diagnostic tools to their use in clinical trials for both participants screening and outcome evaluation. This position article critically reviews the role of distinct PET molecular tracers for different neurodegenerative proteinopathies, highlighting their strengths, weaknesses, and opportunities, with special emphasis on methodological challenges and future applications. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Genetic factors are known to contribute to Late Onset Alzheimer’s disease (LOAD) but their contribution to pathophysiology, specially to prodomic phases accessible to therapeutic approaches are far to be understood. To translate genetic risk of Alzheimer's disease (AD) into mechanistic insight, we generated transgenic mouse lines that express a ~195 kbp human BAC that includes only BIN1, a gene associated to LOAD. This model gives a modest BIN1 overexpression, dependent of the number of BAC copies. At 6 months of age, we detected impaired entorhinal cortex (EC)-hippocampal pathways with specific impairments in EC-dentate gyrus synaptic long-term potentiation, dendritic spines of granular cells and recognition episodic memory. Structural changes were quantified using MRI. Their whole-brain functional impact were analyzed using resting state fMRI with a hypoconnectivity centered on entorhinal cortex. These early phenotype defects independent of any changes in A-beta can be instrumental in the search for new AD drug targets.

Gliomas are highly dynamic and heterogeneous tumours of the central nervous system (CNS). They constitute the most common neoplasm of the CNS and the second most common cause of death from intracranial disease after stroke. The advances in detailing the genetic profile of paediatric and adult gliomas along with the progress in MRI and PET multimodal molecular imaging technologies have greatly improved prognostic stratification of patients with glioma and informed on treatment decisions. Amino acid PET has already gained broad clinical application in the study of gliomas. PET imaging targeting the translocator protein (TSPO) has recently been applied to decipher the heterogeneity and dynamics of the tumour microenvironment (TME) and its various cellular components especially in view of targeted immune therapies with the goal to delineate pro- and anti-glioma immune cell modulation. The current review provides a comprehensive overview on the historical developments of TSPO PET for gliomas and summarizes the most relevant experimental and clinical data with regard to the assessment and quantification of various cellular components with the TME of gliomas by in vivo TSPO PET imaging.

Inflammation is a highly dynamic and complex adaptive process to preserve and restore tissue homeostasis in neurological disorders and often serves as a prognostic marker for disease outcome. The underlying cellular and factorial heterogeneity represents an opportunity in the development of disease-modifying therapies. Molecular imaging of neuroinflammation (NI) may support the characterization of key aspects of the dynamic interplay of various inducers, sensors, transducers, and effectors of the multifactorial inflammatory response in vivo in animal models and patients. The characterization of the NI response by molecular imaging will (i) support early diagnosis and disease follow-up, (ii) guide (stereotactic) biopsy sampling, (iii) highlight the dynamic changes during disease pathogenesis in a noninvasive manner, (iv) help monitoring existing therapies, (v) support the development of novel NI-modifying therapies, and (vi) aid stratification of patients, according to their individual NI profile. This book chapter will review the basic principles of NI, recent developments and applications of novel molecular imaging targets, key considerations for the selection and development of imaging targets, as well as examples of successful clinical translation of NI imaging.

The tumour microenvironment (TME) surrounding tumour cells is a highly dynamic and heterogeneous composition of immune cells, fibroblasts, precursor cells, endothelial cells, signalling molecules and extracellular matrix (ECM) components. Due to the heterogeneity and the constant crosstalk between the TME and the tumour cells, the components of the TME are important prognostic parameters in cancer and determine the response to novel immunotherapies. To improve the characterization of the TME, novel non-invasive imaging paradigms targeting the complexity of the TME are urgently needed.The characterization of the TME by molecular imaging will (1) support early diagnosis and disease follow-up, (2) guide (stereotactic) biopsy sampling, (3) highlight the dynamic changes during disease pathogenesis in a non-invasive manner, (4) help monitor existing therapies, (5) support the development of novel TME-targeting therapies and (6) aid stratification of patients, according to the cellular composition of their tumours in correlation to their therapy response.This chapter will summarize the most recent developments and applications of molecular imaging paradigms beyond FDG for the characterization of the dynamic molecular and cellular changes in the TME.

Background Tumor-associated microglia and macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are potent immunosuppressors in the glioma tumor microenvironment (TME). Their infiltration is associated with tumor grade, progression, and therapy resistance. Specific tools for image-guided analysis of spatiotemporal changes in the immunosuppressive myeloid tumor compartments are missing. We aimed (i) to evaluate the role of fluorodeoxyglucose (18F)DPA-714* (translocator protein [TSPO]) PET-MRI in the assessment of the immunosuppressive TME in glioma patients, and (ii) to cross-correlate imaging findings with in-depth immunophenotyping. Methods To characterize the glioma TME, a mixed collective of 9 glioma patients underwent [18F]DPA-714-PET-MRI in addition to [18F]fluoro-ethyl-tyrosine (FET)-PET-MRI. Image-guided biopsy samples were immunophenotyped by multiparametric flow cytometry and immunohistochemistry. In vitro autoradiography was performed for image validation and assessment of tracer binding specificity. Results We found a strong relationship (r = 0.84, P = 0.009) between the [18F]DPA-714 uptake and the number and activation level of glioma-associated myeloid cells (GAMs). TSPO expression was mainly restricted to human leukocyte antigen D related–positive (HLA-DR+) activated GAMs, particularly to tumor-infiltrating HLA-DR+ MDSCs and TAMs. [18F]DPA-714–positive tissue volumes exceeded [18F]FET-positive volumes and showed a differential spatial distribution. Conclusion [18F]DPA-714-PET may be used to non-invasively image the glioma-associated immunosuppressive TME in vivo. This imaging paradigm may also help to characterize the heterogeneity of the glioma TME with respect to the degree of myeloid cell infiltration at various disease stages. [18F]DPA-714 may also facilitate the development of new image-guided therapies targeting the myeloid-derived TME.

Microglia are potential targets for therapeutic intervention in neurological and neurodegenerative diseases affecting the central nervous system. In order to assess the efficacy of therapies aimed to reduce the tissue damaging activities of microglia and/or to promote the protective potential of these cells, suitable pre-clinical and clinical tools for the in vivo analysis of microglia activities and dynamics are required. The aim of this work was to identify new translational markers of the anti-inflammatory / protective state of microglia for the development of novel PET tracers. Methods: New translational markers of the anti-inflammatory/protective activation state of microglia were selected by bioinformatic approaches and were in vitro and ex vivo validated by qPCR and immunohistochemistry in rodent and human samples. Once a viable marker was identified, a novel PET tracer was developed. This tracer was subsequently confirmed by autoradiography experiments in murine and human brain tissues. Results: Here we provide evidence that P2RY12 expression increases in murine and human microglia following exposure to anti-inflammatory stimuli, and that its expression is modulated in the reparative phase of experimental and clinical stroke. We then synthesized a novel carbon-11 labeled tracer targeting P2RY12, showing increased binding in brain sections of mice treated with IL4, and low binding to brain sections of a murine stroke model and of a stroke patient. Conclusion: This study provides new translational targets for PET tracers for the anti-inflammatory/protective activation state of microglia and shows the potential of a rationale-based approach. It therefore paves the way for the development of novel non-invasive methodologies aimed to monitor the success of therapeutic approaches in various neurological diseases.

The tumor microenvironment is highly heterogeneous. For gliomas, the tumor-associated inflammatory response is pivotal to support growth and invasion. Factors of glioma growth, inflammation, and invasion, such as the translocator protein (TSPO) and matrix metalloproteinases (MMP), may serve as specific imaging biomarkers of the glioma microenvironment. In this study, noninvasive imaging by PET with [18F]DPA-714 (TSPO) and [18F]BR-351 (MMP) was used for the assessment of localization and quantification of the expression of TSPO and MMP. Imaging was performed in addition to established clinical imaging biomarker of active tumor volume ([18F]FET) in conjunction with MRI. We hypothesized that each imaging biomarker revealed distinct areas of the heterogeneous glioma tissue in a mouse model of human glioma. Tracers were found to be increased 1.4- to 1.7-fold, with [18F]FET showing the biggest volume as depicted by a thresholding-based, volumes of interest analysis. Tumor areas, which could not be detected by a single tracer and/or MRI parameter alone, were measured. Specific compartments of [18F]DPA-714 (14%) and [18F]BR-351 (11%) volumes along the tumor rim could be identified. [18F]DPA-714 (TSPO) and [18F]BR-351 (MMP) matched with histology. Glioma-associated microglia/macrophages (GAM) were identified as TSPO and MMP sources. Multitracer and multimodal molecular imaging approaches may allow us to gain important insights into glioma-associated inflammation (GAM, MMP). Moreover, this noninvasive technique enables characterization of the glioma microenvironment with respect to the disease-driving cellular compartments at the various disease stages. Cancer Res; 77(8); 1831–41. ©2017 AACR.

Cannabinoid type 2 receptors (CB2R) have emerged as promising targets for the diagnosis and therapy of brain pathologies. However, no suitable radiotracers for accurate CB2R mapping have been found to date, limiting the investigation of the CB2 receptor expression using positron emission tomography (PET) imaging. In this work, we report the evaluation of the in vivo expression of CB2R with [11C]A-836339 PET after cerebral ischemia and in two rat models of neuroinflammation, first by intrastriatal LPS and then by AMPA injection. PET images and in vitro autoradiography showed a lack of specific [11C]A-836339 uptake in these animal models demonstrating the limitation of this radiotracer to image CB2 receptor under neuroinflammatory conditions. Further, using immunohistochemistry, the CB2 receptor displayed a modest expression increase after cerebral ischemia, LPS and AMPA models. Finally, [18F]DPA-714-PET and immunohistochemistry demonstrated decreased neuroinflammation by a selective CB2R agonist, JWH133. Taken together, these findings suggest that [11C]A-836339 is not a suitable radiotracer to monitor in vivo CB2R expression by using PET imaging. Future studies will have to investigate alternative radiotracers that could provide an accurate binding to CB2 receptors following brain inflammation.

BACKGROUND: Glioblastoma (GBM) is the most devastating brain tumor. Despite the use of multimodal treatments, most patients relapse, often due to the highly invasive nature of gliomas. However, the detection of glioma infiltration remains challenging. The aim of this study was to assess advanced PET and MRI techniques for visualizing biological activity and infiltration of the tumor. METHODS: Using multimodality imaging, we investigated [(18)F]DPA-714, a radiotracer targeting the 18 kDa translocator protein (TSPO), [(18)F]FET PET, non-Gaussian diffusion MRI (apparent diffusion coefficient, kurtosis), and the S-index, a composite diffusion metric, to detect tumor infiltration in a human invasive glioma model. In vivo imaging findings were confirmed by autoradiography and immunofluorescence. RESULTS: Increased tumor-to-contralateral [(18)F]DPA-714 uptake ratios (1.49 ± 0.11) were found starting 7 weeks after glioma cell implantation. TSPO-PET allowed visualization of glioma infiltration into the contralateral hemisphere 2 weeks earlier compared with the clinically relevant biomarker for biological glioma activity [(18)F]FET. Diffusion-weighted imaging (DWI), in particular kurtosis, was more sensitive than standard T2-weighted MRI to detect differences between the glioma-bearing and the contralateral hemisphere at 5 weeks. Immunofluorescence data reflect in vivo findings. Interestingly, labeling for tumoral and stromal TSPO indicates a predominant expression of TSPO by tumor cells. CONCLUSION: These results suggest that advanced PET and MRI methods, such as [(18)F]DPA-714 and DWI, may be superior to standard imaging methods to visualize glioma growth and infiltration at an early stage.

Late Onset Alzheimer Disease (LOAD) is the most common form of dementia and one of the most challenging diseases of modern society. Understanding the preclinical stages of AD that begins in the brain at least 2 to 3 decades before evidence of episodic memory defects in patients is pivotal for the design of successful approaches to delay or reverse the transition from normal brain function to cognitive impairments. Our working hypothesis is that LOAD genetic risk factors can be sufficient to generate early phenotypical changes before any changes in either Abeta or Tau. To test this hypothesis, we generated an hBIN1 mouse model based on the human BIN1 gene overexpression that we found in post-mortem brain samples from LOAD patients. BIN1 is the second important risk factor for AD, following the APOE gene. We identified co-deregulated gene repertoires common to both 7-week mouse hippocampus sub-regions and post-mortem brain samples from LOAD patients, demonstrating the validity of this hBIN1 model. We evidenced an early phenotype of neurodegeneration starting at 3 months with structural impairment fiber pathways quantified by high resolution (17.2T) (MRI DTI) and related functional impacts. We found structural changes in entorhinal cortex-dentate gyrus (EC-DG) pathway known to be the earliest brain region impacted in LOAD. Similarly, the function of this pathway was impaired both in vitro and in vivo, with the changes in spine density and dendritic simplification of DG neurons, impaired EC-DG long-term potentiation (LTP) and behavioral deficits linked to object recognition episodic memory. As expected for a neurodegenerative model, we evidenced the progression of dysfunction at the morphological, functional and behavioral levels with age. Structural spreading involved impairment of fibers in somatosensory and temporal associative cortexes at month 15. Functional and behavioral spreading was characterized by impact on pattern separation of spatial episodic memory. Moreover, this neurodegeneration occurred without any detectable changes in Abeta 1-42 and tau. Overall, these data show the possibility to identify a repertoire of molecular changes occurring both in patients and in hBIN1 mice and whose further manipulation can be instrumental to rescue or delay episodic memory defects.

Les nanoparticules (NP) contenant des elements lourds attirent recemment beaucoup l’attention grâce a leur propriete radio-sensibilisante. Un defi dans ce nouveau domaine est la determination d’une distribution intratumorale permettant de quantifier les NP au cours du temps. Ceci permet d’optimiser l’irradiation envoyee dans la zone tumorale en minimisant l’effet secondaire sur les tissus sains. Notre objectif est d’evaluer l’utilisation de l’imagerie TEP pour localiser et quantifier des NP a base de silice et gadolinium ultrafine (AGuIX®), un nanosensibilisant tres prometteur actuellement en phase clinique 2. Le 89Zr (t1/2 ∼ 78 h) est adapte pour realiser le suivi longitudinal de l’accumulation des AGuIX dans la tumeur. Afin de marquer les macromolecules avec le 89Zr, il est souvent necessaire de conjuguer un chelateur comme le Desferrioxamine. Cette modification, en plus d’induire des demandes supplementaires d’autorisation ANSM, peut provoquer un changement dans leurs proprietes in vivo. Dans cette etude, nous avons montre que les AGuIX peuvent etre marquees directement par 89Zr dans une condition non denaturante, ce qui nous a permis de determiner la pharmacocinetique des AGuIX dans un modele du gliome. Les AGuIX® ont ete marquees avec 89Zr en profitant de la presence du chelateur DOTA libre sur la particule dans des conditions directement transferables dans une production BPF. La stabilite du radiotraceur a ete testee in vitro et des essais de transmetalation ont ete realises avec differents ions tels que le Fe3+, Zn2+, Ca2+, Cu2+. 89Zr− AGuIX® ont demontre une forte stabilite dans ces conditions. Un modele syngenique de tumeur cerebrale (Gliome, 9L) a ete mis en place par l’implantation stereotaxique des cellules dans le striatum de cerveau des rats Fisher's. Les images TEP-CT ont ete acquises a differents moments apres l’injection de la particule marquee. Nous avons pu demontrer non seulement une stabilite in vivo du traceur, mais egalement une accumulation significative des NP dans la tumeur. Le temps de vie du 89Zr permet de suivre cette accumulation dont le Cmax a ete observe a 24 h. L’accumulation de NP a ete aussi confirmee par autoradiographie des coupes de cerveaux. La distribution ex vivo a indique que des NP marquees n’ont pas ete retenues dans des organes majeurs et eliminees principalement par la voie renale. Ces donnees nous permettront de valider ce traceur afin de mesurer l’effet EPR et d’optimiser l’efficacite en radiotherapie.

Upregulation of the cannabinoid type 2 receptors (CB2R) unveils inflammation processes of pathological disorders, such as cancer, pain, or neurodegenerative diseases. Among others, CB2R agonist A-836339 has been labeled with carbon-11 for PET imaging of the CB2R and displayed promising results in a mouse model of Alzheimer’s disease. The aim of the present work was to develop fluorinated analogs of A-836339 for labeling with fluorine-18 to design a new PET tracer for CB2R imaging. Seven fluorinated analogs of A-836339 were synthesized in two to three steps and their binding affinities and selectivities for both the human and the mouse CB2R were measured as well as their early ADME profiles. Among them, compound 2f (KihCB2R = 0.1 nM, KihCB1R/KihCB2R = 300) displayed high affinity and selectivity for CB2R but also promising lipophilicity, kinetic solubility, and membrane permeation properties and was further selected for in vitro metabolism studies. Incubation of 2f with human or rat liver microsomes follow...

Purpose Many radioligands have been explored for imaging the 18-kDa translocator protein (TSPO), a diagnostic and therapeutic target for inflammation and cancer. Here, we investigated the TSPO radioligand [18F]DPA-714 for positron emission tomography (PET) imaging of cancer and inflammation. Procedures [18F]DPA-714 PET imaging was performed in 8 mouse and rat models of breast and brain cancer and 4 mouse and rat models of muscular and bowel inflammation. Results [18F]DPA-714 showed different uptake levels in healthy organs and malignant tissues of mice and rats. Although high and displaceable [18F]DPA-714 binding is observed ex vivo, TSPO-positive PET imaging of peripheral lesions of cancer and inflammation in mice did not show significant lesion-to-background signal ratios. Slower [18F]DPA-714 metabolism and muscle clearance in mice compared to rats may explain the elevated background signal in peripheral organs in this species. Conclusion Although TSPO is an evolutionary conserved protein, inter- and intra-species differences call for further exploration of the pharmacological parameters of TSPO radioligands. Electronic supplementary material The online version of this article (doi:10.1007/s11307-015-0877-x) contains supplementary material, which is available to authorized users.

Cannabinoid type 2 receptors (CB2R) have emerged as promising targets for the diagnosis and therapy of brain pathologies. However, no suitable radiotracers for accurate CB2R mapping have been found to date, limiting the investigation of the CB2 receptor expression using positron emission tomography (PET) imaging. In this work, we report the evaluation of the in vivo expression of CB2R with [11C]A-836339 PET after cerebral ischemia and in two rat models of neuroinflammation, first by intrastriatal LPS and then by AMPA injection. PET images and in vitro autoradiography showed a lack of specific [11C]A-836339 uptake in these animal models demonstrating the limitation of this radiotracer to image CB2 receptor under neuroinflammatory conditions. Further, using immunohistochemistry, the CB2 receptor displayed a modest expression increase after cerebral ischemia, LPS and AMPA models. Finally, [18F]DPA-714-PET and immunohistochemistry demonstrated decreased neuroinflammation by a selective CB2R agonist, JWH133. Taken together, these findings suggest that [11C]A-836339 is not a suitable radiotracer to monitor in vivo CB2R expression by using PET imaging. Future studies will have to investigate alternative radiotracers that could provide an accurate binding to CB2 receptors following brain inflammation.

Bookchapter 28 'Imaging in Neurooncology' within book: Small animal imaging: basics and practical guide, second edition

On the one hand, the translocator protein (TSPO) radioligand N,N-diethyl-2-(2-(4-(2-(18)F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ((18)F-DPA-714) has been suggested to serve as an alternative radiotracer to image human glioma, and on the other hand the alkylphosphocholine erufosine (ErPC3) has been reported to induce apoptosis in otherwise highly apoptosis-resistant glioma cell lines. The induction of apoptosis by ErPC3 requires TSPO, a mitochondrial membrane protein highly expressed in malignant gliomas. In this preclinical study, we monitored the effect of ErPC3 treatment in vivo using (18)F-DPA-714 PET. METHODS: In vitro studies investigated the antitumor effect of ErPC3 in 9L rat gliosarcoma cells. In vivo, glioma-bearing rats were imaged with (18)F-DPA-714 for the time of treatment. RESULTS: A significant decrease in 9L cell proliferation and viability and a significant increase in apoptosis and caspase-3 activation were demonstrated on ErPC3 treatment in cell culture. In the rat model, ErPC3 administration resulted in significant changes in (18)F-DPA-714 tumor uptake over the course of the treatment. Immunohistochemistry revealed reduced tumor volume and increased cell death in ErPC3-treated animals accompanied by infiltration of the tumor core by CD11b-positive microglia/macrophages and glial fibrillary acidic protein-positive astrocytes. CONCLUSION: Our findings demonstrate a potent antitumor effect of ErPC3 in vitro, in vivo, and ex vivo. PET imaging of TSPO expression using (18)F-DPA-714 allows effective monitoring and quantification of disease progression and response to ErPC3 therapy in intracranial 9L gliomas.

This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License.-- The INMiND consortium: et al., Inflammation is a highly dynamic and complex adaptive process to preserve and restore tissue homeostasis. Originally viewed as an immune-privileged organ, the central nervous system (CNS) is now recognized to have a constant interplay with the innate and the adaptive immune systems, where resident microglia and infiltrating immune cells from the periphery have important roles. Common diseases of the CNS, such as stroke, multiple sclerosis (MS), and neurodegeneration, elicit a neuroinflammatory response with the goal to limit the extent of the disease and to support repair and regeneration. However, various disease mechanisms lead to neuroinflammation (NI) contributing to the disease process itself. Molecular imaging is the method of choice to try to decipher key aspects of the dynamic interplay of various inducers, sensors, transducers, and effectors of the orchestrated inflammatory response in vivo in animal models and patients. Here, we review the basic principles of NI with emphasis on microglia and common neurologic disease mechanisms, the molecular targets which are being used and explored for imaging, and molecular imaging of NI in frequent neurologic diseases, such as stroke, MS, neurodegeneration, epilepsy, encephalitis, and gliomas., This review is supported in part by DiMI-NoE LSHB-CT-2005-512146, INMiND-LSIP 278850, and IZKF-SchwJ3/001/11.

The hypothesis of this study was that distinct experimental glioblastoma phenotypes resembling human disease can be noninvasively distinguished at various disease stages by imaging in vivo. Methods: Cultured spheroids from 2 human glioblastomas were implanted into the brains of nude rats. Glioblastoma growth dynamics were followed by PET using 18F-FDG, 11C-methyl-l-methionine (11C-MET), and 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) and by MRI at 3–6 wk after implantation. For image validation, parameters were coregistered with immunohistochemical analysis. Results: Two tumor phenotypes (angiogenic and infiltrative) were obtained. The angiogenic phenotype showed high uptake of 11C-MET and 18F-FLT and relatively low uptake of 18F-FDG. 11C-MET was an early indicator of vessel remodeling and tumor proliferation. 18F-FLT uptake correlated to positive Ki67 staining at 6 wk. T1- and T2-weighted MR images displayed clear tumor delineation with strong gadolinium enhancement at 6 wk. The infiltrative phenotype did not accumulate 11C-MET and 18F-FLT and impaired the 18F-FDG uptake. In contrast, the Ki67 index showed a high proliferation rate. The extent of the infiltrative tumors could be observed by MRI but with low contrast. Conclusion: For angiogenic glioblastomas, noninvasive assessment of tumor activity corresponds well to immunohistochemical markers, and 11C-MET was more sensitive than 18F-FLT at detecting early tumor development. In contrast, infiltrative glioblastoma growth in the absence of blood–brain barrier breakdown is difficult to noninvasively follow by existing imaging techniques, and a negative 18F-FLT PET result does not exclude the presence of proliferating glioma tissue. The angiogenic model may serve as an advanced system to study imaging-guided antiangiogenic and antiproliferative therapies.

A deeper understanding of the role of specific genes, proteins, pathways and networks in health and disease, coupled with the development of technologies to assay these molecules and pathways in patients, promises to revolutionise the practice of clinical medicine. Especially the discovery and development of novel drugs targeted to disease-specific alterations could benefit significantly from non-invasive imaging techniques assessing the dynamics of specific disease-related parameters. Here we review the application of imaging biomarkers in the management of patients with brain tumours, especially malignant glioma. In our other review we focused on imaging biomarkers of general biochemical and physiological processes related with tumour growth such as energy, protein, DNA and membrane metabolism, vascular function, hypoxia and cell death. In this part of the review, we will discuss the use of imaging biomarkers of specific disease-related molecular genetic alterations such as apoptosis, angiogenesis, cell membrane receptors and signalling pathways and their application in targeted therapies.

The purpose of this study was to investigate the potential of 3'-deoxy-3'-[¹⁸F]fluorothymidine ([¹⁸F]FLT) positron emission tomography (PET) to detect early treatment responses in gliomas. Human glioma cells were stably transduced with genes yielding therapeutic activity, sorted for different levels of exogenous gene expression, and implanted subcutaneously into nude mice. Multimodality imaging during prodrug therapy included (a) magnetic resonance imaging, (b) PET with 9-(4-[¹⁸F]fluoro-3-hydroxymethylbutyl)guanine assessing exogenous gene expression, and (c) repeat [¹⁸F]FLT PET assessing antiproliferative therapeutic response. All stably transduced gliomas responded to therapy with significant reduction in tumor volume and [¹⁸F]FLT accumulation within 3 days after initiation of therapy. The change in [¹⁸F]FLT uptake before and after treatment correlated to volumetrically calculated growth rates. Therapeutic efficacy as monitored by [¹⁸F]FLT PET correlated to levels of therapeutic gene expression measured in vivo. Thus, [¹⁸F]FLT PET assesses early antiproliferative effects, making it a promising radiotracer for the development of novel treatments for glioma.

Inflammatory responses are closely associated with many neurologic disorders and influence their outcome. In vivo imaging can document events accompanying neuroinflammation, such as changes in blood flow, vascular permeability, tightness of the blood-to-brain barrier, local metabolic activity, and expression of specific molecular targets. Here, we briefly review current methods for imaging neuroinflammation, with special emphasis on nuclear imaging techniques.

Positron emission tomography (PET) allows non-invasive assessment of physiological, metabolic and molecular processes in vivo. With the achievements in detector technology, spatial resolution of PET has been improved (1–2mm) enabling investigations in small experimental animals such as mice. With the development in tracer technology a variety of endogenously expressed and exogenously introduced genes can be analyzed by PET. This opens up the exciting and rapidly evolving field of molecular imaging aiming towards the non-invasive localization of the dynamics of disease specific molecular alterations and biological processes in animal models and humans in vivo. The main and most intriguing advantage of molecular imaging is the kinetic analysis of a given molecular event in the same experimental subject over time. This allows non-invasive characterization of animal models of human disease at various disease stages and after therapeutic intervention. Optical imaging (OI) is a non-invasive molecular imaging technology that uses light to interrogate cellular and molecular function in the living body. Although OI technologies are still limited by light scattering and depth of light penetration they provide a low cost and rapid alternative to the more expensive and time-consuming PET imaging. By introducing multi-modality reporter constructs (PET, fluorescence and/or bioluminescence) drawbacks of each modality can be overcome and advantages will complement one another. Thus, allowing on the one side rapid, cost-effective optical reporter imaging and on the other side tomographic as well as quantitative imaging of reporter gene expression by PET. With PET being a modality well developed for imaging in human subjects as well as small animals it provides a link from bench-to-bedside and may facilitate translation into clinical applications. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN01-04.