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This study provides a first direct comparison between positron emission tomography (PET) radioligands targeting the allosteric site of the metabotropic glutamate receptor 5 (mGluR5): [11C]ABP688 and [18F]FPEB. A blocking paradigm was set up to substantiate the common binding site of both radioligands. Second, both radioligands were applied in Sapap3 knockouts showing compulsive-like behavior characterized by a lower in vivo mGluR5 availability. METHODS First, wildtype mice (n=7) received four μPET/CT scans: an [11C]ABP688 and [18F]FPEB scan, and two blocking scans using cold FPEB and cold ABP688, respectively. A second experiment compared both radioligands in wildtype (n=7) and Sapap3 knockout mice (n=10). The simplified reference tissue method was used to calculate the nondisplaceable binding potential (BPND) representing the in vivo availability of the mGluR5 in the brain. RESULTS Using cold FPEB as a blocking compound for [11C]ABP688 μPET and vice versa, we observed averaged global reductions in mGluR5 availability of circa 98% for [11C]ABP688 and 82%-96% for [18F]FPEB. For knockouts, the [11C]ABP688 BPND was on average 25% lower compared to wildtype controls (p

Purpose As several therapies aimed at lowering mutant huntingtin (mHTT) brain levels in Huntington’s disease (HD) are currently being investigated, noninvasive positron emission tomography (PET) imaging of mHTT could be utilized to directly evaluate therapeutic efficacy and monitor disease progression. Here we characterized and longitudinally assessed the novel radioligand [11C]CHDI-626 for mHTT PET imaging in the zQ175DN mouse model of HD. Methods After evaluating radiometabolites and radioligand kinetics, we conducted longitudinal dynamic PET imaging at 3, 6, 9, and 13 months of age (M) in wild-type (WT, n = 17) and heterozygous (HET, n = 23) zQ175DN mice. Statistical analysis was performed to evaluate temporal and genotypic differences. Cross-sectional cohorts at each longitudinal time point were included for post-mortem [3H]CHDI-626 autoradiography. Results Despite fast metabolism and kinetics, the radioligand was suitable for PET imaging of mHTT. Longitudinal quantification could discriminate between genotypes already at premanifest stage (3 M), showing an age-associated increase in signal in HET mice in parallel with mHTT aggregate load progression, as supported by the post-mortem [3H]CHDI-626 autoradiography. Conclusion With clinical evaluation underway, [11C]CHDI-626 PET imaging appears to be a suitable preclinical candidate marker to monitor natural HD progression and for the evaluation of mHTT-lowering therapies.

Purpose Our aim in this study was to compare different non-invasive pharmacokinetic models and assess test–retest reproducibility of the radioligand [11C]SCH23390 for the quantification of dopamine D1-like receptor (D1R) in both wild-type (WT) mice and heterozygous (HET) Q175DN mice as Huntington’s disease (HD) model. Procedures Adult WT (n = 9) and HET (n = 14) mice underwent a 90-min [11C]SCH23390 positron emission tomography (PET) scan followed by computed tomography (CT) to evaluate the pharmacokinetic modelling in healthy and diseased conditions. Additionally, 5 WT mice and 7 HET animals received a second [11C]SCH23390 PET scan for test–retest reproducibility. Parallel assessment of the simplified reference tissue model (SRTM), the multilinear reference tissue model (MRTM) and the Logan reference tissue model (Logan Ref) using the striatum as a receptor-rich region and the cerebellum as a receptor-free (reference) region was performed to define the most suitable method for regional- and voxel-based quantification of the binding potential (BPND). Finally, standardised uptake value ratio (SUVR-1) was assessed as a potential simplified measurement. Results For all models, we measured a significant decline in dopamine D1R density (e.g. SRTM = − 38.5 ± 5.0 %, p BPND in both WT mice (SRTM 60 min: − 17.7 ± 2.8 %, p = 0.0078) and diseased HET (SRTM 60 min: − 13.1 ± 4.1 %, p = 0.0001). Striatal BPND measurements were very reproducible with an average test–retest variability below 5 % when using both MRTM and SRTM. Parametric BPND maps generated with SRTM were highly reliable, showing nearly perfect agreement to the regional analysis (r2 = 0.99, p R1 with both regional- and voxel-based analyses. SUVR-1 at different time intervals were not sufficiently reliable when compared to BPND (r2 Conclusions Ninety-minute acquisition and the use of SRTM for pharmacokinetic modelling is recommended. [11C]SCH23390 PET imaging demonstrates optimal characteristics for the study of dopamine D1R density in models of psychiatric and neurological disorders as exemplified in the Q175DN mouse model of HD.

Pretargeted positron emission tomography (PET) imaging based on the bioorthogonal inverse-electron-demand Diels–Alder reaction between tetrazines (Tz) and trans-cyclooctenes (TCO) has emerged as a ...

Since accurate quantification of 2-deoxy-2–18F-fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) requires dynamic acquisition with arterial input function, more practical semi-quantitative (static) approaches are often preferred. However, static standardized uptake values (SUV) are typically biased due to large variations in body weight (BW) occurring over time in animal studies. This study aims to improve static [18F]FDG PET SUV quantification by better accounting for BW variations in rats. We performed dynamic [18F]FDG PET imaging with arterial blood sampling in rats (n = 27) with different BW (range 0.230–0.487 kg). By regressing the area under the curve of the input function divided by injected activity against BW (r2=0.697), we determined a conversion factor f(BW) to be multiplied with SUV and SUVglc to obtain ratSUV and ratSUVglc, providing an improved estimate of the net influx rate Ki (r = 0.758, p

Positron emission tomography (PET) imaging is a molecular imaging modality with an extreme high versatility. Theoretically, all biological processes can be visualized longitudinally and quantified in vivo with high sensitivity, once a radioligand for a certain target of interest is developed. This chapter introduces the principle of PET and how relevant biological parameters can be extracted from PET images using pharmacokinetic modelling. In addition, we discuss awake PET imaging in small animal (μPET) studies. The novelty of point source tracking enables to follow tracer distribution in the brain of rodents during the conduct of certain (pathological) behavior. As a consequence, anesthesia-related factors are eliminated which continue to be an obstacle for bench-to-bedside translation. Lastly, this chapter emphasizes the value of μPET in the exploration and evaluation of disease mechanisms, as illustrated by a pharmacological and genetic rodent model for obsessive compulsive disorder (OCD). Longitudinal brain PET studies can be set up to investigate whether behavioral alterations parallel changes in the binding of radioligands for multiple targets. Altogether, μPET imaging provides unique whole brain information on underlying disease mechanisms and potential treatment targets, especially when the PET data are collected in awake animals.

PET scans of the mouse brain are usually performed with anesthesia to immobilize the animal. However, it is desirable to avoid the confounding factor of anesthesia in mouse-brain response. Methods: We developed and validated brain PET imaging of awake, freely moving mice. Head-motion tracking was performed using radioactive point-source markers, and we used the tracking information for PET-image motion correction. Regional F-18-FDG brain uptake in a test, retest, and memantine-challenge study was measured in awake (n = 8) and anesthetized (n = 8) C57BL/6 mice. An awake uptake period was considered for the anesthesia scans. Results: Awake (motion-corrected) PET images showed an F-18-FDG uptake pattern comparable to the pattern of anesthetized mice. The test-retest variability (represented by the intraclass correlation coefficient) of the regional SUV quantification in the awake animals (0.424-0.555) was marginally lower than that in the anesthetized animals (intraclass correlation coefficient, 0.491-0.629) over the different regions. The increased memantine-induced F-18-FDG uptake was more pronounced in awake (+63.6%) than in anesthetized (+24.2%) animals. Additional behavioral information, acquired for awake animals, showed increased motor activity on a memantine challenge (total distance traveled, 18.2 +/- 5.28 m) compared with test-retest (6.49 +/- 2.21 m). Conclusion: The present method enables brain PET imaging on awake mice, thereby avoiding the confounding effects of anesthesia on the PET reading. It allows the simultaneous measurement of behavioral information during PET acquisitions. The method does not require any additional hardware, and it can be deployed in typical high-throughput scan protocols.

Tumor hypoxia is related with tumor aggressiveness, chemo- and radiotherapy resistance, and thus a poor clinical outcome. Therefore, over the past decades, every effort has been made to develop strategies to battle the negative prognostic influence of tumor hypoxia. For appropriate patient selection and follow-up, noninvasive imaging biomarkers such as positron emission tomography (PET) radiolabeled ligands are unprecedentedly needed. Importantly, before being able to implement these new therapies and potential biomarkers into the clinical setting, preclinical in vivo validation in adequate animal models is indispensable. In this review, we provide an overview of the different attempts that have been made to create differential hypoxic in vivo cancer models with a particular focus on their applicability in PET imaging studies.

To avoid the confounding effects of anesthesia and immobilization stress in rat brain positron emission tomography (PET), motion tracking based unrestrained awake rat brain imaging is being developed. In this work we propose a fast and accurate rat head motion tracking method based on small PET point sources. PET point sources (3-4) attached to the rat's head are tracked in image space using 15-32 ms time frames. Our point source tracking (PST) method was validated using a manually moved microDerenzo phantom that was simultaneously tracked with an optical tracker (OT) for comparison. The PST method was further validated in three awake [18F]FDG rat brain scans. Compared to the OT, the PST based correction at the same frame rate (31.2 Hz) reduced the reconstructed FWHM by 0.39 - 0.66 mm for the different tested rod sizes of the microDerenzo phantom. The FWHM could be further reduced by another 0.07 - 0.13 mm when increasing the PST frame rate (66.7 Hz). Regional brain [18F]FDG uptake in the motion corrected scan was strongly correlated (p

Preclinical positron emission tomography (PET) imaging in small animals is generally performed under anesthesia to immobilize the animal during scanning. More recently, for rat brain PET studies, methods to perform scans of unrestrained awake rats are being developed in order to avoid the unwanted effects of anesthesia on the brain response. Here, we investigate the use of a projected structure stereo camera to track the motion of the rat head during the PET scan. The motion information is then used to correct the PET data. The stereo camera calculates a 3D point cloud representation of the scene and the tracking is performed by point cloud matching using the iterative closest point algorithm. The main advantage of the proposed motion tracking is that no intervention, e.g. for marker attachment, is needed. A manually moved microDerenzo phantom experiment and 3 awake rat [18F]FDG experiments were performed to evaluate the proposed tracking method. The tracking accuracy was 0.33 mm rms. After motion correction image reconstruction, the microDerenzo phantom was recovered albeit with some loss of resolution. The reconstructed FWHM of the 2.5 and 3 mm rods increased with 0.94 and 0.51 mm respectively in comparison with the motion-free case. In the rat experiments, the average tracking success rate was 64.7%. The correlation of relative brain regional [18F]FDG uptake between the anesthesia and awake scan reconstructions was increased from on average 0.291 (not significant) before correction to 0.909 (p

Molecular imaging of cell death may provide a detailed readout of the cellular response to novel therapies and prognostic information on tumor treatment efficacy, assisting in the design of individualized therapy. We compared the predictive power of cell death imaging using 99mTc-duramycin with the current gold standard 18F-FDG for treatment response evaluation after targeted therapy. Methods: Early therapy response evaluation was assessed by 99mTc-duramycin SPECT and 18F-FDG PET imaging in treatment-sensitive COLO205 and treatment-resistant HT29 human colorectal cancer xenografts 24 h after a single dose of conatumumab or IgG1 control. The specificity of 99mTc-duramycin for apoptosis was assessed using 99mTc-linear duramycin control radiotracer. Radiotracer uptake was validated ex vivo by γ-counting and autoradiography and compared with cleaved caspase-3 (CC3) activation and DNA fragmentation (TdT-mediated dUTP nick-end labeling [TUNEL]). Data were analyzed with the Student t test and Pearson correlation. All statistical tests were 2-sided. Results: COLO205 tumor uptake of 99mTc-duramycin was increased 7-fold from baseline in conatumumab- versus IgG1-treated control mice (P < 0.001), in good correlation with histologic analysis of apoptosis (CC3, r = 0.842, and TUNEL, r = 0.894; P < 0.001). No response was detected in HT29 tumors. No change in 99mTc-linear duramycin uptake could be detected in COLO205 tumors after treatment, indicating specificity of the 99mTc-duramycin tumor signal. 18F-FDG uptake was not significantly increased from baseline in conatumumab- versus IgG1-treated COLO205 and HT29 tumor-bearing mice (P = 0.104 and 0.779, respectively) and did not correlate with immunohistochemical evidence of apoptosis. Conclusion: We have demonstrated that 99mTc-duramycin specifically accumulates in apoptotic tumors in which 18F-FDG was not able to differentiate responding from nonresponding tumors early after treatment. 99mTc-duramycin holds promise as a noninvasive imaging radiotracer for early treatment evaluation in the clinic.

Awake rat brain positron emission tomography (PET) has previously been developed to avoid the influence of anesthesia on the rat brain response. In the present work, we further the awake rat brain scanning methodology to establish simultaneous scanning of two interacting rats in a high resolution, large field of view PET scanner. Awake rat imaging methodology based on point source tracking was adapted to be used in a dedicated human brain scanner, the ECAT high resolution research tomograph (HRRT). Rats could freely run on a horizontal platform of 19.4 23 cm placed inside the HRRT. The developed methodology was validated using a motion resolution phantom experiment, 3 awake single rat [18F]FDG scans as well as an [18F]FDG scan of 2 interacting rats. The precision of the point source based motion tracking was 0.359mm (standard deviation). Minor loss of spatial resolution was observed in the motion corrected reconstructions (MC) of the resolution phantom compared to the motion-free reconstructions (MF). The full-width-at-half-maximum of the phantom rods were increased by on average 0.37mm in the MC compared to the MF. During the awake scans, extensive motion was observed with rats moving throughout the platform area. The average rat head motion speed was 1.69 cm/s. Brain regions such as hippocampus, cortex and cerebellum could be recovered in the motion corrected reconstructions. Relative regional brain uptake of MC and MF was strongly correlated (Pearson's r ranging from 0.82 to 0.95, p < 0.0001). Awake rat brain PET imaging of interacting rats was successfully implemented on the HRRT scanner. The present method allows a large range of motion throughout a large field of view as well as to image two rats simultaneously opening the way to novel rat brain PET study designs.

Synaptic pathology is associated with several brain disorders, thus positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) using the radioligand [11C]UCB-J may provide a tool to measure synaptic alterations. Given the pivotal role of mouse models in understanding neuropsychiatric and neurodegenerative disorders, this study aims to validate and characterize [11C]UCB-J in mice. We performed a blocking study to verify the specificity of the radiotracer to SV2A, examined kinetic models using an image-derived input function (IDIF) for quantification of the radiotracer, and investigated the in vivo metabolism. Regional TACs during baseline showed rapid uptake of [11C]UCB-J into the brain. Pretreatment with levetiracetam confirmed target engagement in a dose-dependent manner. VT (IDIF) values estimated with one- and two-tissue compartmental models (1TCM and 2TCM) were highly comparable (r=0.999, p 1 (IDIF). A scan duration of 60 min was sufficient for reliable VT (IDIF) and K1 (IDIF) estimations. In vivo metabolism of [11C]UCB-J was relatively rapid, with a parent fraction of 22.5 ± 4.2% at 15 min p.i. In conclusion, our findings show that [11C]UCB-J selectively binds to SV2A with optimal kinetics in the mouse representing a promising tool to noninvasively quantify synaptic density in comparative or therapeutic studies in neuropsychiatric and neurodegenerative disorder models.

Background In a colorectal cancer xenograft model, we investigated the therapeutic effect of metformin on tumor hypoxia with [F-18]flortanidazole ([F-18]HX4) small-animal positron emission tomography (mu PET). We also assessed the additive effect of metformin on long-term radiotherapy outcome and we studied the potential of [F-18]HX4 as a predictive and/or prognostic biomarker within this setup. Methods Colo205-bearing mice (n = 40) underwent a baseline [F-18]HX4 hypoxia mu PET/computed tomography (CT) scan. The next day, mice received 100 mg/kg metformin or saline intravenously (n = 20/group) and [F-18]HX4 was administered intravenously 30 min later, whereupon a second mu PET/CT scan was performed to assess changes in tumor hypoxia. Two days later, mice were further divided into four therapy groups (n = 10/group): control (1), metformin (2), radiotherapy (3), and metformin + radiotherapy, i.e., combination (4). Then, they received a second dose of metformin (groups 2 and 4) or saline (groups 1 and 3), followed by a single radiotherapy dose of 15 Gy (groups 3 and 4) or sham irradiation (groups 1 and 2) 30 min later. Tumor growth was followed three times a week by caliper measurements to assess the therapeutic outcome. Results [F-18]HX4 uptake decreased in metformin-treated tumors with a mean intratumoral reduction in [F-18]HX4 tumor-to-background ratio (TBR) from 2.53 +/- 0.30 to 2.28 +/- 0.26 (p = 0.04), as opposed to saline treatment (2.56 +/- 0.39 to 3.08 +/- 0.39; p = 0.2). The median tumor doubling time (TDT) was 6, 8, 41, and 43 days in the control, metformin, radiotherapy and combination group, respectively (log-rank p < 0.0001), but no metformin-specific therapy effects could be detected. Baseline [F-18]HX4 TBR was a negative prognostic biomarker for TDT (hazard ratio, 2.39; p = 0.02). Conclusions Metformin decreased [F-18]HX4 uptake of Colo205-tumors, but had no additive effect on radiotherapy efficacy. Nevertheless, [F-18]HX4 holds promise as a prognostic imaging biomarker.

Objective To determine whether state-associated changes in microglial activity, measured with translocator-protein positron emission tomography (TSPO PET), can be identified in psychosis patients through longitudinal evaluation of their regional tracer uptake over the clinical course from acute psychosis to post-treatment follow-up, and comparison to healthy controls. We also evaluated the relation between tracer uptake, clinical symptoms and peripheral immunological markers. Method Second-generation radioligand [18F]-PBR111 TSPO PET-CT was used for longitudinal dynamic imaging in 14 male psychosis patients and 17 male age-matched healthy control subjects. Patients were first scanned during an acute psychotic episode followed by a second scan after treatment. Prior genotyping of subjects for the rs6917 polymorphism distinguished high- and mixed-affinity binders. The main outcome was regional volume of distribution (VT), representing TSPO binding. Plasma concentrations of CRP, cytokines and kynurenines were measured at each timepoint. Results We found a significant three-way interaction between time of scan, age and cohort (cortical grey matter F6.50, p.020). Age-dependent differences in VT existed between cohorts during the psychotic state, but not at follow-up. Patients’ relative change in VT over time correlated with age (cortical grey matter Pearson’s r.574). PANSS positive subscale scores correlated with regional VT during psychosis (cortical grey matter r.767). Plasma CRP and quinolinic acid were independently associated with lower VT. Conclusions We identified a differential age-dependent pattern of TSPO binding from psychosis to follow-up in our cohort of male psychosis patients. We recommend future TSPO PET studies in psychosis patients to differentiate between clinical states and consider potential age-related effects.

Disease-modifying treatment trials are increasingly advanced to the prodromal or preclinical phase of Alzheimer's disease (AD), and inclusion criteria are based on biomarkers rather than clinical symptoms. Therefore, it is of great interest to determine which biomarkers should be combined to accurately predict conversion from mild cognitive impairment (MCI) to AD dementia. However, up to date, only few studies performed a complete A/T/N subject characterization using each of the CSF and imaging markers, or they only investigated long-term (≥ 2 years) prognosis. This study aimed to investigate the association between cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), amyloid- and 18F-FDG positron emission tomography (PET) measures at baseline, in relation to cognitive changes and conversion to AD dementia over a short-term (12-month) period. We included 13 healthy controls, 49 MCI and 16 AD dementia patients with a clinical-based diagnosis and a complete A/T/N characterization at baseline. Global cortical amyloid-β (Aβ) burden was quantified using the 18F-AV45 standardized uptake value ratio (SUVR) with two different reference regions (cerebellar grey and subcortical white matter), whereas metabolism was assessed based on 18F-FDG SUVR. CSF measures included Aβ1–42, Aβ1–40, T-tau, P-tau181, and their ratios, and MRI markers included hippocampal volumes (HV), white matter hyperintensities, and cortical grey matter volumes. Cognitive functioning was measured by MMSE and RBANS index scores. All statistical analyses were corrected for age, sex, education, and APOE ε4 genotype. As a result, faster cognitive decline was most strongly associated with hypometabolism (posterior cingulate) and smaller hippocampal volume (e.g., Δstory recall: β = +0.43 [p, Highlights • FDG-PET and MRI HV are the strongest predictors of cognitive decline and conversion to AD. • Combination of visuospatial construction testing with FDG-PET or MRI HV present high predicting power of conversion. • CSF and amyloid-PET seem less suitable markers of disease progression. • Increased AV45-PET predicts short-term cognitive decline if SUVR is referenced to WM instead of CB.

PurposeThis study aimed at investigating binding specificity, suitability of reference region-based kinetic modelling, and pharmacokinetics of the metabotropic glutamate receptor 1 (mGluR1) radioligand [11C]ITDM in mice.ProceduresWe performedin vivoblocking as well as displacement of [11C]ITDM during positron emission tomography (PET) imaging using the specific mGluR1 antagonist YM-202074. Additionally, we assessedin vitroblocking of [3H]ITDM at two different doses of YM-202074. As an alternative to reference region models, we validated the use of a noninvasive image-derived input function (IDIF) compared to an arterial input function measured with an invasive arteriovenous (AV) shunt using a population-based curve for radiometabolite correction and characterized the pharmacokinetic modelling of [11C]ITDM in the mouse brain. Finally, we also assessed semi-quantitative approaches.ResultsIn vivoblocking with YM-202074 resulted in a decreased [11C]ITDM binding, ranging from − 35.8 ± 8.0 % in pons to − 65.8 ± 3.0 % in thalamus. Displacement was also markedly observed in all tested regions. In addition,in vitro[3H]ITDM binding could be blocked in a dose-dependent manner. The volume of distribution (VT) based on the noninvasive IDIF (VT (IDIF)) showed excellent agreement with theVTvalues based on the metabolite-corrected plasma input function regardless of the metabolite correction (r2 > 0.943,p r2 > 0.960,p r2 = 0.379,p = 0.0011), unlike the SUV ratio to the SUV of the input function, which showed to be a valid approach.ConclusionsNo suitable reference region could be identified for [11C]ITDM as strongly supported byin vivoandin vitroevidence of specific binding in all brain regions. However, by applying appropriate kinetic models, [11C]ITDM PET imaging represents a promising tool to visualize mGluR1 in the mouse brain.

Introduction Dual-biomarker positron emission tomography (PET), providing complementary information on cerebral blood flow and amyloid-β deposition, is of clinical interest for Alzheimer's disease (AD). The purpose of this study was to validate the perfusion components of early-phase 18F-florbetapir (eAV45), the 18F-AV45 delivery rate (R1), and 18F-FDG against 15O-H2O PET and assess how they change with disease severity. Methods This study included ten controls, 19 amnestic mild cognitive impairment, and 10 AD dementia subjects. Within-subject regional correlations between modalities, between-group regional and voxel-wise analyses of covariance per modality, and receiver operating characteristic analyses for discrimination between groups were performed. Results FDG standardized uptake value ratio, eAV45 (0–2 min) standardized uptake value ratio, and AV45-R1 were significantly associated with H2O PET (regional Pearson r = 0.54–0.82, 0.70–0.94, and 0.65–0.92, respectively; P < .001). All modalities confirmed reduced cerebral blood flow in the posterior cingulate of patients with amnestic mild cognitive impairment and AD dementia, which was associated with lower cognition (r = 0.36–0.65, P < .025) and could discriminate between patient and control groups (area under the curve > 0.80). However, eAV45 was less sensitive to reflect the disease severity than AV45-R1 or FDG. Discussion R1 is preferable over eAV45 for accurate representation of brain perfusion in dual-biomarker PET for AD.

Purpose The purpose of this study was to characterize imaging biomarkers for the potential benefit of hypoxia-inducible factor-1 (HIF-1)α inhibition (by PX-12) during 5-fluorouracil (5-FU) chemotherapy in the treatment of colorectal cancer (CRC). Procedures Therapy response to 5-FU ± PX-12 was assessed with baseline [18F]fluoromisonidazole ([18F]FMISO) and longitudinal 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) positron emission computed tomography (μPET/CT) in CRC xenograft model (n = 36) during breathing of a hypoxic (10 % O2) or normoxic (21 % O2) atmosphere. Ex vivo, immunohistochemistry was performed. Results Baseline [18F]FMISO uptake and relative tumor volume (RTV) 2 days after 5-FU or 5-FU + PX-12 administration correlated significantly (p ≤ 0.01). Under hypoxic breathing conditions, [18F]FDG uptake (−53.1 ± 8.4 %) and Ki67 expression (−16 %) decreased and RTV stagnated in the 5-FU + PX-12 treatment group, but not in 5-FU alone-treated tumors. Under normoxic breathing, [18F]FDG uptake (−23.5 ± 15.2 % and −72.8 ± 7.1 %) and Ki67 expression (−5 % and −19 %) decreased and RTV stagnated in both the 5-FU and the combination treatment group, respectively. Conclusion Baseline [18F]FMISO μPET may predict the beneficial effect of HIF-1α inhibition during 5-FU chemotherapy in CRC.

Motion tracking with finite time sampling causing an associated unknown residual motion between two motion measurements is one of the factors contributing to resolution loss in small animal PET motion correction. The aim of this work is (i) to provide a means to estimate the effect of the finite motion sampling on the spatial resolution of the motion correction reconstructions and (ii) to correct for this residual motion thereby minimizing resolution loss. We calculate a tailored spatially variant deconvolution kernel from the measured motion data which is then used to deconvolve the motion corrected image using a 3D Richardson-Lucy algorithm. A simulation experiment of numerical phantoms as well as a microDerenzo phantom experiment wherein the phantom was manually moved at different speeds was performed to assess the performance of our proposed method. In the motion corrected images of the microDerenzo phantom there was an average rod FWHM differences between the slow and fast motion cases of 9.7%. This difference was reduced to 5.8% after applying the residual motion deconvolution. In awake animal experiments, the proposed method can serve to mitigate the finite sampling factor degrading the spatial resolution as well as the resolution differences between fast-moving and slow-moving animals. Graphical abstract Motion correction of positron emission tomography (PET) scans of moving subjects can be performed by measuring the motion of the subject during the PET scan with an optical tracking camera. The motion tracking data obtained from the tracking camera is then used to correct the PET image reconstructions for motion. Due to finite time sampling of the motion data, the motion corrected reconstructions suffer from loss of spatial resolution. In the proposed method, a spatially variant deconvolution kernel is calculated from the motion tracking data, which is then used to correct the motion-corrected PET reconstructions for the blurring effect of the finite motion sampling through a Richardson-Lucy deconvolution.

There is currently a lack of prognostic biomarkers to predict the different sequelae following traumatic brain injury (TBI). The present study investigated the hypothesis that subacute neuroinflammation and microstructural changes correlate with chronic TBI deficits. Rats were subjected to controlled cortical impact (CCI) injury, sham surgery, or skin incision (naive). CCI-injured (n = 18) and sham-operated rats (n = 6) underwent positron emission tomography (PET) imaging with the translocator protein 18 kDa (TSPO) radioligand [18F]PBR111 and diffusion tensor imaging (DTI) in the subacute phase (≤3 weeks post-injury) to quantify inflammation and microstructural alterations. CCI-injured, sham-operated, and naive rats (n = 8) underwent behavioral testing in the chronic phase (5.5-10 months post-injury): open field and sucrose preference tests, two one-week video-electroencephalogram (vEEG) monitoring periods, pentylenetetrazole (PTZ) seizure susceptibility tests, and a Morris water maze (MWM) test. In vivo imaging revealed pronounced neuroinflammation, decreased fractional anisotropy, and increased diffusivity in perilesional cortex and ipsilesional hippocampus of CCI-injured rats. Behavioral analysis revealed disinhibition, anhedonia, increased seizure susceptibility, and impaired learning in CCI-injured rats. Subacute TSPO expression and changes in DTI metrics significantly correlated with several chronic deficits (Pearson's |r| = 0.50-0.90). Certain specific PET and DTI parameters had good sensitivity and specificity (area under the receiver operator characteristic [ROC] curve = 0.85-1.00) to distinguish between TBI animals with and without particular behavioral deficits. Depending on the investigated behavioral deficit, PET or DTI data alone, or the combination, could very well predict the variability in functional outcome data (adjusted R2 = 0.54-1.00). Taken together, both TSPO PET and DTI seem promising prognostic biomarkers to predict different chronic TBI sequelae.

The positron emission tomography (PET) tracer [F-18]MNI-659, selective for phosphodiesterase 10A (PDE10A), is a promising tool to assess an early biomarker for Huntington's disease (HD). In this study we investigated [F-18]MNI-659 uptake in the Q175 mouse model of HD. Given the focal striatal distribution of PDE10A as well as the striatal atrophy occurring in HD, the spatial normalization approach applied during the processing could sensibly affect the accuracy of the regional quantification. We compared the use of a magnetic resonance images (MRI) template based on individual MRI over a PET and CT templates for regional quantification and spatial normalization of [F-18]MNI-659 PET images. We performed [F-18] MNI-659 PET imaging in six months old heterozygous (HET) Q175 mice and wild-type (WT) littermates, followed by X-ray computed tomography (CT) scan. In the same week, individual T-2-weighted MRI were acquired. Spatial normalization and regional quantification of the PET/CT images was performed on MRI, [F-18]MNI-659 PET, or CT template and compared to binding potential (BP ND ) using volumes manually delineated on the individual MR images. Striatal volume was significantly reduced in HET mice (-7.7%, p

Purpose Prefrontal cortex (PFC) deep brain stimulation (DBS) has been proposed as a therapy for addiction and depression. This study investigates changes in rat cerebral glucose metabolism induced by different DBS frequencies using μPET. Procedures One hour DBS of the prelimbic area (PL) of the medial PFC (mPFC) (60 Hz, 130 Hz or sham) in rats (n = 9) was followed by 2-deoxy-2-[18 F] fluoro-d-glucose ([18 F]FDG) μPET. Results Sixty Hz DBS elicited significant hypermetabolism in the ipsilateral PL ([18 F]FDG uptake +5.2 ± 2.3 %, p

Quantification in positron emission tomography (PET) imaging of an orthotopic mouse model of colorectal cancer (CRC) is challenging due to difficult tumor delineation. We aimed to establish a reproducible delineation approach, evaluate its feasibility for reliable PET quantification and compare its added translational value with its subcutaneous counterpart. A subcutaneous Colo205-luc2 tumor fragment harvested from a donor mouse was transplanted onto the caecum of nude mice, with (n = 10) or without (n = 10) the addition of an X-ray detectable thread. Animals underwent 2-deoxy-2-[F-18]fluoro-D-glucose ([F-18]FDG) PET imaging, complemented with X-ray computed tomography (CT) and magnetic resonance imaging (MRI, 7T). Animals without a thread underwent additional contrast enhanced (Exitron) CT imaging. Tumors were delineated on the MRI, mu PET image or contrast enhanced mu CT images and correlations between in vivo and ex vivo [F-18]FDG tumor uptake as well as between image-derived and caliper-measured tumor volume were evaluated. Finally, cancer hallmarks were assessed immunohistochemically for the characterization of both models. Our results showed the strongest correlation between both in vivo and ex vivo uptake (r = 0.84, p < 0.0001) and image-derived and caliper-measured tumor volume (r = 0.96, p < 0.0001) when the tumor was delineated on the MR image. Orthotopic tumors displayed an abundance of stroma, higher levels of proliferation (p = 0.0007), apoptosis (p = 0.02), and necrosis (p < 0.0001), a higher number of blood vessels (p < 0.0001); yet lower tumor hypoxia (p < 0.0001) as compared with subcutaneous tumors. This orthotopic mouse model proved to be a promising tool for the investigation of CRC through preclinical imaging studies provided the availability of anatomical MR images for accurate tumor delineation. Furthermore, the tumor microenvironment of the orthotopic tumor resembled more that of human CRC, increasing its likelihood to advance translational nuclear imaging studies of CRC.

Background Increased brain uptake on [18F]AV45 PET is a biomarker for Alzheimers disease (AD). The standardised uptake value ratio (SUVR) is widely used for quantification but is subject to variability. Here we evaluate how SUVR of a cortical target region is affected by blood flow changes in the target and two frequently used reference regions. Methods Regional baseline time-activity curves (TACs) were simulated based on metabolite-corrected plasma input functions and pharmacokinetic parameters obtained from our previously acquired data in healthy control (HC; n = 10), amnestic mild cognitive impairment (aMCI; n = 15) and AD cohorts (n = 9). Blood flow changes were simulated by altering the regional tracer delivery rate K1 (and clearance rate k2) between -40% and +40% from its regional baseline value in the target region and/or cerebellar grey (CB) or subcortical white matter (WM) reference regions. The corresponding change in SUVR was calculated at 5060 min post-injection. Results A -40% blood flow reduction in the target resulted in an increased SUVRtarget (e.g. SUVRprecuneus: +10.0±5% in HC, +2.5±2% in AD), irrespective of the used reference region. A -40% blood flow reduction in the WM reference region increased SUVRWM (+11.5±4% in HC, +13.5±3% in AD) while a blood flow reduction in CB decreased SUVRCB (-9.5±6% in HC, -5.5±2% in AD), irrespective of the used target region. A -40% flow reduction in both the precuneus and reference WM (i.e., global flow change) induced an increased SUVR (+22.5±8% in HC, +16.0±4% in AD). When considering reference CB instead, SUVR was decreased by less than -5% (both in HC and AD). Conclusion Blood flow changes introduce alterations in [18F]AV45 PET SUVR. Flow reductions in the CB and WM reference regions resulted in a decreased and increased SUVR of the target, respectively. SUVR was more affected by global blood flow changes when considering WM instead of CB normalization.

In this work we aim to track the head motion of the awake mouse during the PET scan and correct the scan for motion to obtain motion-free brain images. The mouse head motion is tracked using radioactive point sources attached to the head (point source tracking, PST). In addition, a specially designed holder with a platform area of 9 × 10 cm was used to maintain the mouse inside the scanner field of view. Two mice were injected with [ 18 F]FDG and scanned awake during 20 min and under anesthesia 20 min to obtain a motion-free reconstruction for comparison. The mice moved over the entire available platform area. The average mouse head speed was 0.804 and 0.788 cm/s and the tracking success rate was 85.3% and 84.9% for the two mice respectively. After motion correction, the mouse brain FDG uptake pattern was recovered in the reconstructed image. The pearson's r correlation between awake and anesthesia reconstructions brain relative regional uptake was 0.875 and 0.986 the two mice respectively. The mouse head was successfully tracked using the PST method and the brain motion corrected reconstructions showed high correlation with motionfree reconstructions.

Brain inflammation is an important factor in the conversion of a healthy brain into an epileptic one, a phenomenon known as epileptogenesis, offering a new entry point for prognostic tools. The development of anti-epileptogenic therapies to treat before or at disease onset is hampered by our inability to predict the severity of the disease outcome. In a rat model of temporal lobe epilepsy we aimed to assess whether in vivo non-invasive imaging of brain inflammation at disease onset was predictive of spontaneous recurrent seizures (SRS) frequency and severity of depression-like and sensorimotor-related comorbidities. To this end, translocator protein, a biomarker of inflammation, was imaged by means of positron emission tomography (PET) 2 and 4 weeks post-status epilepticus using [F-18]-PBR111. Translocator protein was highly upregulated 2 weeks post-status epilepticus in limbic structures (up to 2.1-fold increase compared to controls in temporal lobe, P < 0.001), whereas 4 weeks post-status epilepticus, upregulation decreased (up to 1.6-fold increase compared to controls in temporal lobe, P < 0.01) and was only apparent in a subset of these regions. Animals were monitored with video-electroencephalography during all stages of disease (acute, latent-first seizures appearing around 2 weeks post-status epilepticus-and chronic phases), for a total of 12 weeks, in order to determine SRS frequency for each subject (range 0.00-0.83 SRS/day). We found that regional PET uptake at 2 and 4 weeks post-status epilepticus correlated with the severity of depression-like and sensorimotor-related comorbidities during chronic epilepsy (P < 0.05 for each test). Regional PET imaging did not correlate with SRS frequency, however, by applying a multivariate data-driven modeling approach based on translocator protein PET imaging at 2 weeks post-status epilepticus, we accurately predicted the frequency of SRS (R = 0.92; R-2 = 0.86; P < 0.0001) at the onset of epilepsy. This study not only demonstrates non-invasive imaging of translocator protein as a prognostic biomarker to ascertain SRS frequency, but also shows its capability to reflect the severity of depression-like and sensorimotor-related comorbidities. Our results are an encouraging step towards the development of anti-epileptogenic treatments by providing early quantitative assessment of SRS frequency and severity of comorbidities with high clinical relevance.(C) 2016 Elsevier Inc. All rights reserved. S.D. is supported by Research Foundation Flanders (FWO) funding 1.5.110.14 N, 1.5.144.12 N and ERA-NET NEURON G.A009.13 N, and finally by Queen Elisabeth Medical Foundation (Q.E.M.F.) for Neurosciences. D.B. has a PhD fellowship from the Research Foundation Flanders (FWO, 11W2516 N). S.D. and S.S. are supported by the Bijzonder Onderzoeks Fonds (BOF) of the University of Antwerp. A.V.D.L. is supported by the European Union's Seventh Framework Programme under grant agreement number 278850 (INMiND). EJ. has a post-doctoral fellowship from the Research Foundation Flanders (FWO, 12R1917 N). E.S. is supported by a Methusalem grant from the universities of Antwerp and Hasselt, awarded to Prof. Herman Goossens and Prof. Geert Molenberghs. N.H. acknowledges support from the University of Antwerp scientific chair in Evidence-Based Vaccinology, financed in 2009-2015 by an unrestricted gift from Pfizer.

Background: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-beta (A beta) increases when the CSF A beta(1-42)/A beta(1-40) ratio is used as compared to CSF A beta(1-42) levels alone. Objective: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting. Methods: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [F-18] Florbetapir ([F-18]AV45) PET scan, [F-18] FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (A beta(1-42), A beta(1-40), T-tau, P-tau(181)). Results: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [F-18]AV45 PET measures when the CSF A beta(1-42)/A beta(1-40) was applied compared to A beta(1-42) alone. CSF biomarkers were stronger associated to [F-18]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matter Conclusion: The concordance between CSF A beta and [F-18]AV45 PET increases when the CSF A beta(1-42)/A beta(1-40) ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.

The substrate-based positron emission tomography (PET) tracer [18F]CP18 is capable of detecting the activity of caspase-3/7, two key executioner proteases in the apoptosis pathway, through selective cleavage of the ligand by the activated proteases and subsequent accumulation in apoptotic cells. Using an in vitro and in vivo model of colorectal cancer (CRC), we investigated whether [18F]CP18 tracer accumulation provides a measure for apoptosis and reliably reflects early treatment response to chemotherapeutics. Procedures [18F]CP18 cell uptake was assessed in treated Colo205 cells (saline, 5-fluorouracil (5-FU), irinotecan or their combination) and correlated with caspase-3/7 activity. [18F]CP18 imaging was performed in Colo205 xenografts, starting with a baseline μPET/micro X-ray computed tomography (​μCT) scan, followed by a 3-day treatment with saline (n = 5), 5-FU (low sensitivity, n = 4), irinotecan (high sensitivity, n = 5), or a combination of both (n = 7). The study was concluded with a second [18F]CP18 scan, 24 h after final treatment administration, followed by tumor removal for gamma counting (%ID/g) and for cleaved caspase-3 immunohistochemistry (apoptotic index/necrosis). Tumors were delineated on μCT images and, using the obtained volumes of interest, average percentage injected dose per cubic centimeter (%ID/cm3) was calculated from every μPET image. Results In vitro, [18F]CP18 cell uptake was positively correlated with caspase-3/7 activity (r = 0.59, p = 0.003). A drug-dependent increase in [18F]CP18 tumor uptake compared to baseline was observed in animals treated with 5-FU (+14 ± 25 %), irinotecan (+56 ± 54 %), and their combination (+158 ± 69 %, p = 0.002). %ID/cm3 showed a positive relationship with both %ID/g (r = 0.83, p < 0.0001) and the apoptotic index (r = 0.60, p = 0.004), but not with tumor necrosis (r = 0.22, p = 0.36). Conclusion Both our in vitro and in vivo findings have shown the ability of [18F]CP18-PET to visualize therapy-induced cancer cell apoptosis and possibly serve as a biomarker for early therapy response.

Purpose To evaluate the tumour growth delay of a peritoneal carcinomatosis (PC) of colorectal origin after intraperitoneal chemotherapy with paclitaxel/randomly-methylated-β-cyclodextrin (Pac/RAME-β-CD) versus Taxol® at normo- and hyperthermic conditions in rats. Methods Hyperthermic intraperitoneal chemotherapy (HIPEC) was performed 7 days post implantation of the tumour with both formulations at a Pac concentration of 0.24 mg/ml. Tumour evaluation was performed via positron emission tomography (PET) and magnetic resonance imaging (MRI) imaging, measuring tumour activity and tumour volume, respectively. Scans were taken at 2 and 7 days post treatment. Results PET and MRI data showed a significant reduction in tumour activity and tumour volume for rats treated with Pac/RAME-β-CD (at normo- and hyperthermic conditions), compared to the control group. Treatment with Taxol® did not result in a significant reduction of tumour activity and tumour volume. No significant differences between the normo- and hyperthermic conditions were observed for both formulations, indicating that hyperthermia and paclitaxel were not synergistic despite the direct cytotoxic effect of hyperthermia. Conclusion Monitoring tumour growth via PET and MRI indicated that Pac/RAME-β-CD inclusion complexes had a significantly higher efficacy compared to Taxol® in a rat model for peritoneal carcinomatosis.

Geant4 application for tomographic emission (GATE) is a geometry and tracking 4 (Geant4) application toolkit for accurate simulation of positron emission tomography and single photon emission computed tomography (SPECT) scanners. GATE simulations with realistic count levels are very CPU-intensive as they take up to several days with single-CPU computers. Therefore, we implemented both standard forced detection (FD) and convolution-based forced detection (CFD) with multiple projection sampling, which allows the simulation of all projections simultaneously in GATE. In addition, a FD and CFD specialized Geant4 navigator was developed to overcome the detailed but slow tracking algorithms in Geant4. This article is focused on the implementation and validation of these aforementioned developments. The results show a good agreement between the FD and CFD versus analog GATE simulations for Tc-99m SPECT. These combined developments accelerate GATE by three orders of magnitude in the case of FD. CFD is an additional two orders of magnitude faster than FD. This renders realistic simulations feasible within minutes on a single CPU. Future work will extend our framework to higher energy isotopes, which will require the inclusion of a septal penetration and collimator scatter model.