Search

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, including canagliflozin, reduce the risk of cardiovascular and kidney outcomes in patients with and without type 2 diabetes, albeit with a large inter-individual variation. The underlying mechanisms for this variation in response might be attributed to differences in SGLT2 occupancy, resulting from individual variation in plasma and tissue drug exposure and receptor availability. We performed a feasibility study for the use of [ 18 F]Canagliflozin positron emission tomography (PET) imaging to determine the association between clinical canagliflozin doses and SGLT2 occupancy in patients with type 2 diabetes. We obtained two 90-min dynamic PET scans with diagnostic intravenous [ 18 F]Canagliflozin administration and a full kinetic analysis in seven patients with type 2 diabetes. Patients received 50, 100 or 300mg oral canagliflozin (n=2:4:1) 2.5 hours before the second scan. Canagliflozin pharmacokinetics and urinary glucose excretion were measured. The apparent SGLT2 occupancy was derived from the difference between the apparent volume of distribution of [ 18 F]Canagliflozin in the baseline and post-drug PET scans. Individual canagliflozin area under the curve from oral dosing until 24-hours (AUC P0-24h ) varied largely (range 1715-25747 μg/L*h, mean 10580 μg/L*h) and increased dose dependently with mean values of 4543, 6525 and 20012 μg/L*h for 50, 100 and 300mg respectively (P=0.046). SGLT2 occupancy ranged between 65 and 87%, but did not correlate with canagliflozin dose, plasma exposure or urinary glucose excretion. We report the feasibility of [ 18 F]Canagliflozin PET imaging to determine canagliflozin kidney disposition and SGLT2 occupancy. This suggests the potential of [ 18 F]Canagliflozin as a tool to visualize and quantify clinically SGLT2 tissue binding.

Adenosine A2A and dopamine D2 receptors in the basal ganglia form heterotetrameric structures that are involved in the regulation of motor activity and neuropsychiatric functions. The present study examines the A2A receptor-mediated modulation of D2 receptor binding in vivo using positron emission tomography (PET) with the D2 antagonist tracer [11C]raclopride. Healthy male Wistar rats (n = 8) were scanned (60 min dynamic scan) with [11C]raclopride at baseline and 7 days later following an acute administration of the A2A agonist CGS21680 (1 mg/kg), using a MicroPET Focus-220 camera. Nondisplaceable binding potential (BPND) values were calculated using a simplified reference tissue model (SRTM), with cerebellum as the reference tissue. SRTM analysis did not show any significant changes in [11C]raclopride BPND (p = 0.102) in striatum after CGS21680 administration compared to the baseline. As CGS21680 strongly affects hemodynamics, we also used arterial blood sampling and a metabolite-corrected plasma input function for compartment modeling using the reversible two-tissue compartment model (2TCM) to obtain the BPND from the k3/k4 ratio and from the striatum/cerebellum volume of distribution ratio (DVR) in a second group of animals. These rats underwent dynamic [11C]raclopride scans after pretreatment with a vehicle (n = 5), a single dose of CGS21680 (1 mg/kg, n = 5), or a single dose of the A2A antagonist KW6002 (1 mg/kg, n = 5). The parent fraction in plasma was significantly higher in the CGS21680-treated group (p = 0.0001) compared to the vehicle-treated group. GCS21680 administration significantly reduced the striatal k3/k4 ratio (p < 0.01), but k3 and k4 estimates may be less reliable. The BPND (DVR-1) decreased from 1.963 ± 0.27 in the vehicle-treated group to 1.53 ± 0.55 (p = 0.080) or 1.961 ± 0.11 (p = 0.993) after the administration of CGS21680 or KW6002, respectively. Our study suggests that the A2A agonist CGS21680, but not the antagonist KW6002, may reduce the D2 receptor availability in the striatum.

Purpose Multiple sclerosis (MS) is a disease characterized by inflammatory demyelinated lesions. New treatment strategies are being developed to stimulate myelin repair. Quantitative myelin imaging could facilitate these developments. This first-in-man study aimed to evaluate [11C]MeDAS as a PET tracer for myelin imaging in humans. Methods Six healthy controls and 11 MS patients underwent MRI and dynamic [11C]MeDAS PET scanning with arterial sampling. Lesion detection and classification were performed on MRI. [11C]MeDAS time-activity curves of brain regions and MS lesions were fitted with various compartment models for the identification of the best model to describe [11C]MeDAS kinetics. Several simplified methods were compared to the optimal compartment model. Results Visual analysis of the fits of [11C]MeDAS time-activity curves showed no preference for irreversible (2T3k) or reversible (2T4k) two-tissue compartment model. Both volume of distribution and binding potential estimates showed a high degree of variability. As this was not the case for 2T3k-derived net influx rate (Ki), the 2T3k model was selected as the model of choice. Simplified methods, such as SUV and MLAIR2 correlated well with 2T3k-derived Ki, but SUV showed subject-dependent bias when compared to 2T3k. Both the 2T3k model and the simplified methods were able to differentiate not only between gray and white matter, but also between lesions with different myelin densities. Conclusion [11C]MeDAS PET can be used for quantification of myelin density in MS patients and is able to distinguish differences in myelin density within MS lesions. The 2T3k model is the optimal compartment model and MLAIR2 is the best simplified method for quantification. Trial registration. NL7262. Registered 18 September 2018.

The histamine H3 receptor has been considered as a target for the treatment of various central nervous system diseases. Positron emission tomography (PET) studies with the radiolabeled potent and selective histamine H3 receptor antagonist [11C]GSK-189254 in rodents could be used to examine the mechanisms of action of novel therapeutic drugs or to assess changes of regional H3 receptor density in animal models of neurodegenerative disease. [11C]GSK-189254 was intravenously administered to healthy Wistar rats (n = 10), and a 60 min dynamic PET scan was carried out. Arterial blood samples were obtained during the scan to generate a metabolite-corrected plasma input function. PET data were analyzed using a one-tissue compartment model (1T2k), irreversible (2T3k) or reversible two-tissue compartment models (2T4k), graphical analysis (Logan and Patlak), reference tissue models (SRTM and SRTM2), and standard uptake values (SUVs). The Akaike information criterion and the standard error of the estimated parameters were used to select the most optimal quantification method. This study demonstrated that the 2T4k model with a fixed blood volume fraction and Logan graphical analysis can best describe the kinetics of [11C]GSK-189254 in the rat brain. SUV40-60 and the reference tissue-based measurements DVR(2T4k), BPND(SRTM), and SUV ratio could also be used as a simplified method to estimate H3 receptor availability in case blood sampling is not feasible.

In this contribution, several opportunities and challenges for long axial field of view (LAFOV) PET are described. It is an anthology in which the main issues have been highlighted. A consolidated overview of the camera system implementation, business and financial plan, opportunities and challenges is provided. What the nuclear medicine and molecular imaging community can expect from these new PET/CT scanners is the delivery of more comprehensive information to the clinicians for advancing diagnosis, therapy evaluation and clinical research.

Pharmacokinetic modelling with arterial sampling is the gold standard for analysing dynamic PET data of the brain. However, the invasive character of arterial sampling prevents its widespread clinical application. Several methods have been developed to avoid arterial sampling, in particular reference region methods. Unfortunately, for some tracers or diseases, no suitable reference region can be defined. For these cases, other potentially non-invasive approaches have been proposed: (1) a population based input function (PBIF), (2) an image derived input function (IDIF), or (3) simultaneous estimation of the input function (SIME). This systematic review aims to assess the correspondence of these non-invasive methods with the gold standard. Studies comparing non-invasive pharmacokinetic modelling methods with the current gold standard methods using an input function derived from arterial blood samples were retrieved from PubMed/MEDLINE (until December 2021). Correlation measurements were extracted from the studies. The search yielded 30 studies that correlated outcome parameters (VT, DVR, or BPND for reversible tracers; Ki or CMRglu for irreversible tracers) from a potentially non-invasive method with those obtained from modelling using an arterial input function. Some studies provided similar results for PBIF, IDIF, and SIME-based methods as for modelling with an arterial input function (R2 = 0.59–1.00, R2 = 0.71–1.00, R2 = 0.56–0.96, respectively), if the non-invasive input curve was calibrated with arterial blood samples. Even when the non-invasive input curve was calibrated with venous blood samples or when no calibration was applied, moderate to good correlations were reported, especially for the IDIF and SIME (R2 = 0.71–1.00 and R2 = 0.36–0.96, respectively). Overall, this systematic review illustrates that non-invasive methods to generate an input function are still in their infancy. Yet, IDIF and SIME performed well, not only with arterial blood calibration, but also with venous or no blood calibration, especially for some tracers without plasma metabolites, which would potentially make these methods better suited for clinical application. However, these methods should still be properly validated for each individual tracer and application before implementation.

Purpose The aim of this review is to give an overview of the current status of targeted optical fluorescence imaging in the field of oncology, cardiovascular, infectious and inflammatory diseases to further promote clinical translation. Methods A meta-narrative approach was taken to systematically describe the relevant literature. Consecutively, each field was assigned a developmental stage regarding the clinical implementation of optical fluorescence imaging. Results Optical fluorescence imaging is leaning towards clinical implementation in gastrointestinal and head and neck cancers, closely followed by pulmonary, neuro, breast and gynaecological oncology. In cardiovascular and infectious disease, optical imaging is in a less advanced/proof of concept stage. Conclusion Targeted optical fluorescence imaging is rapidly evolving and expanding into the clinic, especially in the field of oncology. However, the imaging modality still has to overcome some major challenges before it can be part of the standard of care in the clinic, such as the provision of pivotal trial data. Intensive multidisciplinary (pre-)clinical joined forces are essential to overcome the delivery of such compelling phase III registration trial data and subsequent regulatory approval and reimbursement hurdles to advance clinical implementation of targeted optical fluorescence imaging as part of standard practice.

The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson's disease has been well established. Here, D2 receptor antagonists were used to assess changes in [18F]-FEOBV binding to the vesicular acetylcholine transporter (VAChT) in rodents using positron emission tomography (PET). After pretreatment with either 10 mg/kg haloperidol, 1 mg/kg raclopride, or vehicle, 90 min dynamic PET scans were performed with arterial blood sampling. The net influx rate (Ki) was obtained from Patlak graphical analysis, using a metabolite-corrected plasma input function and dynamic PET data. [18F]-FEOBV concentration in whole-blood or plasma and the metabolite-corrected plasma input function were not significantly changed by the pretreatments (adjusted p > 0.07, Cohen's d 0.28-1.89) while the area-under-the-curve (AUC) of the parent fraction of [18F]-FEOBV was significantly higher after haloperidol treatment (adjusted p = 0.022, Cohen's d = 2.51) than in controls. Compared to controls, the AUC of [18F]-FEOBV, normalized for injected dose and body weight, was nonsignificantly increased in the striatum after haloperidol (adjusted p = 0.4, Cohen's d = 1.77) and raclopride (adjusted p = 0.052, Cohen's d = 1.49) treatment, respectively. No changes in the AUC of [18F]-FEOBV were found in the cerebellum (Cohen's d 0.63-0.74). Raclopride treatment nonsignificantly increased Ki in the striatum 1.3-fold compared to control rats (adjusted p = 0.1, Cohen's d = 1.1) while it reduced Ki in the cerebellum by 28% (adjusted p = 0.0004, Cohen's d = 2.2) compared to control rats. Pretreatment with haloperidol led to a nonsignificant reduction in Ki in the striatum (10%, adjusted p = 1, Cohen's d = 0.44) and a 40-50% lower Ki than controls in all other brain regions (adjusted p < 0.0005, Cohen's d = 3.3-4.7). The changes in Ki induced by the selective D2 receptor antagonist raclopride can in part be quantified using [18F]-FEOBV PET imaging. Haloperidol, a nonselective D2/σ receptor antagonist, either paradoxically decreased cholinergic activity or blocked off-target [18F]-FEOBV binding to σ receptors. Hence, further studies evaluating the binding of [18F]-FEOBV to σ receptors using selective σ receptor ligands are necessary.

The histamine H

The Blood-Brain Barrier P-glycoprotein (P-gp) function can be altered in several neurodegenerative diseases and due to the administration of different drugs which may cause alterations in drug concentrations and consequently lead to a reduced effectiveness or increased side-effects. The novel PET radiotracer [

Background: Positron emission tomography (PET) with 16α-[18F]-fluoro-17β-estradiol ([18F]-FES) can visualize estrogen receptor (ER) expression, but it is challenging to determine the ER status of liver metastases, due to high physiological [18F]-FES uptake. We evaluated whether [18F]-FES-PET can be used to determine the ER status of liver metastases, using corresponding liver biopsies as the gold standard. Methods: Patients with metastatic breast cancer (n = 23) were included if they had undergone a [18F]-FES-PET, liver metastasis biopsy, CT-scan, and [18F]-FDG-PET. [18F]-FES-PET scans were assessed by visual and quantitative analysis, tracer uptake was correlated with ER expression measured by immunohistochemical staining and the effects of region-of-interest size and background correction were determined. Results: Visual analysis allowed ER assessment of liver metastases with 100% specificity and 18% sensitivity. Quantitative analysis improved the sensitivity. Reduction of the region-of-interest size did not further improve the results, but background correction improved ER assessment, resulting in 83% specificity and 77% sensitivity. Using separate thresholds for ER+ and ER− metastases, positive and negative predictive values of 100% and 75%, respectively, could be obtained, although 30% of metastases remained inconclusive. Conclusion: In the majority of liver metastases, ER status can be determined with [18F]-FES-PET if background correction and separate thresholds are applied.

Multiple sclerosis (MS) is a disease characterized by inflammatory demyelinated lesions. New treatment strategies are being developed to stimulate myelin repair. Quantitative myelin imaging could facilitate these developments. This first-in-man study aimed to evaluate [Six healthy controls and 11 MS patients underwent MRI and dynamic [Visual analysis of the fits of [[NL7262. Registered 18 September 2018.

The aim of this study is to investigate the influence of sex, age, fat mass, fasting blood glucose level (FBGL), and estimated glomerular filtration rate (eGFR) on blood pool activity in patients with large vessel vasculitis (LVV). Blood pool activity was measured in the superior caval vein using mean, maximum, and peak standardized uptake values corrected for body weight (SUVs) and lean body mass (SULs) in 41 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scans of LVV patients. Sex influence on the blood pool activity was assessed with t-tests, while linear correlation analyses were used for age, fat mass, FBGL, and eGFR. Significantly higher SUVs were found in women compared with men, whereas SULs were similar between sexes. In addition, higher fat mass was associated with increased SUVs (r = 0.56 to 0.65; all p < 0.001) in the blood pool, but no correlations were found between SULs and fat mass (r = −0.25 to −0.15; all p > 0.05). Lower eGFR was associated with a higher FDG blood pool activity for all uptake values. In FDG-PET/CT studies with LVV patients, we recommend using SUL over SUV, while caution is advised in interpreting SUV and SUL measures when patients have impaired kidney function.

[11C]Preladenant was developed as a novel adenosine A2A receptor positron emission tomography radioligand. The present study aims to evaluate the suitability of [11C]preladenant positron emission tomography for the quantification of striatal A2A receptor density and the assessment of striatal A2A receptor occupancy by KW-6002. Sixty- or ninety-minute dynamic positron emission tomography imaging was performed on rats. Tracer kinetics was quantified by the two-tissue compartment model, Logan graphical analysis and several reference tissue-based models. Test–retest reproducibility was assessed by repeated imaging on two consecutive days. Two-tissue compartment model and Logan plot estimated comparable distribution volume ( VT) values of ∼10 in the A2A receptor-rich striatum and substantially lower values in all extra-striatal regions (∼1.5–2.5). The simplified reference tissue model with midbrain or occipital cortex as the reference region proved to be the best non-invasive model for quantification of A2A receptor, showing a striatal binding potential ( BPND) value of ∼5.5, and a test–retest variability of ∼5.5%. The brain metabolite analysis showed that at 60-min post injection, 17% of the radioactivity in the brain was due to radioactive metabolites. The ED50 of KW-6002 in rat striatum for i.p. injection was 0.044–0.062 mg/kg. The study demonstrates that [11C]preladenant is a suitable tracer to quantify striatal A2A receptor density and assess A2A receptor occupancy by A2A receptor-targeting molecules.

[Ninety-minute dynamic [The 1TCM did not fit the data. Time-activity curves were more reliably estimated by the irreversible than the reversible 2TCM for 60 and 90 min as the influx rate K[

P-glycoprotein is a protective efflux transporter at the blood–brain barrier showing altered function in many neurological disorders. The purpose of this study was to validate [18F]MC225 as a radiotracer for measuring P-glycoprotein function with positron emission tomography. Three groups of Sprague-Dawley rats were used to assess tracer uptake at baseline (group 1), after inhibition of P-glycoprotein (group 2), and after inhibition of both P-glycoprotein and breast cancer resistance protein (Bcrp, group 3). A two-tissue compartment model with a metabolite-corrected plasma input function provided the best fit to the positron emission tomography data, but parameter estimates were more reliable in a one-tissue compartment model, which was selected as the preferred model. Regional distribution volumes ( VT) in the control group ranged from 6 to 11, which is higher than for other radiotracers. [18F]MC225 showed transporter selectivity, since inhibition of P-glycoprotein caused a two to fourfold increase in the cerebral VT values, but additional inhibition of Bcrp did not cause any further increase. Metabolic stability of [18F]MC225 was moderate (at 1 h post-injection 15% of plasma radioactivity and 76% of brain radioactivity represented intact parent). Thus, [18F]MC225 may be a useful radiotracer to measure especially increases of P-glycoprotein function at the blood–brain barrier.

The estrogen receptor (ER) is a target for endocrine therapy in breast cancer patients. Individual quantification of ERα and ERβ expression, rather than total ER levels, might enable better prediction of the response to treatment. We recently developed the tracer 2

PURPOSE: In this study, we compared the ability of [(11)C]CIC, [(11)C]MeDAS and [(11)C]PIB to reveal temporal changes in myelin content in focal lesions in the lysolecithin rat model of multiple sclerosis. Pharmacokinetic modelling was performed to determine the best method to quantify tracer uptake.METHODS: Sprague-Dawley rats were stereotactically injected with either 1 % lysolecithin or saline into the corpus callosum and striatum of the right brain hemisphere. Dynamic PET imaging with simultaneous arterial blood sampling was performed 7 days after saline injection (control group), 7 days after lysolecithin injection (demyelination group) and 4 weeks after lysolecithin injection (remyelination group).RESULTS: The kinetics of [(11)C]CIC, [(11)C]MeDAS and [(11)C]PIB was best fitted by Logan graphical analysis, suggesting that tracer binding is reversible. Compartment modelling revealed that all tracers were fitted best with the reversible two-tissue compartment model. Tracer uptake and distribution volume in lesions were in agreement with myelin status. However, the slow kinetics and homogeneous brain uptake of [(11)C]CIC make this tracer less suitable for in vivo PET imaging. [(11)C]PIB showed good uptake in the white matter in the cerebrum, but [(11)C]PIB uptake in the cerebellum was low, despite high myelin density in this region. [(11)C]MeDAS distribution correlated well with myelin density in different brain regions.CONCLUSION: This study showed that PET imaging of demyelination and remyelination processes in focal lesions is feasible. Our comparison of three myelin tracers showed that [(11)C]MeDAS has more favourable properties for quantitative PET imaging of demyelinated and remyelinated lesions throughout the CNS than [(11)C]CIC and [(11)C]PIB.

Tumor hypoxia hampers the efficacy of radiotherapy because of its increased resistance to ionizing radiation. The aim of the present study was to estimate the potential added clinical value of the specific hypoxia tracer F-18-fluoroazomycin arabinoside (F-18-FAZA) over commonly used F-18-FDG in the treatment of advanced-stage non-small cell lung cancer (NSCLC). Methods: Eleven patients with stage Ill or stage IV NSCLC underwent F-18-FDG and F-18-FAZA PET before chemoradiotherapy. The maximum standardized uptake value (SUVmax) was used to depict F-18-FDG uptake, and the tumor-to-background (T/B) ratio and tumor fractional hypoxic volume (FHV) were used to quantify hypoxia. The spatial correlation between F-18-FDG and F-18-FAZA uptake values was investigated using voxel-based analysis. Partial-volume correction was applied. Results: All 11 patients showed clear uptake of F-18-FAZA in the primary tumor. However, different patterns of F-18-FDG and F-18-FAZA uptake distributions were observed and varied widely among different tumors. No significant correlation was observed between F-18-FDG SUVmax and F-18-FAZA T/B ratio (P = 0.055). The median FHV of 1.4 was 48.4% (range, 5.0-91.5). A significant positive correlation was found between the F-18-FAZA T/B ratio and FHV of 1.4 (P

Preclinical positron emission tomography studies are important to follow disease progression and develop new pharmacological agents. We investigated whether kinetic modeling of 5-HT2A tracer [C-11]MDL 100907 is possible in rats.Kinetic modeling with either metabolite-corrected plasma curve or with the cerebellum as a reference tissue resulted in a good correlation of nondisplaceable binding potential (BPND) calculated from a two-tissue compartment model (2TCM) or different reference tissue models. Injecting the tracer by a slower bolus decreases the variation in 2TCM outcome parameters and results in a good correlation between k(3)/k(4) and the other models. Application of 0.2 mg/kg cold MDL 100907 resulted in almost complete occupancy of 5-HT2A receptors.A reference tissue model can be used for [C-11]MDL kinetic modeling in rats, which is preferable in pharmacological or longitudinal studies.

Introduction: The PET tracer, 1-O-(4-(2-fluoroethyl-carbamoyloxymethyl)-2-nitrophenyl)-O-beta-D-glucopyronuronate ([F-18]FEAnGA), was recently developed for PET imaging of extracellularl beta-glucuronidase (beta-GUS). However,[F-18]FEAnGA exhibited rapid renal clearance, which resulted in a relatively low tracer uptake in the tumor. To improve the pharmacokinetics of [F-18]FEAnGA, we developed its more lipophilic methyl ester analog, [F-18]FEAnGA-Me.Methods: [F-18]FEAnGA-Me was obtained by alkylation of the O-protected glucuronide methyl ester precursor with [F-18]-fluoroethylamine ([F-18]FEA), followed by removal of the acetate protecting groups with NaOMe/MeOH. The PET tracer was evaluated by in vitro and in vivo studies.Results: [F-18]FEAnGA-Me was obtained in 5%-10% overall radiochemical yield. It is 10-fold less hydrophilic than [F-18]FEAnGA and it is stable in PBS and in the presence of beta-GUS for 1 h. However, in the presence of esterase or plasma [F-18]FEAnGA-Me is converted to [F-18]FEAnGA, and subsequently converted to [F-18]FEA by beta-GUS. MicroPET studies in Wistar rats bearing a C6 glioma and a sterile inflammation showed similar uptake in tumors after injection of either [F-18]FEAnGA-Me or [F-18]FEAnGA. Both tracers had a rapid two-phase clearance of total plasma radioactivity with a half-life of 1 and 8 min. The [F-18]FEAnGA fraction generated from [F-18]FEAnGA-Me by in vivo hydrolysis had a circulation half-life of 1 and 11 min in plasma. Similar distribution volume in the viable part of the tumor was found after injection of either [F-18]FEAnGA-Me or [F-18]FEAnGA.Conclusion: The imaging properties of [F-18]FEAnGA-Me were not significantly better than those of [F-18]FEAnGA. Therefore, other strategies should be applied in order to improve the kinetics of these tracers. (C) 2012 Elsevier Inc. All rights reserved.

Purpose N-(4-[18F]Fluorobenzoyl)interleukin-2 ([18F]FB-IL2) specifically binds to interleukin-2 receptors (IL-2R) and thus may be used to detect inflammation processes using positron emission tomography (PET). We now validated whether [18F]FB-IL2 can be used to quantify activated human peripheral blood mononuclear cells (hPBMC) in rats by pharmacokinetic modelling. Methods Eleven Wistar rats were subcutaneously inoculated in the shoulder with different amounts of phytohaemagglutinin (PHA) activated hPBMC 15 min before i.v. injection of [18F]FB-IL2. A 60-min dynamic PET scan was acquired and arterial blood sampling and metabolite analysis were performed. At the end of the scan, animals were terminated and the inflammatory lesion dissected. PET data were analysed using Logan and Patlak analysis as well as one-tissue and two-tissue compartment models. Model preferences according to the Akaike information criterion (AIC) and correlation between PET measurements and the number of CD25-positive cells were evaluated. Results A high correlation between ex vivo tracer uptake (standardized uptake value) in the xenograft and the number of inoculated CD25-positive cells was observed (R2 = 0.90). Plasma time-activity curves showed a rapid washout of the radiopharmaceutical from blood, while the time-activity curves of the inflammatory lesions showed slower washout. Time-activity curves could be fitted well by the Logan analysis method, indicating that the binding between [18F]FB-IL2 and CD25 is reversible. AIC indicated that data could be modelled best by a two-tissue reversible compartment model. A high correlation was observed between the binding potential and the number of CD25-positive cells (R2 = 0.876, p

Introduction Myocardial perfusion gating techniques offer the possibility of measurement of left ventricular end-systolic (ESV) and end-diastolic volume (EDV) and left ventricular ejection fraction (LVEF) in clinical and preclinical trials. The aim of this study was to evaluate left ventricular volumes (LVV) and LVEF with 13 N-NH 3 in comparison with the reference 18 F-FDG in different rat models. Methods In this study, 18 male Wistar rats, 12 control rats and 6 rats with myocardial infarction (MI) were imaged with micro-PET. The ratswere scanned with gated 13 N-NH 3 and 18 F-FDG sequentially for the assessment of LVV and LVEF. A validated three-dimensional segmentation algorithm was used to calculate LVV and LVEF. Results Mean LVEF measured with 13 N-NH 3 was 45.6±8.9 and 75.3±9.4%, mean ESV was 0.40±0.12 and 0.14±0.11 ml, and mean EDVwas 0.53±16 and 0.75±0.18 ml for MI and control rats, respectively. Moderate to good correlations were observed between values of 13 N-NH 3 and 18 F-FDG for calculation of ESV [ r =0.80, P r =0.63, P =.005, SEE=0.14) and LVEF ( r =0.84, P 13 N-NH 3 was significantly lower in MI rats in comparison to measurement with 18 F-FDG (45.6±8.9 vs 54.9±9.3 %; P =.04). Conclusion Correlations were moderate to good for the assessment of ESV, EDV and LVEF between gated 13 N-NH 3 and 18 F-FDG. LVEF was underestimated with gated 13 N-NH 3 in rats with myocardial infarction. In healthy rats, LV volumes and LVEF can be measured reproducibly with either approach.

Activation of microglia is a hallmark of inflammatory, infectious, and degenerative diseases of the central nervous system. Several studies have indicated that there is an increase in release of beta-glucuronidase by activated microglia into the extracellular space at the site of neuroinflammation. beta-glucuronidase is involved in the hydrolysis of glycosaminoglycans on the cell surface and the degradation of the extracellular matrix. Therefore, beta-glucuronidase might be a biomarker for ongoing neurodegeneration induced by neuroinflammation. In this study, we investigated whether the PET tracer F-18-FEAnGA was able to detect beta-glucuronidase release during neuroinflammation in a rat model of herpes encephalitis. Methods: Male Wistar rats were intranasally inoculated with herpes simplex virus 1 (HSV-1) or phosphate-buffered saline as a control. C-11-(R)-PK11195 and F-18-FEAnGA small-animal PET scans were acquired for 60 min. Logan graphical analysis was used to calculate F-18-FEAnGA distribution volumes (DVLogan) in various brain areas. Results: After administration of F-18-FEAnGA, the area under the activity concentration-versus-time curve of the whole brain was 2 times higher in HSV-1-infected rats than in control rats. In addition, the DVLogan of F-18-FEAnGA was most increased in the frontopolar cortex, frontal cortex, bulbus olfactorius, cerebral cortex, cerebellum, and brainstem of HSV-1-infected rats, when compared with control rats. The conversion of F-18-FEAnGA to 4-hydroxy-3-nitrobenzyl alcohol was found to be 1.6 times higher in HSV-1-infected rats than in control rats and correlated with the DVLogan of F-18-FEAnGA in the same areas of the brain. Furthermore, the DVLogan of F-18-FEAnGA also correlated with beta-glucuronidase activity in the same brain regions. In addition, DVLogan of F-18-FEAnGA showed a tendency to correlate with C-11-(R)-PK11195 uptake (marker for activated microglia) in the same brain regions. Conclusion: Despite relatively low brain uptake, F-18-FEAnGA was able to detect an increased release of beta-glucuronidase during neuroinflammation.

Rationale A new system is presented and evaluated for real-time monitoring of blood leakage during hyperthermic isolated limb perfusion (HILP) surgery, the Veenstra HILP system. This system incorporates two software models to determine blood leakage: a single-nuclide algorithm and a newly developed dual-nuclide algorithm. The latter algorithm has the advantage that, in principle, it is independent of system sensitivity and thus independent of changes in geometrical efficiency. A physical description of the system is given, together with the required hardware and software specifications.Methods In-vitro measurements, corresponding to the intended clinical use, are presented to investigate the relevant performance characteristics of the system: count rate linearity, measurement uncertainty, response time, and accuracy. As the Veenstra HILP system provides the opportunity to use different filter settings and averaging time, the influence of these settings on the time response and measurement uncertainty is described.Results Count rate linearity was better than 1% for the count rate domain typically observed during HILP procedures. The response time of the system degrades with increasing total averaging time. In contrast, measurement uncertainty in the blood leakage factor improves with increasing radiotracer count rates and increasing total averaging time. For both blood leakage algorithms, measurement accuracy is better than 1.0 and 1.5%, respectively.Conclusion Measurements have shown that the system is well suited for the real-time monitoring of blood leakage during HILP surgery. Furthermore, a good agreement was observed between the theoretical and measured response time and measurement uncertainty. Nucl Med Commun 32: 853-862 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Nuclear Medicine Communications 2011, 32: 853-862

P-glycoprotein (P-gp), a major efflux pump in the blood-brain barrier (BBB) has a profound effect on entry of drugs, peptides and other substances into the central nervous system (CNS). The brain's permeability can be negatively influenced by modulation of the transport function of P-gp. Inflammatory mediators play a role in schizophrenia, and may be able to influence the integrity of the BBB, via P-gp modulation. We hypothesized that P-gp function in the BBB is changed in patients with schizophrenia. Positron-emission tomography was used to measure brain uptake of [(11)C]verapamil, which is normally extruded from the brain by P-gp. We found that patients with chronic schizophrenia under treatment with antipsychotic drugs compared with healthy controls showed a significant decrease in [(11)C]verapamil uptake in the temporal cortex, the basal ganglia, and the amygdala, and amygdalae, and a trend towards a significant decrease was seen throughout the brain. The decrease of [(11)C]verapamil uptake correlates with an increased activity of the P-gp pump. Increased P-gp activity may be a factor in drug resistance in schizophrenia, induced by the use of antipsychotic agents.

The differential diagnosis of neurodegenerative brain diseases on clinical grounds is difficult, especially at an early disease stage. Several studies have found specific regional differences of brain metabolism applying [(18)F]-fluoro-deoxyglucose positron emission tomography (FDG-PET), suggesting that this method can assist in early differential diagnosis of neurodegenerative brain diseases.We have studied patients who had an FDG-PET scan on clinical grounds at an early disease stage and included those with a retrospectively confirmed diagnosis according to strictly defined clinical research criteria. Ninety-six patients could be included of which 20 patients with Parkinson's disease (PD), 21 multiple system atrophy (MSA), 17 progressive supranuclear palsy (PSP), 10 corticobasal degeneration (CBD), 6 dementia with Lewy bodies (DLB), 15 Alzheimer's disease (AD), and 7 frontotemporal dementia (FTD). FDG PET images of each patient group were analyzed and compared to18 healthy controls using Statistical Parametric Mapping (SPM5).Disease-specific patterns of relatively decreased metabolic activity were found in PD (contralateral parietooccipital and frontal regions), MSA (bilateral putamen and cerebellar hemispheres), PSP (prefrontal cortex and caudate nucleus, thalamus, and mesencephalon), CBD (contralateral cortical regions), DLB (occipital and parietotemporal regions), AD (parietotemporal regions), and FTD (frontotemporal regions).The integrated method addressing a spectrum of various neurodegenerative brain diseases provided means to discriminate patient groups also at early disease stages. Clinical follow-up enabled appropriate patient inclusion. This implies that an early diagnosis in individual patients can be made by comparing each subject's metabolic findings with a complete database of specific disease related patterns.

Background Assessment of left ventricular (LV) ejection fraction (LVEF) and LV volume are essential for the evaluation of prognosis in cardiac disease. LVEF and LV volumes can be measured with several imaging modalities, such as magnetic resonance imaging (MRI) or computed tomography; however, these are relatively expensive and time consuming. In contrast, planar radionuclide ventriculography (PRV) for LVEF assessment is a cost-effective, fast, and reliable technique, but PRV for LV volumes calculation is less common.Aim Evaluation of a new hybrid geometrical count-based method (HGCBM) in comparison with two count-based methods (CBMs) and a geometrical method (GM) for the calculation of LV volumes with PRV using MRI as reference.Methods Thirty cardiac patients underwent routine PRV with a standard dose of 500 MBq of (99m)Tc-pertechnetate and additional cardiac MRI as reference method. LV volumes of PRV data were calculated by four different methods. The CBMs and GM are based on the assumption that the shape of the LV can be approximated by an ellipsoid or sphere, and the new HGCBM extracts the volume from the projected count rates themselves.Results All methods underestimated the LV volumes as compared with the MRI-measured volumes. The difference (mean +/- SD) of end-diastolic volume (EDV) between PRV and MRI was 33 +/- 23 ml for GM, 12 +/- 26 ml for HGCBM, 50 +/- 38 ml for CBM1, and 13 +/- 40 ml for CBM2. The correlation coefficients for EDV between PRV methods and MRI were r = 0.90 for GM and r = 0.85 for HGCBM. The CBMs showed poor correlation r = 0.64 with the MRI data and a high SD. The difference of end-systolic volume (ESV) between PRV and MRI was 23 +/- 19 ml for GM, 9 +/- 22 ml for HGCBM, 29 +/- 29 ml for CBM1, and 9 +/- 28 ml for CBM2. The correlation coefficients for ESV between PRV methods and MRI were r = 0.955 for GM and r = 0.914 for HGCBM, r = 0.85 for CBM1 and CBM2. Although GM showed a slightly higher correlation than HGCBM, the difference of EDV and ESV between PRV and MRI was much higher for GM in comparison with HGCBM. Both CBMs showed poor agreement with MRI data.Conclusion PRV using the new HGCMB method in comparison with other methods is an easy and accurate method to determine LV volumes. However, all methods underestimate ESV and EDV slightly as compared with MRI. Nucl Med Commun 30:727-735 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.

The aetiology of depressive disorder remains unknown, although genetic susceptibility and exposure to neurotoxins are currently being discussed as possible contributors to this disorder. In normal circumstances, the brain is protected against bloodborne toxic influences by the blood-brain barrier, which includes the molecular efflux pump P-glycoprotein (P-gp) in the vessel wall of brain capillaries. We hypothesized that P-gp function in the blood-brain barrier is changed in patients with major depression. Positron emission tomography Was used to measure brain uptake of [C-11]verapamil, which is normally expelled from the brain by P-gp. Cerebral Volume of distribution (V-T) of [C-11]verapamil was used as a measure of P-gp function. Both region-of-interest (ROI) analysis and voxel analysis using statistical parametric mapping (SPM2) were performed to assess regional brain P-gp function. We found that patients with a major depressive episode, using antidepressants, compared to health), controls showed a significant decrease of [C-11]verapamil uptake in different areas throughout the brain, in particular in frontal and temporal regions. The decreased [C-11]verapamil uptake correlates with an increased function of the P-gp protein and may be related to chronic use of psychotropic drugs, Our results may explain why treatment-resistant depression can develop.

Contains fulltext : 70810.pdf (Publisher’s version ) (Closed access) INTRODUCTION: Several studies have shown the usefulness of positron emission tomography (PET) quantification using standardised uptake values (SUV) for diagnosis and staging, prognosis and response monitoring. Many factors affect SUV, such as patient preparation procedures, scan acquisition, image reconstruction and data analysis settings, and the variability in methodology across centres prohibits exchange of SUV data. Therefore, standardisation of 2-[(18)F] fluoro-2-deoxy-D-glucose (FDG) PET whole body procedures is required in multi-centre trials. METHODS: A protocol for standardisation of quantitative FDG whole body PET studies in the Netherlands (NL) was defined. This protocol is based on standardisation of: (1) patient preparation; (2) matching of scan statistics by prescribing dosage as function of patient weight, scan time per bed position, percentage of bed overlap and image acquisition mode (2D or 3D); (3) matching of image resolution by prescribing reconstruction settings for each type of scanner; (4) matching of data analysis procedure by defining volume of interest methods and SUV calculations and; (5) finally, a multi-centre QC procedure is defined using a 20-cm diameter phantom for verification of scanner calibration and the NEMA NU 2 2001 Image Quality phantom for verification of activity concentration recoveries (i.e., verification of image resolution and reconstruction convergence). DISCUSSION: This paper describes a protocol for standardization of quantitative FDG whole body multi-centre PET studies. CONCLUSION: The protocol was successfully implemented in the Netherlands and has been approved by the Netherlands Society of Nuclear Medicine.

Objective The aim of this study was to evaluate the value of attenuation correction (AC) of Tc-99m tetrofosmin single-photon emission tomography (SPECT) imaging for the assessment of left ventricular ejection fraction (LVEF).Methods Attenuation corrected and non-attenuation corrected (NC) resting Tc-99m tetrofosmin SPECT were compared for the assessment of LVEF. Planar multi-gated radionuclide angiography (MUGA) served as the reference for LVEF assessment. Patients (n = 56) with left ventricular dysfunction who underwent MUGA and rest gated Tc-99m tetrofosmin SPECT within I month were included.Results The average LVEF on NC gated SPECT was 37.4 +/- 11.8% and on AC SPECT 38.5 +/- 13.4% (P = NS). The absolute mean difference of the LVEF between the MUGA and NC gated SPECT and AC gated SPECT was -0.2% (95% CI -1.7 to 1.3) and -1.3% (95% Cl -2.7 to 0.03), respectively (P = NS both vs. MUGA). The correlation between NC gated SPECT and AC gated SPECT versus MUGA measurement was high with a correlation coefficient of 0.89 (P Conclusions Profile AC gated Tc-99m tetrofosmin SPECT agrees well with MUGA and NC gated Tc-99m tetrofosmin SPECT for the assessment of LVEF. EDVs and ESVs are significantly higher with AC gated SPECT when compared with NC gated SPECT.

In the last few decades functional neuroimaging tools have emerged to study the function of the human brain in vivo. These techniques have increased the knowledge of how the brain processes stimuli of different sensory modalities, including auditory processing. Positron emission tomography (PET) has been used for nearly 20 years to study changes in cerebral blood flow associated with auditory stimulation in normal and hearing impaired subjects. PET studies gave insight into the neural base of processing basic sound features such as frequency and intensity, but complex stimuli such as speech and music have also been investigated extensively. Knowledge of the normal auditory function of the brain helps us to understand the neural base of hearing deficits and provides ideas for possible treatments. Although functional magnetic resonance imaging (fMRI) is replacing PET in many neuroimaging studies nowadays, PET still holds unique advantages and can give us valuable knowledge about the auditory cortex and auditory perception.