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Purpose Different pharmacokinetic methods for [18F]FDDNP studies were evaluated using both simulations and clinical data. Procedures Methods included two-tissue reversible plasma (2T4k), simplified reference tissue input (SRTM), and a modified 2T4k models. The latter included an additional compartment for metabolites (2T1M). For plasma input models, binding potential, BPND, was obtained both directly (=k3/k4) and indirectly (using volume of distribution ratios). Results For clinical data, 2T1M was preferred over 2T4k according to Akaike criterion. Indirect BPND using 2T1M correlated better with SRTM then direct BPND. Fairly constant volume of distribution of metabolites was found across brain and across subjects, which was strongly related to bias in BPND obtained from SRTM as seen in simulations. Furthermore, in simulations, SRTM showed constant bias with best precision if metabolites entered brain. Conclusions SRTM is the method of choice for quantitative analysis of [18F]FDDNP even if it is unclear whether labeled metabolites enter the brain.

Background— Cardiac disease is the leading cause of mortality in type 2 diabetes mellitus (T2DM). Pioglitazone has been associated with improved cardiac outcome but also with an elevated risk of heart failure. We determined the effects of pioglitazone on myocardial function in relation to cardiac high-energy phosphate, glucose, and fatty acid metabolism and triglyceride content in T2DM patients. Methods and Results— Seventy-eight T2DM men without structural heart disease or inducible ischemia as assessed by dobutamine stress echocardiography were assigned to pioglitazone (30 mg/d) or metformin (2000 mg/d) and matching placebo for 24 weeks. The primary end point was change in cardiac diastolic function from baseline relative to myocardial metabolic changes, measured by magnetic resonance imaging, proton and phosphorus magnetic resonance spectroscopy, and [ 18 F]-2-fluoro-2-deoxy- d -glucose and [ 11 C]palmitate positron emission tomography. No patient developed heart failure. Both therapies similarly improved glycemic control, whole-body insulin sensitivity, and blood pressure. Pioglitazone versus metformin improved the early peak flow rate ( P =0.047) and left ventricular compliance. Pioglitazone versus metformin increased myocardial glucose uptake ( P P =0.006), a change that was paralleled by a reduced myocardial glucose uptake and fatty acid oxidation. Neither treatment affected cardiac high-energy phosphate metabolism or triglyceride content. Only pioglitazone reduced hepatic triglyceride content ( P Conclusions— In T2DM patients, pioglitazone was associated with improvement in some measures of left ventricular diastolic function, myocardial glucose uptake, and whole-body insulin sensitivity. The functional changes, however, were not associated with myocardial substrate and high-energy phosphate metabolism.

This study was designed to evaluate myocardial substrate and high-energy phosphate (HEP) metabolism in asymptomatic men with well-controlled, uncomplicated type 2 diabetes with verified absence of cardiac ischemia, and age-matched control subjects, and to assess the association with myocardial function.Metabolic abnormalities, particularly an excessive exposure of the heart to circulating nonesterified fatty acids and myocardial insulin resistance are considered important contributors to diabetic cardiomyopathy in animal models of diabetes. The existence of myocardial metabolic derangements in uncomplicated human type 2 diabetes and their possible contribution to myocardial dysfunction still remain undetermined.In 78 insulin-naive type 2 diabetes men (age 56.5 +/- 5.6 years, body mass index 28.7 +/- 3.5 kg/m(2), glycosylated hemoglobin A(1c) 7.1 +/- 1.0%; expressed as mean +/- SD) without cardiac ischemia and 24 normoglycemic control subjects (age 54.5 +/- 7.1 years, body mass index 27.0 +/- 2.5 kg/m(2), glycosylated hemoglobin A(1c) 5.3 +/- 0.2%), we assessed myocardial left ventricular (LV) function by magnetic resonance imaging, and myocardial perfusion and substrate metabolism by positron emission tomography using H(2)(15)O, carbon (11)C-palmitate, and 18-fluorodeoxyglucose 2-fluoro-2-deoxy-D-glucose. Cardiac HEP metabolism was assessed by phosphorous P 31 magnetic resonance spectroscopy.In patients, compared with control subjects, LV diastolic function (E/A ratio: 1.04 +/- 0.25 vs. 1.26 +/- 0.36, p = 0.003) and myocardial glucose uptake (260 +/- 128 nmol/ml/min vs. 348 +/- 154 nmol/ml/min, p = 0.015) were decreased, whereas myocardial nonesterified fatty acid uptake (88 +/- 31 nmol/ml/min vs. 68 +/- 18 nmol/ml/min, p = 0.021) and oxidation (85 +/- 30 nmol/ml/min vs. 63 +/- 19 nmol/ml/min, p = 0.007) were increased. There were no differences in myocardial HEP metabolism or perfusion. No association was found between LV diastolic function and cardiac substrate or HEP metabolism.Patients versus control subjects showed impaired LV diastolic function and altered myocardial substrate metabolism, but unchanged HEP metabolism. We found no direct relation between cardiac diastolic function and parameters of myocardial metabolism.

Positron emission tomography (PET) is a powerful tool for imaging and quantifying (patho)physiological processes in the human body. PET has been successfully used for staging diseases and evaluating response to treatment. Furthermore, PET may contribute to drug development and individualized treatment planning. This article reviews the use of several PET tracers in drug development and their clinical application in the fields of neurology, oncology and cardiology.

PURPOSE: NK1 receptors have been implicated in various neuropsychiatric and other disorders. R116301 is a selective NK1 receptor antagonist. In this pilot study, [(11)C]R116301 was evaluated as a potential positron emission tomography (PET) ligand for the NK1 receptor. PROCEDURES: Two dynamic PET studies were performed in three normal volunteers before and after a blocking dose of aprepitant. Data were analyzed using striatum to cerebellum standardized uptake value (SUV) ratios. RESULTS: Baseline SUV ratios at 60-90 min after injection ranged from 1.22 to 1.70. Following aprepitant administration, this specific signal was completely blocked. Aprepitant administration did not significantly affect uptake in cerebellum, confirming the absence of NK1 receptors in cerebellum. CONCLUSION: These preliminary results indicate that [(11)C]R116301 has potential as a radioligand for in vivo assessment of NK1 receptors in the human brain

[(18)F]FDDNP is a positron emission tomography (PET) tracer for determining amyloid plaques and neurofibrillary tangles in the brain in vivo. In order to quantify binding of this tracer properly, a metabolite-corrected plasma input function is required. The purpose of the present study was to develop a sensitive method for measuring [(18)F]FDDNP and its radiolabelled metabolites in plasma. The second aim was to assess whether these radiolabelled metabolites enter the brain. In humans, there was extensive metabolism of [(18)F]FDDNP. After 10 min, more than 80% of plasma radioactivity was identified as polar (18)F-labelled fragments, probably formed from N-dealkylation of [(18)F]FDDNP. These labelled metabolites were reproduced in vitro using human hepatocytes. PET studies in rats showed that these polar metabolites can penetrate the blood-brain barrier and result in uniform brain uptake.

[11C]Palmitate PET can be used to study myocardial fatty acid metabolism in vivo. Several models have been applied to describe and quantify its kinetics, but to date no systematic analysis has been performed to define the most suitable model. In this study a total of 21 plasma input models comprising one to three compartments and up to six free rate constants were compared using statistical analysis of clinical data and simulations. To this end, 14 healthy volunteers were scanned using [11C]palmitate, whilst myocardial blood flow was measured using H2 15O. Models including an oxidative pathway, representing production of 11CO2, provided significantly better fits to the data than other models. Model robustness was increased by fixing efflux of 11CO2 to the oxidation rate. Simulations showed that a three-tissue compartment model describing oxidation and esterification was feasible when no more than three free rate constants were included. Although further studies in patients are required to substantiate this choice, based on the accuracy of data description, the number of free parameters and generality, the three-tissue model with three free rate constants was the model of choice for describing [11C]palmitate kinetics in terms of oxidation and fatty acid accumulation in the cell.

The High Resolution Research Tomograph (HRRT) is a dedicated human brain positron emission tomography (PET) scanner. The aim of the present study was to validate the use of image derived input functions (IDIF) as an alternative for arterial sampling for HRRT human brain studies. To this end, IDIFs were extracted from 3D ordinary Poisson ordered subsets expectation maximization (OP-OSEM) and reconstruction based partial volume corrected (PVC) OP-OSEM images. IDIFs, either derived directly from regions of interest or further calibrated using manual samples taken during scans, were evaluated for dynamic [ 11 C]flumazenil data ( n = 6). Results obtained with IDIFs were compared with those obtained using blood sampler input functions (BSIF). These comparisons included areas under the curve (AUC) for peak (0–3.3 min) and tail (3.3–55.0 min). In addition, slope, intercept and Pearson's correlation coefficient of tracer kinetic analysis results based on IDIF and BSIF were calculated for each subject. Good peak AUC ratios (0.83 ± 0.21) between IDIF and BSIF were found for calibrated IDIFs extracted from OP-OSEM images. This combination of IDIFs and images also provided good slope values (1.07 ± 0.11). Improved resolution, as obtained with PVC OP-OSEM, changed AUC ratios to 1.14 ± 0.35 and, for tracer kinetic analysis, slopes changed to 0.95 ± 0.13. For all reconstructions, non-calibrated IDIFs gave poorer results (> 61 ± 34% higher slopes) compared with calibrated IDIFs. The results of this study indicate that the use of IDIFs, extracted from OP-OSEM or PVC OP-OSEM images, is feasible for dynamic HRRT data, thereby obviating the need for online arterial sampling.

Extraction of arterial input functions from dynamic brain scans may obviate the need for arterial sampling and would increase the clinical applicability of quantitative PET studies. The aim of the present study was to evaluate applicability and accuracy of image derived input functions (IDIFs) following reconstruction based partial volume correction (PVC). Settings for the PVC ordered subset expectation maximization (PVC-OSEM) reconstruction algorithm were varied. In addition, different methods for defining arterial regions of interest (ROI) in order to extract IDIFs were evaluated. [(11)C]flumazenil data of 10 subjects were used in the present study. Results obtained with IDIFs were compared with those using standard on-line measured arterial input functions. These included areas under the curve (AUC) for peak (1-2 min) and tail (2-60 min), volume of distribution (V(T)) obtained using Logan analysis, and V(T) and K(1) obtained with a basis function implementation of a single tissue compartment model. Best results were obtained with PVC-OSEM using 4 iterations and 16 subsets. Based on (11)C point source measurements, a 4.5 mm FWHM (full width at half maximum) resolution kernel was used to correct for partial volume effects. A ROI consisting of the four hottest pixels per plane (over the carotid arteries) was the best method to extract IDIFs. Excellent peak AUC ratios (0.99+/-0.09) between IDIF and blood sampler input function (BSIF) were found. Furthermore, extracted IDIFs provided V(T) and K(1) values that were very similar to those obtained using BSIFs. The proposed method appears to be suitable for analysing [(11)C]flumazenil data without the need for online arterial sampling.

Purpose (R)-[C-11]verapamil is a new PET tracer for P-glycoprotein-mediated transport at the blood-brain barrier. For kinetic analysis of (R)-[C-11]verapamil PET data the measurement of a metabolite-corrected arterial input function is required. The aim of this study was to assess peripheral (R)-[C-11]verapamil metabolism in patients with temporal lobe epilepsy and compare these data with previously reported data from healthy volunteers.Methods Arterial blood samples were collected from eight patients undergoing (R)-[C-11]verapamil PET and selected samples were analysed for radiolabelled metabolites of (R)-[C-11]verapamil by using an assay that measures polar N-demethylation metabolites by solid-phase extraction and lipophilic N-dealkylation metabolites by HPLC.Results Peripheral metabolism of (R)-[C-11]verapamil was significantly faster in patients compared to healthy volunteers (AUC of (R)-[C-11]verapamil fraction in plasma: 29.4 +/- 3.9 min for patients versus 40.8 +/- 5.0 min for healthy volunteers; p Conclusions Faster metabolism of (R)-[C-11]verapamil in epilepsy patients may be caused by hepatic cytochrome P450 enzyme induction by antiepileptic drugs. Based on these data caution is warranted when using an averaged arterial input function derived from healthy volunteers for the analysis of patient data. Moreover, our data illustrate how antiepileptic drugs may decrease serum levels of concomitant medication, which may eventually lead to a loss of therapeutic efficacy.

The cause of Parkinson's disease (PD) is unknown. Genetic susceptibility and exposure to environmental toxins contribute to specific neuronal loss in PD. Decreased blood-brain barrier (BBB) P-glycoprotein (P-gp) efflux function has been proposed as a possible causative link between toxin exposure and PD neurodegeneration.In the present study BBB P-gp function was investigated in viva in 10 early stage PD patients and 8 healthy control subjects using (R)-[C-11]-verapamil and PET. Cerebral volume of distribution (V-d) of verapamil was used as measure of P-gp function. Both region of interest (ROI) analysis and voxel analysis using statistical parametric mapping (SPM) were performed to assess regional brain P-gp function. In addition, MDR1 genetic polymorphism was assessed.In the present study, a larger variation in V-d of (R)-[C-11]-verapamil was seen in the PD group as compared to the control group. However, decreased BBB P-gp function in early stage PD patients could not be confirmed. (C) 2008 Elsevier Ltd. All rights reserved.

Learning Objectives After completing this course, the reader will be able to: Discuss the principles of perfusion imaging with H215O-PET and DCE-MRI.Compare the differences between and the limitations of the two methods.Critically review publications on the use of both methods in monitoring response to anticancer therapy. CME This article is available for continuing medical education credit at CME.TheOncologist.com Positron emission tomography (PET) with H215O and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) provide noninvasive measurements of tumor blood flow. Both tools offer the ability to monitor the direct target of antiangiogenic treatment, and their use is increasingly being studied in trials evaluating such drugs. Antiangiogenic therapy offers great potential and, to an increasing extent, benefit for oncological patients in a variety of palliative and curative settings. Because this type of targeted therapy frequently results in consolidation of the tumor mass instead of regression, monitoring treatment response with the standard volumetric approach (Response Evaluation Criteria in Solid Tumors) leads to underestimation of the response rate. Monitoring direct targets of anticancer therapy might be superior to indirect size changes. In addition, measures of tumor blood flow contribute to a better understanding of tumor biology. This review shows that DCE-MRI and H215O-PET provide reliable measures of tumor perfusion, provided that a certain level of standardization is applied. Heterogeneity in scan acquisition and data analysis complicates the interpretation of study results. Also, limitations inherent to both techniques must be considered when interpreting DCE-MRI and H215O-PET results. This review focuses on the technical and physiological aspects of both techniques and aims to provide the essential information necessary to critically evaluate the use of DCE-MRI and H215O-PET in an oncological setting.

Inflammation in Alzheimer's disease (AD) may be assessed using ( R)-[11C]PK11195 and positron emission tomography. Data can be analyzed using the simplified reference tissue model, provided a suitable reference region is available. This study evaluates various reference regions for analyzing ( R)-[11C]PK11195 scans in patients with mild cognitive impairment (MCI) and probable AD. Healthy subjects ( n = 10, 30 ± 10 years and n = 10, 70 ± 6 years) and patients with MCI ( n = 10, 74 ± 6 years) and probable AD ( n = 9, 71 ± 6 years) were included. Subjects underwent a dynamic three-dimensional ( R)-[11C]PK11195 scan including arterial sampling. Gray matter, white matter, total cerebellum and cerebrum, and cluster analysis were evaluated as reference regions. Both plasma input binding potentials of these reference regions ( BPPLASMA) and corresponding reference region input binding potentials of a target region ( BPSRTM) were evaluated. Simulations were performed to assess cluster analysis performance at 5% to 15% coefficient of variation noise levels. Reasonable correlations for BPPLASMA ( R2 = 0.52 to 0.94) and BPSRTM ( R2 = 0.59 to 0.76) were observed between results using anatomic regions and cluster analysis. For cerebellum white matter, cerebrum white matter, and total cerebrum a considerable number of unrealistic BPSRTM values were observed. Cluster analysis did not extract a valid reference region in 10% of the scans. Simulations showed that potentially cluster analysis suffers from negative bias in BPPLASMA. Most anatomic regions outperformed cluster analysis in terms of absence of both scan rejection and bias. Total cerebellum is the optimal reference region in this patient category.

IMPORTANCE: Serotonin is involved in negative affect, but whether anxiety syndromes, such as social anxiety disorder (SAD), are characterized by an overactive or underactive serotonin system has not been established. Serotonin 1A autoreceptors, which inhibit serotonin synthesis and release, are downregulated in SAD, and serotonin transporter availability might be increased; however, presynaptic serotonin activity has not been evaluated extensively.OBJECTIVE: To examine the serotonin synthesis rate and serotonin transporter availability in patients with SAD and healthy control individuals using positron emission tomography (PET) with the radioligands 5-hydroxytryptophan labeled with carbon 11 ([11C]5-HTP) and 11C-labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile [11C]DASB.DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional study at an academic clinical research center. Eighteen patients with SAD (9 men and 9 women; mean [SD] age, 32.6 [8.2] years) and 18 sex- and age-matched healthy controls (9 men and 9 women; mean [SD] age, 34.7 [9.2] years) underwent [11C]5-HTP PET imaging. We acquired [11C]DASB PET images for 26 additional patients with SAD (14 men and 12 women; mean [SD] age, 35.2 [10.7] years) and the same 18 sex- and age-matched healthy controls. Participants were recruited through newspaper advertisements. Data were acquired from March 12, 2002, through March 5, 2012, and analyzed from March 28, 2013, through August 29, 2014.MAIN OUTCOMES AND MEASURES: The influx rate of [11C]5-HTP as a measure of serotonin synthesis rate capacity and [11C]DASB binding potential as an index of serotonin transporter availability were acquired during rest. We used the Liebowitz Social Anxiety Scale to measure severity of social anxiety symptoms.RESULTS: The PET data were not available for analysis in 1 control for each scan. Increased [11C]5-HTP influx rate was observed in the amygdala, raphe nuclei region, caudate nucleus, putamen, hippocampus, and anterior cingulate cortex of patients with SAD compared with healthy controls (P < .05 corrected), supporting an enhanced serotonin synthesis rate. Increased serotonin transporter availability in the patients with SAD relative to healthy controls was reflected by elevated [11C]DASB binding potential in the raphe nuclei region, caudate nucleus, putamen, thalamus, and insula cortex (P < .05 corrected).CONCLUSIONS AND RELEVANCE: Neurotransmission in SAD is characterized by an overactive presynaptic serotonin system, with increased serotonin synthesis and transporter availability. Our findings could provide important new insights into the etiology of anxiety disorders.

Non-invasive determination of HER2-expression in metastatic breast cancer by using Ga-68-ABY025 PET/CT.

Radiation dosimetry of thyroid cancer therapy with 131I can be performed by coadministration of 124I followed by longitudinal PET scans over several days. The photons emitted by 131I may affect PET image quality. The aim of this study was to assess the influence of large amounts of 131I on PET image quality and accuracy with various acquisition settings.Noise equivalent count (NEC) rates of 124I only were measured with a standard clinical PET scanner. Apart from the standard 350- to 650-keV energy window, 425- to 650-keV and 460- to 562-keV windows were used and data were acquired both with (2-dimensional) and without (3-dimensional [3D]) septa. A phantom containing 6 hot spheres, filled with a combination of 131I and 124I and with a sphere-to-background ratio of 18:1, was scanned repeatedly with energy window settings as indicated and emission and transmission scan durations of 7 and 3 min, respectively. NEC rates were calculated and compared with those measured with the phantom filled with only 124I. Sphere-to-background ratios in the reconstructed images were determined. One patient with known metastatic thyroid cancer was scanned using energy window settings and scan times as indicated 3 and 6 d after administration of 5.5 GBq of 131I and 75 MBq of 124I.The highest 124I-only NEC rates were obtained using a 425- to 650-keV energy window in 3D mode. In the presence of (131)I, the settings giving the highest NEC rate and contrast were 425-650 keV and 460-562 keV in 3D mode, with the clinical scans giving the highest quality images with the same settings.Acquisition in 3D mode with a 425- to 650-keV or 460- to 562-keV window leads to the highest image quality and contrast when imaging 124I in the presence of large amounts of 131I using a standard clinical PET scanner.

Several long-lived positron emitters, such as /sup 76/Br(t/sub 1/2/=16.2 h, 55% /spl beta//sup +/) and /sup 124/I(t/sub 1/2/=4.2 d, 23% /spl beta//sup +/, emit photons simultaneously with positrons. Coincidence detection of these photons with each other or with annihilation photons leads to essentially true coincidences that can not be distinguished from coincidences involving two annihilation photons. These photons also lead to higher singles count rates and thus to a higher dead time. Furthermore, photons that are rejected by the energy discriminator, the number of which is considerably increased for prompt gamma emitting nuclides, are not counted as singles but do contribute to dead time and lead to inaccuracy of the standard dead time correction. The aim of the present study was to assess the effect of additional gamma radiation on dead time correction accuracy and to improve the existing dead time correction for prompt gamma emitting nuclides. Singles life time as a function of singles rate is lower for /sup 76/Br than for /sup 18/F, whereas coincidence life times are similar. Total dead time for /sup 76/Br is considerably increased compared to /sup 11/C for similar singles count rates. Multiplication of the measured /sup 76/Br singles rate with a fixed factor of 1.3 leads to a similar dead time as a function of singles rate as for /sup 11/C and in an accurate prediction of the total dead time by the standard dead time correction. Multiplication factors for different energy windows correlate well with the relative number of rejected photons.

BackgroundPositron emission tomography (PET) is a powerful imaging technique with the potential of obtaining functional or biochemical information by measuring distribution and kinetics of radiolabelled molecules in a biological system, bothin vitroandin vivo. PET images can be used directly or after kinetic modelling to extract quantitative values of a desired physiological, biochemical or pharmacological entity. Because such images are generally noisy, it is essential to understand how noise affects the derived quantitative values. A pre-requisite for this understanding is that the properties of noise such as variance (magnitude) and texture (correlation) are known.MethodsIn this paper we explored the pattern of noise correlation in experimentally generated PET images, with emphasis on the angular dependence of correlation, using the autocorrelation function (ACF). Experimental PET data were acquired in 2D and 3D acquisition mode and reconstructed by analytical filtered back projection (FBP) and iterative ordered subsets expectation maximisation (OSEM) methods. The 3D data was rebinned to a 2D dataset using FOurier REbinning (FORE) followed by 2D reconstruction using either FBP or OSEM. In synthetic images we compared the ACF results with those from covariance matrix. The results were illustrated as 1D profiles and also visualized as 2D ACF images.ResultsWe found that the autocorrelation images from PET data obtained after FBP were not fully rotationally symmetric or isotropic if the object deviated from a uniform cylindrical radioactivity distribution. In contrast, similar autocorrelation images obtained after OSEM reconstruction were isotropic even when the phantom was not circular. Simulations indicated that the noise autocorrelation is non-isotropic in images created by FBP when the level of noise in projections is angularly variable. Comparison between 1D cross profiles on autocorrelation images obtained by FBP reconstruction and covariance matrices produced almost identical results in a simulation study.ConclusionWith asymmetric radioactivity distribution in PET, reconstruction using FBP, in contrast to OSEM, generates images in which the noise correlation is non-isotropic when the noise magnitude is angular dependent, such as in objects with asymmetric radioactivity distribution. In this respect, iterative reconstruction is superior since it creates isotropic noise correlations in the images.

An important application of quantitative imaging in nuclear medicine is the estimation of absorbed doses in radionuclide therapy. Depending on the radionuclide used for therapy, quantitative imaging of the kinetics of the therapeutic radiopharmaceutical could be done using planar imaging, SPECT or PET. Since many nuclear medicine departments have a gamma camera system that is also suitable for coincidence imaging, the performance of these systems with respect to quantitative imaging of PET isotopes that could be of use in radionuclide dosimetry is of interest. We investigated the performance of a gamma camera with coincidence imaging capabilities with 99mTc, 111In, 18F and 76Br and a dedicated PET system with 18F and 76Br, using a single standard set of phantom measurements. Here, 76Br was taken as a typical example of prompt gamma-emitting PET isotopes that are applicable in radionuclide therapy dosimetry such as 86Y and 124I. Image quality measurements show comparable image contrasts for 76Br coincidence imaging and 111In SPECT. Although the spatial resolution of coincidence imaging is better than single photon imaging, the contrast obtained with 76Br is not better than that with 99mTc or 111In because of the prompt gamma involved. Additional improvements are necessary to allow for quantitative coincidence imaging of long-lived, prompt gamma producing positron emitters.

The aim of this work was to compare the quantitative accuracy of iteratively reconstructed cardiac (18)F-FDG PET with that of filtered backprojection for both 2-dimensional (2D) and 3-dimensional (3D) acquisitions and to establish an optimal procedure for imaging myocardial viability with (18)F-FDG PET.Eight patients underwent dynamic cardiac (18)F-FDG PET using an interleaved 2D/3D scan protocol, enabling comparison of 2D and 3D acquisitions within the same patient and study. A 10-min transmission scan was followed by a 10-min, 25-frame dynamic 3D scan and then by a series of 10 alternating 5-min 3D and 2D scans. Images were reconstructed with filtered backprojection (FBP) or attenuation-weighted ordered-subsets expectation maximization (OSEM), combined with Fourier rebinning (FORE) for 3D acquisitions, applying all usual corrections. Regions of interest (ROIs) were drawn in the myocardium, left ventricle, and ascending aorta, with the last 2 being used to define image-derived input functions (IDIFs). Patlak graphical analysis was used to compare net (18)F-FDG uptake in the myocardium, calculated from either 2D or 3D data, after reconstruction with FBP or OSEM. Either IDIFs or arterial sampling was used as the input function. The same analysis was performed on parametric images.A good correlation (r(2)0.99) was found between net (18)F-FDG uptake values for a myocardium ROI determined using each acquisition and reconstruction method and blood-sampling input functions. A similar result was found for parametric images. The ascending aorta was the best choice for IDIF definition.Good correlation and no bias of net (18)F-FDG uptake in relation to that based on FBP images, combined with less image noise, make 3D acquisition with FORE plus attenuation-weighted OSEM reconstruction the preferred choice for cardiac (18)F-FDG PET studies.

Parenteral iron-polysaccharide complexes are increasingly applied. The pharmacokinetics of iron sucrose have been assessed by our group using positron emission tomography (PET). A single intravenous injection of 100 mg iron as iron (III) hydroxide-polymaltose complex, labelled with a tracer in the form of 52Fe/59Fe, was similarly assessed in six patients using PET for about 8 h. Red cell utilization was followed for 4 weeks. Iron polymaltose was similarly distributed to the liver, spleen and bone marrow. However, a larger proportion of this complex was rapidly distributed to the bone marrow. The shorter equilibration phase for the liver, about 25 min, indicates the minimal role of the liver for direct distribution. Splenic uptake also reflected the reticuloendothelial handling of this complex. Red cell utilization ranged from 61% to 99%. Despite the relatively higher uptake by the bone marrow, there was no saturation of marrow transport systems at this dose level. In conclusion, high red cell utilization of iron polymaltose occurred in anaemic patients. The major portion of the injected dose was rapidly distributed to the bone marrow. In addition, the reticuloendothelial uptake of this complex may reflect the safety of polysaccharide complexes. Non-saturation of transport systems to the bone marrow indicated the presence of a large interstitial transport pool, which might possibly be transferrin.

Several positron emitting nuclides with applications in PET, such as 76Br, 124I, 110In and 86Y, also emit gamma radiation in their decays. Measured coincidences between annihilation photons and this cascade gamma radiation are essentially true coincidences and the standard PET corrections do not account for them. We investigated the performance of 76Br in 2D and 3D PET, the effect of the gamma radiation emitted by 76Br on quantitative accuracy and the distribution of cascade gamma radiation coincidences in 2D and 3D PET sinograms. A correction method for cascade gamma radiation coincidences was implemented and evaluated. Count rate linearity was affected by the gamma radiation from the 76Br decay. Spatial resolution and sphere recovery were slightly worse for 76Br compared to 18F. Correction for cascade gamma radiation coincidences by subtraction of a linear projection tail fit improved total correction accuracy to similar values as for positron-only emitters such as 18F, and improved image contrast significantly.

The somatostatin analog diethylenetriaminepentaacetic acid (DTPA)-D-Phe1-octreotide labeled with 111In has been applied extensively for diagnosis of neuroendocrine tumors using SPECT or planar scintigraphy. However, the spatial resolution of planar scintigraphy and SPECT prohibits imaging of small tumors, and the quantification accuracy of both methods is limited.We developed a method to prepare the positron-emitting radiopharmaceutical 110mIn-DTPA-D-Phe1-octreotide based on a commercially available kit. Phantom studies were done to investigate and compare the performance of 110mIn PET and 111In SPECT. A clinical imaging study using 110mIn-DTPA-D-Phe1-octreotide and PET was done to investigate the application of this radiopharmaceutical.An almost 3-fold better resolution and much better quantitative capabilities were found for 110mIn PET than for 111In SPECT. The clinical imaging study demonstrated the potential use of 110mIn-octreotide in PET to image tumors and quantify radioactivity uptake in humans using (110m)In-DTPA-D-Phe1-octreotide.PET with 110mIn-DTPA-D-Phe1-octreotide greatly improved detection of small tumors and offers a possibility of more accurate quantification of tumor uptake than can be obtained with 111In-DTPA-D-Phe1-octreotide and SPECT.

Dear Sir, With interest we read the study by Cho et al [1], evaluating the usefulness of FDG PET/CT for differentiating malignant endobronchial lesions with distal atelectasis from benign bronchial stenosis. In this retrospective study, they adequately demonstrated the additional value of FDG PET/CT in this challenging clinical problem. Besides differentiation of endobronchial lesions, accurate discrimination between malignant tumours and atelectatic lung tissue can facilitate the definition of radiotherapy target volumes. As a result, the size of radiotherapy fields can be decreased [2], potentially reducing radiotherapy-induced side-effects. For these purposes, the PET technique may be of additional value to discriminate the obstructive lesion from the atelectatic lung tissue. Although Cho et al [1] mentioned different patterns of FDG uptake in atelectatic lung tissue, we wonder whether the FDG uptake in the obstructive lesions could be adequately distinguished from the FDG uptake in the atelectatic lung tissue. As FDG uptake is dependent on perfusion for its delivery to tissue, variation in tissue vascularity may contribute to variable FDG uptake in obstructive atelectasis. In a previous PET/CT study, we quantified tumour perfusion in lung cancer patients using radiolabelled water ([15O]H2O) [3]. The measured perfusion values in atelectatic lung tissue differed significantly as compared with perfusion values in malignant tumours. Figure 1 shows an example of a patient with relatively high perfusion in atelectatic lung tissue as compared with the malignant tumour. These observations suggest that perfusion measurements may have additional value to discriminate atelectatic lung tissue from malignant lesions. Therefore, we believe that additional perfusion measurements of atelectatic lung tissue may improve diagnosis and radiotherapy planning of malignant endobronchial lesions. Fig. 1 PET-CT images of obstructive atelectasis in a 52-year old male patient with metastatic non-small cell lung cancer. The parametric perfusion image in Fig. 1a demonstrates high perfusion (arrow) in obstruction atelectasis, whereas the perfusion in the primary ...

To optimize radioimmunotherapy, in vivo information on individual patients, such as radionuclide uptake, kinetics, metabolic patterns and optimal administration methods, is important. An overriding problem is to determine accurately the absorbed dose in the target organ as well as critical organs. Positron Emission Tomography (PET) is a superior technique to quantify regional kinetics in vivo with a spatial resolution better than 1 cm3 and a temporal resolution better than 10 s. However, target molecules often have distribution times of several hours to days. Conventional PET nuclides are not applicable and alternative positron-emitting nuclides with matching half-lives and with suitable labelling properties are thus necessary. Over many years we have systematically developed convenient production methods and labelling techniques of suitable positron nuclides, such as 110In(T(1/2) = 1.15 h), 86Y(T(1/2) = 14 h), 76Br(T(1/2) = 16 h) and 124I(T(1/2) = 4 days). 'Dose planning' can be done, for example, with 86Y- or 124I-labelled ligands before therapy, and 90Y- and 131I-labelled analogues and double-labelling, e.g. with a 86Y/90Y-labelled ligand, can be used to determine the true radioactivity integral from a pure beta-emitting nuclide. The usefulness of these techniques was demonstrated in animal and patient studies by halogen-labelled MAbs and EGF-dextran conjugates and peptides chelated with metal ions.

A monoclonal antibody labeled with the positron-emitting radionuclide 76Br (T(1/2) 16.2 h) has previously been shown useful for positron emission tomography (PET) imaging of experimental tumors. Our aim in the present study was to investigate the effects of the complex decay scheme of this radionuclide on normal organ dosimetry and PET image quality. Three mini-pigs were injected intravenously with 46-75 MBq of the 76Br-labeled anti-CEA antibody 38S1, and the whole-body kinetics followed by PET imaging for 19 h. From PET data, absorbed doses in human organs were estimated using the MIRDOSE 3.0 software. The highest 76Br concentrations were found in lungs, after a correction for the air volume in this organ. The lungs received the highest absorbed dose (mGy/MBq, mean+/-maximum error), 0.84+/-0.16, followed by liver, 0.74+/-0.28, and small intestine, 0.55+/-0.05, while the effective dose equivalent was 0.41+/-0.03 mSv/MBq. The PET imaging properties of 76Br in a two-dimensional 2D PET camera, including central area resolution and scattering effects, were investigated in phantoms and compared to those of 18F. In a 0.97 g/cm3 material, approximating soft tissue density, the FMHW ("full width at half-maximum") value of the point spread function was 7.7+/-0.2 mm for 76Br and 6.0+/-0.1 mm for 18F. In conclusion, radioimmuno PET using 76Br-labeled antibodies resulted in a fairly even distribution of the radiation dose, where the highest absorbed organ doses were only about two to three times higher than the mean absorbed body dose. The high energy beta+ spectrum in the 76Br decay had only minor effects on the resolution, but may decrease the quantification accuracy, especially in organs with a lower density such as a lung.

Purpose: Nowadays, PET and dynamic contrast enhanced CT or MRI are used to assess tumor blood perfusion. Although [15O]H2O PET is the gold standard, it is hardly available for routine clinical practice, due to the short half-life of 15O. However, the lack of uniformity in scanning and analytic methods limits the use of CT perfusion (CTP) in clinical trials and practice. This study compares [15O]H2O PET with CT based perfusion in lung tumors and assesses the effects of various CTP postprocessing and analytical methods on the CTP results using [15O]H2O PET as the reference technique. Methods: Various CTP analysis and image postprocessing methods were assessed. Furthermore, parametric images were obtained using the Slope method. Volumes of interests were defined using several different segmentation methods including Hounsfield unit based contouring thresholds, both with and without framewise application of dynamic contouring thresholds to exclude lung tissue or intravascular contrast. A head-to-head comparison of tumor perfusion obtained by CTP and [15O]H2O PET was performed using linear regressions, Bland-Altman plots, and an intraclass correlation coefficient (ICC). In addition, the different postprocessing methods were compared reciprocally. Results: In six lung cancer patients, perfusion assessed using CTP studies combined with the Slope method correlated best with [15O]H2O PET (ICC = 0.88; R2 = 0.89; Y = 0.80). The Mullani-Gould method showed best correlation with the Slope method (ICC ≥ 0.71; R2 ≥ 0.80; Y = 0.71–1.35). These correlations were obtained using dynamic contouring thresholds and show the influence of CTP postprocessing methods. Conclusions: Tumor perfusion assessed by CTP in combination with dynamic contouring thresholds using the Slope method correlates well with [15O]H2O PET. This suggests that CTP can be used as a method to evaluate tumor perfusion in lung cancer.

Background P-glycoprotein [Pgp] dysfunction may be involved in neurodegenerative diseases, such as Alzheimer's disease, and in drug resistant epilepsy. Positron emission tomography using the Pgp substrate tracer (R)-[11C]verapamil enables in vivo quantification of Pgp function at the human blood-brain barrier. Knowledge of test-retest variability is important for assessing changes over time or after treatment with disease-modifying drugs. The purpose of this study was to assess reproducibility of several tracer kinetic models used for analysis of (R)-[11C]verapamil data. Methods Dynamic (R)-[11C]verapamil scans with arterial sampling were performed twice on the same day in 13 healthy controls. Data were reconstructed using both filtered back projection [FBP] and partial volume corrected ordered subset expectation maximization [PVC OSEM]. All data were analysed using single-tissue and two-tissue compartment models. Global and regional test-retest variability was determined for various outcome measures. Results Analysis using the Akaike information criterion showed that a constrained two-tissue compartment model provided the best fits to the data. Global test-retest variability of the volume of distribution was comparable for single-tissue (6%) and constrained two-tissue (9%) compartment models. Using a single-tissue compartment model covering the first 10 min of data yielded acceptable global test-retest variability (9%) for the outcome measure K1. Test-retest variability of binding potential derived from the constrained two-tissue compartment model was less robust, but still acceptable (22%). Test-retest variability was comparable for PVC OSEM and FBP reconstructed data. Conclusion The model of choice for analysing (R)-[11C]verapamil data is a constrained two-tissue compartment model.

3059 Background: Current strategies combining anti-angiogenic drugs with chemotherapy provide clinical benefit in patients with advanced-stage NSCLC cancer. It has been hypothesized that pre-treatment with anti-angiogenic drugs may transiently normalize abnormal tumor vasculature and contribute to improved delivery of subsequent chemotherapy (Nat Med 2001;7:987-9). The purpose of the present study was to investigate this concept in NSCLC patients using a perfusion tracer ([15O]H2O), radiolabeled chemotherapy ([11C]docetaxel) and positron emission tomography (PET) before and after a single infusion of bevacizumab. Methods: A total of 70 PET scans were scheduled in 10 NSCLC patients. Patients underwent dynamic PET scans with [15O]H2O and [11C]docetaxel before, and at 5 hours and 4 days after IV administration of bevacizumab (15 mg·kg-1). An additional [15O]H2O scan was performed at 2 hours. Systemic effects of bevacizumab were investigated by assessing: (1) plasma levels of vascular endothelial growth facto...

Background The incremental value of CAC over traditional risk factors to predict coronary vasodilator dysfunction and inherent myocardial blood flow (MBF) impairment is only scarcely documented (MBF). The aim of this study was therefore to evaluate the relationship between CAC content, hyperemic MBF, and coronary flow reserve (CFR) in patients undergoing hybrid 15O-water PET/CT imaging.

2543 Background: Although docetaxel is an effective treatment of lung cancer, a number of patients do not benefit from this therapy due to tumor resistance. Positron emission tomography (PET) is a ...

Objectives Thymidylate synthase (TS) is a key enzyme for de novo synthesis of DNA and as such a target for anticancer drugs. In a mouse model, effective TS inhibition resulted in a 1.8 fold increase of 3′-deoxy-3′-[(18)F]fluorothymidine (18F-FLT) cellular uptake (Cancer Res 2006;66:8558-64). Here we investigated changes in 18F-FLT uptake 4 hours after the first dose of pemetrexed in patients with non-small cell lung cancer (NSCLC). Methods Twelve NSCLC patients (mean age 64 yrs, 4 male) treated with pemetrexed (in combination with cisplatin, carboplatin or monotherapy) were included. Patients underwent dynamic 18F-FLT PET at baseline and 4 hours after the first therapeutic dose of pemetrexed. For primary tumors, regions of interest (ROI) were defined with a 41, 50 and 70% threshold of the maximum pixel, and the maximum standardized uptake value (SUVmax) was determined (as well as full kinetic analysis). One, 2, 3, 4 and 6 hours after pemetrexed administration, blood samples were collected to measure deoxyuridine levels using LCMSMS. After six weeks, RECIST was used to evaluate tumor response. Association between 18F-FLT uptake and RECIST was tested with a chi-square test. Results According to RECIST 3 patients had PR, 7 SD and 2 PD. Four hours after administration of pemetrexed, two patients had increased 18F-FLT uptake (beyond test-retest borders, 22% for SUVmax), while three patients had a significantly decreased uptake (see Table). In 7 out of 12 patients, the change in 18F-FLT uptake was within the test-retest variability. In all patients deoxyuridine levels raised after administration of pemetrexed with a average maximum at 4 hours. There was no significant association between 18F-FLT uptake and RECIST. Conclusions Measuring TS inhibition in a clinical setting 4 hours after pemetrexed revealed a non-systematic change in 18F-FLT uptake. The association with response measurement on CT was not significant.18F-FLT PET and RECIST per patientPt No.Baseline 18F-FLT uptake (SUVmax)18F-FLT uptake 4 hours after pemetrexed (SUVmax)Change 18F-FLT in uptake (%)RECIST after 6 weeks14.74.94.1SD24.44.75.0SD34.12.3−44.7SD44.04.411.0PD53.54.528.6PR63.42.2−33.3SD74.85.05.7SD812.57.9−36.6PR911.312.17.1PD105.67.228.3SD115.15.35.7PR124.73.7−21.5SD Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5225.