Adriaan Lammertsma

Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder.

γ-Aminobutyric acid (GABAA) receptors are thought to play an important role in modulating the central nervous system in response to stress. Animal data have shown alterations in the GABAA receptor complex by uncontrollable stressors. SPECT imaging with benzodiazepine ligands showed lower distribution volumes of the benzodiazepine-GABAA receptor in the prefrontal cortex of patients with post-traumatic stress disorder (PTSD) in one, but not in another study. The objective of the present study was to assess differences in the benzodiazepine-GABAA receptor complex in veterans with and without PTSD using [11C]flumazenil and positron emission tomography (PET). Nine drug naive male Dutch veterans with deployment related PTSD and seven male Dutch veterans without PTSD were recruited, and matched for age, region and year of deployment. Each subject received a [11C]flumazenil PET scan and a structural magnetic resonance imaging scan. Dynamic 3D PET scans with a total duration of 60 min were acquired, and binding in template based and manually defined regions of interest (ROI) was quantified using validated plasma input and reference tissue models. In addition, parametric binding potential images were compared on a voxel-by-voxel basis using statistical parametric mapping (SPM2). ROI analyses using both template based and manual ROIs showed significantly reduced [11C]flumazenil binding in PTSD subjects throughout the cortex, hippocampus and thalamus. SPM analysis confirmed these results. The observed global reduction of [11C]flumazenil binding in patients with PTSD provides circumstantial evidence for the role of the benzodiazepine-GABAA receptor in the pathophysiology of PTSD and is consistent with previous animal research and clinical psychopharmacological studies.

High resolution PET imaging characteristics of /sup 68/Ga, /sup 124/I and /sup 89/Zr compared to /sup 18/F

In this study the imaging characteristics influencing the quantitative accuracy of 68Ga, 124I and 89 Zr were determined and compared to those of 18F using a 3D high resolution PET (high resolution research tomograph, HRRT) scanner. Although there were large discrepancies found in the sensitivity of these isotopes, which can be explained by their positron abundancy, none of the assessed imaging characteristic prevents the isotopes for usage in (high resolution) quantitative PET imaging. Care has to be taken, however, that accurate correction methods are used for dead time, background and scatter, and partial volume

Diagnostic accuracy of quantitative H215O PET measurements of hyperemic myocardial blood flow versus coronary flow reserve for the detection of obstructive coronary artery disease

Carotid artery intima media thickness, but not coronary artery calcium, predicts coronary vascular resistance in patients evaluated for coronary artery diseaseSecretoneurin, a peptide from the chromogranin-secretogranin family, regulates cardiomyocyte calcium homeostasisPredictors of low physical activity in patients with stable coronary heart disease in the global STABILITY study

SAT0650 [18F]FLUORO-PEG-FOLATE pet: a novel imaging technique to visualize rheumatoid arthritis

Background Imaging arthritis activity in rheumatoid arthritis (RA) patients using PET macrophage tracers holds promise for both early diagnostics and monitoring response to therapy (1,2). Previously, (R)-[11C]PK11195 has been used, but this macrophage tracer is limited due to high background uptake, especially in bone and bone marrow. Recently, a novel macrophage tracer, [18F]fluoro-PEG-folate, was developed, which showed excellent targeting of the folate receptor beta on activated macrophages in synovial tissue in a preclinical arthritic rat model (3). Objectives To assess the value of [18F]fluoro-PEG-folate PET-CT for imaging inflamed joints in patients with clinically active RA. Methods Nine RA patients with at least two clinically inflamed hand joints were included. PET-CT scans of the hands were acquired after intravenous administration of either 185 MBq of [18F]fluoro-PEG-folate (n=6) or 425 MBq of (R)-[11C]PK11195 (n=3). Volumes of Interest (VOI) were drawn over joints with visually marked uptake and Standardized Uptake Values (SUVs) were calculated. Background VOIs were drawn on metacarpal bone in order to calculate Target-to-Background (T/B) ratios. Results No side effects were observed, establishing the safety of [18F]fluoro-PEG-folate for use in humans. [18F]fluoro-PEG-folate clearly showed uptake in arthritic joints, as shown in Figure 1. In patients scanned with [18F]fluoro-PEG-folate, 25 positive joints were seen, with a minimum of two joints per patient. Clinical arthritis was confirmed in 10 of these 25 joints, and was absent in 15 positive joints, suggesting the presence of subclinical inflammation. Whilst both [18F]fluoro-PEG-folate and (R)-[11C]PK11195 accumulated in arthritic joints, [18F]fluoro-PEG-folate showed a significantly lower background uptake than (R)-[11C]PK11195 (SUV of 0.18 vs 0.75; p<0.001) respectively. T/B-ratios were significantly higher for [18F]fluoro-PEG-folate (3.60vs 1.72, p=0.009). Conclusions This first in patient study clearly demonstrates the potential of [18F]fluoro-PEG-folate PET-CT as macrophage tracer to image both clinically and sub-clinically affected joints in RA patients. [18F]fluoro-PEG-folate showed better characteristics for arthritis imaging than the established tracer (R)-[11C]PK11195 because of its lower background signal. References Gent YY, et al. J Rheumatology. 2014; 41: 2145–52. Gent YY, et al. Arthritis Rheum. 2012; 64: 62–6. Gent YY, et al. Arthritis Res Ther. 2013; 15: R37. Disclosure of Interest None declared

Molecular Imaging of Inflammation Reveals Differences Between Drug-Resistant and Drug-Sensitive Animals in a Chronic Model of Temporal Lobe Epilepsy

Molecular Imaging of Inflammation Reveals Differences Between Drug-Resistant and Drug-Sensitive Animals in a Chronic Model of Temporal Lobe Epilepsy

AB0761 Synthesis and evaluation of the novel folate receptor ligand [18f]fluoro-peg-folate for macrophage targeting in a rat model of arthritis

Background Detection of (subclinical) synovitis is relevant for both early diagnosis and monitoring of therapy of rheumatoid arthritis (RA). Previously, the potential of imaging of (sub)clinical arthritis was demonstrated by targeting the translocator protein in activated macrophages using (R)-[11C]PK11195 and positron emission tomography (PET)1. Images, however, also showed significant peri-articular background activity. The folate receptor (FR)-β has been recognized as a potential alternative target for imaging of activated macrophages as the receptor features high (nanomolar) binding affinities for folates and folate-conjugated therapeutic compounds. Objectives Synthesis of the novel PET tracer [18F]fluoro-PEG-folate and its evaluation in both in vitro and ex vivo studies using a methylated BSA induced arthritis model. Methods [18F]fluoro-PEG-folate was synthesized in a two-step procedure. Relative binding affinities of non-radioactive fluoro-PEG-folate, folic acid and naturally circulating 5-methyltetrahydrofolate (5-Me-THF) to FR were determined using KB cells with high expression of FR. Both in vivo [18F]fluoro-PEG-folate PET and ex vivo tissue distribution studies were performed in arthritic rats on standard (high folate) or folate-deficient chow and in normal rats. Results were compared with those of the macrophage tracer (R)-[11C]PK11195. Results [18F]fluoro-PEG-folate was synthesized with a purity >97%, a yield of 300-1700 MBq and a specific activity between 40-70 GBq/µmol. Relative in vitro binding affinity for FR of F-PEG-folate was 1.8 fold lower than that of folic acid, but 3 fold higher than that of 5-Me-THF. [18F]fluoro-PEG-folate PET images clearly visualized arthritic rat knees. Confirming the PET data, [18F]fluoro-PEG-folate uptake (in %ID/gram tissue) as determined by tissue distribution studies in arthritic knees (0.34±0.08) was increased compared with both contralateral knees (0.24±0.08) and knees of normal rats (0.16±0.04, p<0.01). Ex vivo uptake in arthritic knees could be blocked (0.03±0.02) by an excess of glucosamine-folate, consistent with [18F]fluoro-PEG-folate being specifically bound to FR. Ex vivo arthritic knee-to-bone and arthritic knee-to-blood ratios of [18F]fluoro-PEG-folate (1.64±0.15 and 23.1±14.3, respectively) were increased compared with those of (R)-[11C]PK11195 (1.14±0.18 and 10.0±1.9, respectively). Reduction of 5-Me-THF levels in rat plasma to those mimicking human levels with folate-deficient chow increased absolute [18F]fluoro-PEG-folate uptake in arthritic joints, but without improving arthritic knee-to-bone ratios. Conclusions The novel PET tracer [18F]fluoro-PEG-folate, designed to target FR on activated macrophages, provided improved contrast in a rat model of arthritis compared with the clinically established macrophage tracer (R)-[11C]PK11195. These results warrant further exploration of [18F]fluoro-PEG-folate as a putative PET tracer for imaging (sub)clinical arthritis in RA patients. References Gent et al. Arthritis & Rheumatism 2012, 64, 62-66 Disclosure of Interest None Declared

PET imaging of [11C]docetaxel uptake and tumor perfusion in lung cancer.

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 noninvasive imaging technique that allows for quantification of radiolabeled docetaxel ([11C]docetaxel) kinetics and might be useful for predicting response to treatment. The aim of the present study was to determine the feasibility and reproducibility of [11C]docetaxel PET scans in lung cancer and to investigate whether [11C]docetaxel uptake was related to tumor perfusion. Methods: Fourteen patients with advanced lung cancer underwent a dynamic PET-CT scan with [11C]docetaxel (60 min) and H215O (10 min). In addition, patients underwent a second [11C]docetaxel PET scan to assess test-retest reproducibility. Lesions were delineated on the CT scan and projected onto the dynamic PET frames. [11C]docetaxel uptake in tumors was quantified using the net influx rate (Ki). Tumor perfusion was quantified by applying the ...