32nd International Austrian Winter Symposium

Table of contents A1 68Ga-PSMA PET/CT in staging and restaging of Prostate Cancer Patients: comparative study with 18F-Choline PET/CT W Langsteger, A Rezaee, W Loidl, HS Geinitz, F Fitz, M Steinmair, G Broinger, L Pallwien-Prettner, M Beheshti A2 F18 Choline PET – CT: an accurate diagnostic tool for the detection of parathyroid adenoma? L Imamovic, M Beheshti, G Rendl, D Hackl, O Tsybrovsky, M Steinmair, K Emmanuel, F Moinfar, C Pirich, W Langsteger A3 [18F]Fluoro-DOPA-PET/CT in the primary diagnosis of medullary thyroid carcinoma A Bytyqi, G Karanikas, M Mayerhöfer, O Koperek, B Niederle, M Hartenbach A4 Variations of clinical PET/MR operations: An international survey on the clinical utilization of PET/MRI T Beyer, K Herrmann, J Czernin A5 Standard Dixon-based attenuation correction in combined PET/MRI: Reproducibility and the possibility of Lean body mass estimation I Rausch, P Rust, MD DiFranco, M Lassen, A Stadlbauer, ME Mayerhöfer, M Hartenbach, M Hacker, T Beyer A6 High resolution digital FDG PET/MRI imaging for assessment of ACL graft viability K Binzel, R Magnussen, W Wei, MU Knopp, DC Flanigan, C Kaeding, MV Knopp A7 Using pre-existing hematotoxicity as predictor for severe side effects and number of treatment cycles of Xofigo therapy A Leisser, M Nejabat, M Hartenbach, G Kramer, M Krainer, M Hacker, A Haug A8 QDOSE – comprehensive software solution for internal dose assessment Wencke Lehnert, Karl Schmidt, Sharok Kimiaei, Marcus Bronzel, Andreas Kluge A9 Clinical impact of Time-of-Flight on next-generation digital PET imaging of Yttrium-90 radioactivity following liver radioembolization CL Wright, K Binzel, J Zhang, Evan Wuthrick, Piotr Maniawski, MV Knopp A10 Snakes in patients! Lessons learned from programming active contours for automated organ segmentation M Blaickner, E Rados, A Huber, M Dulovits, H Kulkarni, S Wiessalla, C Schuchardt, RP Baum, B Knäusl, D Georg A11 Influence of a genetic polymorphism on brain uptake of the dual ABCB1/ABCG2 substrate [11C]tariquidar M Bauer, B Wulkersdorfer, W Wadsak, C Philippe, H Haslacher, M Zeitlinger, O Langer A12 Outcome prediction of temporal lobe epilepsy surgery from P-glycoprotein activity. Pooled analysis of (R)-[11C]-verapamil PET data from two European centres M Bauer, M Feldmann, R Karch, W Wadsak, M Zeitlinger, MJ Koepp, M-C Asselin, E Pataraia, O Langer A13 In-vitro and in-vivo characterization of [18F]FE@SNAP and derivatives for the visualization of the melanin concentrating hormone receptor 1 M Zeilinger, C Philippe, M Dumanic, F Pichler, J Pilz, M Hacker, W Wadsak, M Mitterhauser A14 Reducing time in quality control leads to higher specific radioactivity of short-lived radiotracers L Nics, B Steiner, M Hacker, M Mitterhauser, W Wadsak A15 In vitro 11C-erlotinib binding experiments in cancer cell lines with epidermal growth factor receptor mutations A Traxl, Thomas Wanek, Kushtrim Kryeziu, Severin Mairinger, Johann Stanek, Walter Berger, Claudia Kuntner, Oliver Langer A16 7-[11C]methyl-6-bromopurine, a PET tracer to measure brain Mrp1 function: radiosynthesis and first PET evaluation in mice S Mairinger, T Wanek, A Traxl, M Krohn, J Stanek, T Filip, M Sauberer, C Kuntner, J Pahnke, O Langer A17 18F labeled azidoglucose derivatives as “click” agents for pretargeted PET imaging D Svatunek, C Denk, M Wilkovitsch, T Wanek, T Filip, C Kuntner-Hannes, J Fröhlich, H Mikula A18 Bioorthogonal tools for PET imaging: development of radiolabeled 1,2,4,5-Tetrazines C Denk, D Svatunek, T Wanek, S Mairinger, J Stanek, T Filip, J Fröhlich, H Mikula, C Kuntner-Hannes A19 Preclinical evaluation of [18F]FE@SUPPY- a new PET-tracer for oncology T Balber, J Singer, J Fazekas, C Rami-Mark, N Berroterán-Infante, E Jensen-Jarolim, W Wadsak, M Hacker, H Viernstein, M Mitterhauser A20 Investigation of Small [18F]-Fluoroalkylazides for Rapid Radiolabeling and In Vivo Click Chemistry C Denk, D Svatunek, B Sohr, H Mikula, J Fröhlich, T Wanek, C Kuntner-Hannes, T Filip A21 Microfluidic 68Ga-radiolabeling of PSMA-HBED-CC using a flow-through reactor S Pfaff, C Philippe, M Mitterhauser, M Hartenbach, M Hacker, W Wadsak A22 Influence of 24-nor-ursodeoxycholic acid on hepatic disposition of [18F]ciprofloxacin measured with positron emission tomography T Wanek, E Halilbasic, M Visentin, S Mairinger, B Stieger, C Kuntner, M Trauner, O Langer A23 Automated 18F-flumazenil production using chemically resistant disposable cassettes P Lam, M Aistleitner, R Eichinger, C Artner A24 Similarities and differences in the synthesis and quality control of 177Lu-DOTA-TATE, 177Lu -HA-DOTA-TATE and 177Lu-DOTA-PSMA (PSMA-617) H Eidherr, C Vraka, A Haug, M Mitterhauser, L Nics, M Hartenbach, M Hacker, W Wadsak A25 68Ga- and 177Lu-labelling of PSMA-617 H Kvaternik, R Müller, D Hausberger, C Zink, RM Aigner A26 Radiolabelling of liposomes with 67Ga and biodistribution studies after administration by an aerosol inhalation system U Cossío, M Asensio, A Montes, S Akhtar, Y te Welscher, R van Nostrum, V Gómez-Vallejo, J Llop A27 Fully automated quantification of DaTscan SPECT: Integration of age and gender differences F VandeVyver, T Barclay, N Lippens, M Troch A28 Lesion-to-background ratio in co-registered 18F-FET PET/MR imaging – is it a valuable tool to differentiate between low grade and high grade brain tumor? L Hehenwarter, B Egger, J Holzmannhofer, M Rodrigues-Radischat, C Pirich A29 [11C]-methionine PET in gliomas - a retrospective data analysis of 166 patients N Pötsch, I Rausch, D Wilhelm, M Weber, J Furtner, G Karanikas, A Wöhrer, M Mitterhauser, M Hacker, T Traub-Weidinger A30 18F-Fluorocholine versus 18F-Fluorodeoxyglucose for PET/CT imaging in patients with relapsed or progressive multiple myeloma: a pilot study T Cassou-Mounat, S Balogova, V Nataf, M Calzada, V Huchet, K Kerrou, J-Y Devaux, M Mohty, L Garderet, J-N Talbot A31 Prognostic benefit of additional SPECT/CT in sentinel lymph node mapping of breast cancer patients S Stanzel, G Pregartner, T Schwarz, V Bjelic-Radisic, B Liegl-Atzwanger, R Aigner A32 Evaluation of diagnostic value of TOF-18F-FDG PET/CT in patients with suspected pancreatic cancer S Stanzel, F Quehenberger, RM Aigner A33 New quantification method for diagnosis of primary hyperpatahyroidism lesions and differential diagnosis vs thyropid nodular disease in dynamic scintigraphy A Koljević Marković, Milica Janković, V Miler Jerković, M Paskaš, G Pupić, R Džodić, D Popović A34 A rare case of diffuse pancreatic involvement in patient with merkel cell carcinoma detected by 18F-FDG MC Fornito, D Familiari A35 TSH-stimulated 18F-FDG PET/CT in the diagnosis of recurrent/metastatic radioiodine-negative differentiated thyroid carcinomas in patients with various thyroglobuline levels P Koranda, H Polzerová, I Metelková, L Henzlová, R Formánek, E Buriánková, M Kamínek A36 Breast Dose from lactation following I131 treatment WH Thomson, C Lewis A37 A new concept for performing SeHCAT studies with the gamma camera WH Thomson, J O’Brien, G James, A Notghi A38 Whole body F-18-FDG-PET and tuberculosis: sensitivity compared to x-ray-CT H Huber, I Stelzmüller, R Wunn, M Mandl, F Fellner, B Lamprecht, M Gabriel A39 Emerging role 18F-FDG PET-CT in the diagnosis and follow-up of the infection in heartware ventricular assist system (HVAD) MC Fornito, G Leonardi A40 Validation of Poisson resampling software WH Thomson, J O’Brien, G James A41 Protection of PET nuclear medicine personnel: problems in satisfying dose limit requirements J Hudzietzová, J Sabol, M Fülöp

Aim: This survey aims at gathering information about PET/MR operations worldwide to determine the current clinical applications of PET/ MR imaging. Methods: An internet-based survey of active PET/MR users was ran between 05/2015 and 08/2015 using surveymonkey. All 69 active PET/MR sites were invited to partake in this survey. The survey was composed of 37 questions related to (A) PET/MR center and installation, (B) variations in imaging protocols and (C) potential future applications.
Results: Responses were collected from 38 (55 %) sites: North America (24 %), Europe (59 %) and APAC (17 %) corresponding to the regional installations worldwide. Sites have operated PET/MR for (27 ± 16) months with 58 % sites having 2+ years experience. Sites used PET/MR for indications in oncology (66 %), neurology (18 %), other (10 %) and cardiology (6 %). The most frequent indications in oncology are brain, prostate, gastrointestinal and head/neck cancer. Tracers used most frequently for neuro-PET/MRI are [18F]FDG, [18F]FET and amyloid imaging compounds. Likewise most frequently used travers in oncology are [18F]FDG, somatostatin receptor ligands and choline analogues. [18F]FDG was also most frequently used for other applications. Users consider oncology with a focus on prostate and head/neck cancer a key application of PET/MR, as well as and neurology/neurodegenerative imaging. Pediatric imaging was named by one site only. Responses to upcoming key applications were mixed, thereby representing essentially the same variety of indications that PET/MR is used for today with the exception that many sites anticipate more frequent use of PET/MR in cardiac patients, and in patients with cancers of soft tissues, prostate and gynecological cancers. Conclusion: An international survey among early adopters of PET/MR reveals a mix of clinical routine and research applications with a focus on oncology and neurology. The future of PET/MRI is seen in expanded oncology and cardiac applications whereby system cost and the ability to fully integrate MR and PET information are considered key promotional factors. Correlation was highest for LBM(MR-AC) and LBM(ADP) (r = 0.99). Linear regression of data excluding artifacts resulted in a scaling factor of 1.06 for LBM(MR-AC). Conclusion: LBM estimation from DIXON MR-AC maps correlates well with standard LBM and thus offers routine SUV(LBM)-based quantification in PET/MR. However, MR-AC images must be controlled for systematic artifacts, like missing tissue and tissue swaps, which limit MR-AC reproducibility.

A6
High resolution digital FDG PET/MRI imaging for assessment of ACL graft viability K Binzel 1  Aim: Injury to the anterior cruciate ligament (ACL) is common, particularly among young athletes. Reconstruction with a graft helps restore stability and function to the knee, as the graft heals through the process of ligamentization1. Anatomic imaging alone cannot provide insight as to the progress of graft ligamentization, however. Combined 18F-FDG PET/MR imaging on current systems has been shown to be feasible for the evaluation of ACL graft viability following reconstructive surgery. We evaluated the capabilities of high resolution PET/MRI through combined use of a next generation digital photon counting PET/CT and 3 T MRI in an on-going multi-modality imaging study for the assessment of graft viability. Methods: 10 patients had a standard of care MRI on a 3 T Ingenia CX. Proton density and T1 weighted sequences were acquired on all three planes, with a 3D high resolution image acquired on the sagittal plane. Low-dose PET/CT acquisitions were performed on the Vereos digital PET/CT (all Philips Healthcare). A foam mold of the MR knee coil was used to match knee positioning between PET and MR acquisitions. A single bed position centered on the knees was acquired following a 111 MBq 18F-FDG injection. Listmode data were reconstructed using a 144x144 matrix with 4 mm3 voxel volumes, a 288x288 matrix with 2 mm3 volumes, and a 576x576 matrix with 1 mm3 voxel volumes. Each reconstruction matrix size also used the option of a Gaussian filter and point spread function correction. Patients were grouped according to time since surgery and SUVmax was measured in the proximal, middle, and distal portions of the graft, femoral and tibial tunnels, and the posterior cruciate ligament (PCL), and quadriceps muscle for reference. Matched ROIs were drawn in the contralateral healthy knee. Results: In all cases, PET and MR images were readily co-registered for quantitative evaluation. Excellent image quality was seen at all reconstruction matrix sizes, with the smaller voxel volumes improving visual evaluation of the heterogeneity of uptake throughout the evaluated ACL grafts. As previously validated in phantom tests, the use of smaller voxel volumes also improved quantification of graft metabolic uptake. SUVs measured on 2 and 1 mm3 images were found to be greater than those of default 4 mm3 images for regions of interest in the graft and bone tunnels. SUVs in background regions were less affected by the change in reconstruction matrix size. Addition of the Gaussian filter and point spread function correction during reconstruction further improved visual and quantitative precision. As in previous evaluation of ACL grafts by conventional PET, the trend was seen whereby the metabolic activity in the graft and bone tunnels decreased with longer recovery times since surgery. Conclusion: PET/MRI imaging of the knee, particularly ACL grafts, benefits from the improved signal to noise and capacity for higher resolution reconstruction facilitated by use of PET digital photon counting and digital MR coil systems. The primary advantage in digital PET imaging of small structures is due to the improved quantitative precision enabled by a reduction of partial volume effects. Higher matrix PET reconstruction also enables better voxel-wise registration to MRI. The improved accuracy of quantification with digital PET will allow for more detailed analysis and correlation with clinical evaluations of graft healing and rehabilitation planning following reconstructive surgery. Aim: Hematopoetic toxicity is regarded a major problem of treatment with Xofigo. In this study we analyzed whether pre-therapeutic hematotoxicity (HT) influences the occurrence of side-effects. Methods: In 54 patients with metastatic CRPC that underwent Xofigo therapy data on hemoglobin-levels (Hb), number of platelets (Plts) and leukocytes (Leuk) before, during and after therapy were collected. Pre-therapeutic HT and adverse events (AE) were scored (grade 0-4) according to the CTCAE recommendations. For further analysis patients were categorized with regard to their initial HT grade and correlated with development of severe HT (grade 3 or 4) during therapy, and the number of Xofigo treatments. Aim: The selection and utilization of Yttrium-90 (90Y) microspheres as a targeted radiotherapeutic is driven by the existing clinical need to selectively embolize tumor-induced vasculature and deliver high doses of therapeutic radioactivity to unresectable liver lesions. This is particularly important when external beam radiation therapy is deemed impractical. Bremsstrahlung imaging currently serves as the standard for post-90Y radioembolization assessment but this approach is limited with poor image quality, poor 90Y-to-background contrast, and limited capability for post-therapy quantitative dosimetry. Although it emits high-energy electrons for therapeutic purposes, 90Y is a theranostic agent given that it also produces a small fraction of discrete annihilation photons which are imagable with conventional photomultiplier tube-based PET technology (cPET/CT, [1]). A recent technological innovation has replaced these conventional photomultiplier tubes in the PET gantry with next-generation, solid-state, digital photon counting PET detectors (digital PET or dPET) which have Time-of-Flight capability as well as markedly improved timing resolution. Our aim is to assess the clinical impact of Time-of-Flight on 90Y dPET/CT image quality and post-therapy assessment in patients following liver radioembolization. Methods: In an ongoing trial, we are using a pre-commercial release digital PET/CT system (Vereos, Philips Healthcare) to image and assess 90Y microsphere biodistribution in patients with malignant/metastatic liver lesions after radioembolization therapy. Bremsstrahlung SPECT/CT imaging was performed within a few hours immediately following radioembolization with a total image acquisition time of 22 m. Digital PET imaging was performed in 10 patients at 4 -50 h following liver radioembolization with a total image acquisition time of 21 m. PET data were reconstructed using a 3D OSEM algorithm with and without Time-of-Flight using a voxel size of 4x4x4 mm3. Image characteristics and isocontour volumes of 90Y activity were then assessed by matched comparison using the Intellispace Portal workstation (Philips). In addition, matched comparison with standard bremsstrahlung SPECT/CT imaging (Symbia T16, Siemens Healthcare) was performed to further assess the practicality and clinical utility of this dPET/CT imaging approach.
Results: For all patients, dPET images were rated as evaluable and, when compared with bremsstrahlung SPECT/CT, dPET detection of 90Y radioactivity enabled markedly improved qualitative and volumetric assessment of 90Y microsphere biodistribution. In particular, dPET/CT technology enables post-therapy 90Y imaging with shorter image acquisition times, improved image quality, contrast, and volumetric assessment when compared with standard bSPECT/CT approaches. Furthermore, Time-of-Flight improved overall image quality and 90Y-to-background contrast for dPET/CT images when compared with non-Time-of-Flight dPET but there were no significant differences in the measured intrahepatic volumes of 90Y activity using 1 % isocontours.
Conclusion: There remains an unmet clinical need to improve qualitative and quantitative imaging assessment of 90Y-based radiotherapies. Current imaging approaches for assessing 90Y in vivo are (1) challenging in terms of low quality / poorly quantitative bremsstrahlung techniques and (2) potentially disruptive to clinical workflows given the long image acquisition times needed for current cPET techniques. We demonstrate that Time-of-Flight dPET image quality is superior to the non-Time-of-Flight dPET and standard bremsstrahlung approaches. Using dPET technology in the future, we expect that new strategies for 90Y image acquisition as well as new reconstruction methodologies will facilitate even shorter image acquisition times with better image quality and more accurate dose quantification in patients treated with existing and new 90Y-based theranostics.
interobserver errors whereas the later still lacks a golden standard, especially in case of low image contrast. This talk gives an overview of the work with active contours (snakes!) as a method for automated organ segmentation. Methods: Several versions of active contours were implemented and tested, e.g. two-dimensional (2D) snakes with a closed curve and a three-dimensional (3D) where the active contour is represented as a subdivision surface (SubD). The external force is computed as gradient vector flow (GVF), i.e. the diffusion of the gradient vectors. Inhouse snakes were implemented in Python and SideFX Houdini as well as existing active contours used, such as the corresponding function in Adobe After Effects. The rigidity of the active contour was varied as well as a node network in Houdini implemented, containing multiple image preprocessing modules. The different snakes were evaluated on single-and multi-modality patient imaging and compared to manual contouring. Results: In-house implemented 2D snakes have shown good performance even on low contrast images such as soft tissue organs on CT without contrast media. However the slice by slice approach faces difficulties at the top and bottom of organs. This can be improved by means of 3D SubDs as active contours, though only for specific image parameters, e.g. Ga68-DOTA PET images of the liver. For CT data of liver and kidney without contrast media the volume comparison between manual and 2D segmentation yielded for the kidney a mean deviation of 5.16 % and for the liver 3.09 %. The dice coefficient was on average 0.89 and 0.94 respectively. Regarding 3D segmentation the deviation of the kidney volumes was on average 18.68 % and for the liver 13.02 %, where the dice coefficient was 0.69 and 0.83. Poor resolution of the CT images in z-direction considerably worsens the performance of the 3D active contour. Distracting forces due to inhomogeneous grey values within the organs and low contrast to neighbouring structures requires extensive image preprocessing. Computing the snake's rigidity has a high impact on the performance with concave regions. Conclusion: Even with a versatile tool like active contours and GVF automated segmentation of soft tissue organs in low contrast remains challenging. A best practice model requires the combination of elaborate pre-processing, 2D as well as 3D active contours.

A11
Influence of a genetic polymorphism on brain uptake of the dual Aim: Transport of drugs by membrane transporters is an important source of inter-individual variations in drug distribution, drug response and of major concern regarding drug-drug interactions. The investigational third-generation P-glycoprotein (ABCB1) inhibitor tariquidar has been used in clinical trials in tumour patients to overcome multidrug resistance.
[11C]Tariquidar is transported at tracer doses by ABCB1 and breast cancer resistance protein (ABCG2) and can be used to measure the functional activities of these two transporters at the blood-brain barrier (BBB) [1]. Carriers of a loss-of-function single nucleotide polymorphism (SNP) in the ABCG2 gene (c.421C > A, Q141K) have altered plasma pharmacokinetics of ABCG2 substrate drugs as compared to subjects without the genetic variation [2]. We aim to assess the effect of this ABCG2 SNP on brain distribution of [11C] tariquidar.
Methods: Healthy male volunteers were genotyped for the ABCG2 SNP and allocated to a c.421C/C (wild-type) and c.421C/A (heterozygous) group, respectively (n = 5 per group). Subjects underwent two consecutive 60-min dynamic brain PET scans with [11C]tariquidar, a first scan after administration of a tracer dose of [11C]tariquidar (<20 μg) and a second scan during continuous i.v. infusion of unlabelled tariquidar (3.75 mg/min) in order to inhibit ABCB1 at the BBB. Atlas based region of interest whole brain grey matter was defined on individual magnetic resonance images and time-activity curves extracted from the co-registered dynamic PET images. Arterial blood samples were collected and radioactivity in plasma was measured in a gamma counter. The ratio of the area under the timeactivity curves (AUC) in brain and plasma (AUCbrain/AUCplasma) was calculated for the first and second PET scan. Aim: Overexpression of the ABC-transmembrane transporter Pglycoprotein (Pgp) at the blood-brain barrier contributes to therapy refractory temporal lobe (TL) epilepsy [1]. Surgical removal of TL structures may result in favorable seizure outcome in approximately 60 % of operated cases [2]. Findings from a pilot PET study investigating Pgp function suggest that Pgp overactivity in the TL prior to surgery may be indicative of optimal postoperative outcome [3].  [1,3]. Metabolite corrected arterial input functions were used to estimate the net influx of VPM from plasma into brain (K1) from the first 10 min of PET data [1,3]. Clinical follow-up data on seizure activity and anti-epileptic medication were available for 4 ± 1 years for Manchester and 6 ± 1 years for Vienna patients. Ranking of surgery outcome was done according to the modified Wieser's classification (best outcome assigned rank 1) [3].
Results: Correlation of VPM K1 values in ipsilateral TL with surgery outcome rank in individual patients was highly positive (Pearson r = 0.7573, p = 0.0017, n = 14). Patients with the highest Pgp activity (lowest K1 values) before surgery showed optimal surgery outcome (seizure and medication free) whereas those with the lowest Pgp activity continued to have seizures and to take medication even after surgery. Findings were consistent for both centres.
Conclusion: Pooled analysis of pre-operative VPM PET data consistently predicted outcome after TL epilepsy surgery in two centres, confirming findings from a previous pilot study. PET measurement of Pgp function should be further evaluated as an imaging biomarker for the prediction of TL epilepsy surgery outcome. Aim: The melanin concentrating hormone (MCH) is a cyclic neuropeptide which is predominantly expressed in the lateral hypothalamus and zona incerta [1,2]. The biological effect is mediated by two G-protein coupled receptors (GPCR), the MCH receptor 1 and 2 (MCHR1 and MCHR2) [3]. Changes in the expression of the MCHR1 have been shown to be involved in a variety of pathologies, such as depression and anxiety disorders and are related to the central mechanisms of obesity [4,5]. In this regard, the preparation and first in-vitro studies of [18F]FE@SNAP and [11C]SNAP-7941, as potential positron emission tomography (PET) radiotracers for the visualization of the MCHR1, were performed successfully [6,7,8,9]. Based on the preceding results the present present study aimed at a further in-vitro and in-vivo evaluation of [18F]FE@SNAP and its structurally closed non radioactive derivatives FE@SNAP, SNAP-7941 and (+)-SNAP-7941 to provide high-impact predictive values for a further translation into clinical PET imaging. 19.7 ± 6GBq/μmol). Radiotracer uptake in the brain (SUV; g/mL) was determined under i) baseline conditions, ii) blocking with 15 mg/kg SNAP-7941 and iii) blocking with 15 mg/kg tariquidar. After the imaging the rats were sacrificed, the organs were harvested and subjected to radioactivity measurements. The resulting values were expressed as percent injected dose per gram tissue (%ID/g). In-vivo small animal experiments evinced a brain uptake of 0.28 ± 0.05 g/mL (baseline group; n = 5), 0.28 ± 0.03 g/mL (blocking with SNAP-7941; n = 2) and 0.48 ± 0.17 g/mL (blocking with tariquidar, n = 2). Conclusion: The binding affinity of SNAP-7941 and the (S)-enantiomer revealed comparable results, both in a low nanomolar range. As opposed to this, FE@SNAP evinced a significantly lower Ki. Real-time binding studies of [18F]FE@SNAP showed no differences in the binding kinetics between the receptor subtypes. Specific uptake of [18F]FE@SNAP in the rat brain seems to be prevented by p-gp and/ or BCRP, since small animal μPET experiments revealed a 2-2.5 fold increased brain uptake after p-gp/BCRP inhibition with tariquidar. Further in-vivo investigations with respect to peripheral MCHR1 expression of healthy, obese and diabetic rats need to be performed to further proof the applicability of the MCHR1 concept.

A14
Reducing time in quality control leads to higher specific radioactivity of short-lived radiotracers L Nics 1  Aim: Time plays a pivotal role in the preparation of radiopharmaceuticals (RP) labeled with short-lived radionuclides (e.g. carbon-11, nitrogen-13, gallium-68). In particular, it has to be taken into account that radioactive decay starts to reduce available activity as soon as the produced radionuclide is delivered to the synthesis unit. This is also true for the specific radioactivity (SA; activity per mass unit) which is of significant importance for radiotracers targeting saturable targets such as transporters or receptors. This process lasts until application of the RP after passing the quality control (QC) and final release of the product. So far, time reduction was mostly implemented during the chemical synthesis process or subsequent purification. In contrast, QC procedures were not considered to a full extent in that perspective. Determination of radiochemical purity and SA normally requires the use of high performance liquid chromatography (HPLC) which is also the most time-consuming step in the QC procedure. Recently, Nakao et al. [ Aim: Erlotinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) used to treat patients with non-small cell lung cancer (NSCLC). NSCLC patients with activating mutations (e.g. exon 19 deletion) in the EGFR gene have increased response rates to erlotinib treatment compared to patients with wild-type EGFR. However, patients with activating EGFR mutations eventually develop resistance to erlotinib caused by secondary mutations (e.g. T790M). 11Cerlotinib PET signal was found to be higher in NSCLC tumors with an activating EGFR mutation than in tumors with wild-type EGFR [1]. It is however, not known if 11C-erlotinib PET will be able to distinguish tumors with secondary resistance causing mutations from erlotinibsensitive tumors. Aim of this study was to measure in vitro 11Cerlotinib binding in erlotinib-sensitive and erlotinib-resistance cancer cell lines. Methods: One glioblastoma (U-87 MG) and four NSCLC (erlotinib-sensitive HCC827, erlotinib-resistant HCC827, gefitinib-resistant HCC827, and erlotinib-resistant HCC827 with a secondary EGFR mutation) cell lines were incubated with 11C-erlotinib up to 60 min. In a second set of experiments cell lines were pretreated with unlabeled erlotinib or different P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitors (elacridar, Ko143, tariquidar) and then incubated with 11C-erlotinib for 30 min. Retained radioactivity in the cells was measured in a gamma counter and normalized to cell count.
Results: Uptake of 11C-erlotinib was significantly lower in U-87 MG cells compared to all NSCLC cell lines. No significant differences were observed in the uptake of 11C-erlotinib between the four NSCLC cell lines. In all NSCLC cell lines 11C-erlotinib uptake was significantly reduced following pretreatment with unlabeled erlotinib, which was not the case for U-87 MG cells. Pretreatment with elacridar, Ko143 or tariquidar had no effect on 11C-erlotinib uptake in all tested cell lines. Conclusion: We found significantly lower uptake of 11C-erlotinib in U-87 MG cells with wild-type EGFR compared to all NSCLC cell lines, which had activating EGFR mutations. No significant differences in 11C-erlotinib uptake were observed between erlotinib-sensitive, erlotinib-resistant, and gefitinib-resistant NSCLC cell lines. In all NSCLC cell lines a significant reduction of 11C-erlotinib uptake after pretreatment with unlabeled erlotinib was found, suggesting specific binding to EGFR. Efflux of 11C-erlotinib by P-gp and BCRP was not evident in any of the studied cell lines. Taken together, our findings suggest that 11C-erlotinib PET may be suitable to distinguish wild-type EGFR from EGFR with activating mutations, but unsuitable to identify secondary resistance causing mutations. To further extend our in vitro findings, PET studies will be carried out in tumor-xenografted nude mice using erlotinib-resistant and erlotinib-sensitive NSCLC cell lines. Aim: Multidrug resistance-associated protein 1 (MRP1) is a membrane transporter expressed at the blood-brain and blood-cerebrospinal fluid barriers, which has been suggested to play a role in beta-amyloid clearance from brain into blood [1]. 7-[11C]methyl-6-bromopurine ([11C]7m6BP) is a novel PET tracer to measure MRP1 function in the brain [2]. Visualization of MRP1 function with [11C]7m6BP is based on a pro-drug approach: the probe enters the brain by passive diffusion and gets rapidly converted into its glutathione conjugate S-(6-(7-methylpurinyl))glutathione ([11C]PSG), which is effluxed from the brain by MRP1. 7m6BP PET scans. Whole-brain time-activity curves were obtained and the efflux rate constant (keff) of radioactivity from brain was calculated using data from 17.5-80 min after radiotracer injection. In separate groups of wild-type and Mrp1(−/−) mice radiolabelled metabolites of [11C]7m6BP were analyzed by radio-thin layer chromatography (TLC) in plasma and brain at 15 and 60 min after radiotracer injection (n = 3 per group and time point).
Radio-TLC analysis showed that at 15 min after radiotracer injection all radioactivity in the brain consisted of the desired glutathione conjugate [11C]PSG. Whole brain time-activity curves were characterized by a rapid washout of radioactivity in wild-type mice and a prolonged retention of radioactivity in Mrp1(−/−) mice. Brain efflux rate constant (keff) of radioactivity was significantly (p < 0.05, t-test) reduced in Mrp1(−/−) compared to wild-type mice ((keff (h- Aim: Bioorthogonal ligations are capable of forming covalent bonds in highly complex environments. Since their introduction in 2000 their potential to be used in pretargeting experiments has drawn much attention in the field of (PET-) imaging. (1) Pretargeting means splitting of the tracing compound into a marker, which is enriched in target tissue and a radiolabeled pull down reagent (PDR). By using such an approach, longer periods of time for enrichment of the marker compound can be provided, which is crucial for PET measurements with high contrast of target to normal tissue. After this labeling step the PDR is injected, which should react with the trapped marker in a bioorthogonal way. This would allow the use of short living radioisotopes in PET imaging of slow accumulating markers and leads to enhanced signal-to-noise ratios and lower radioactivity doses. The most prominent bioorthogonal reaction, the strain-promoted azide alkyne cycloaddition (SPAAC), has been used in a wide variety of applications in chemical biology and biomedicine. (2) This reaction features the Huisgen-Cycloaddition between an azide and a strained cycloalkyne to form triazoles. SPAAC has already been used in pretargeted PET imaging featuring short lived 18F as radionuclide by Lee et al. (3) although they do not report about biodistribution and stability of the azide-labeled pull-down-reagent. Aim of this work was the synthesis and in vivo evaluation of 18F labeled azidoglucoses as pull-down reagent for pretargeted PET imaging using SPAAC as bioorthogonal ligation. Using glucose derivatives as PDRs has several advantages, such as good and fast biodistribution and possible active uptake into cells by glucose transporters. Blocking of the 6 position with 18F will prevent phosphorylation and therefore trapping in cells can only occur after bioorthogonal reaction. Two different isomers were evaluated, both containing 18F at position 6 while either 1-OH (18F-AzFDG16) or 2-OH (18F-AzFDG26) was displaced against an azide group. Methods: Precursors for radiosynthesis were prepared in 4 and 3 steps respectively starting from commercially available material. Radiosynthesis were carried out by nucleophilic displacement of a nosylate by 18F-Fluorine followed by alkaline hydrolysis on a tC18 SepPak cartridgeand formulation in saline solution.
In vivo studies were performed by administration of 18F labeled azidoglucoses to female BALB/c mice followed by dynamic PET imaging (n = 6 for 18F-AzFDG16, n = 4 for 18F-AzFDG26) for 120 min. At the end of the imaging experiment the mice were sacrificed and harvested urine and plasma samples were screened for radiometabolites using radio-thin-layer-chromatography (TLC). Selected organs were withdrawn and gamma counted to validate data from the last PET time frame.
Results: 18F-AzFDG16 and 18F-AzFDG26 were obtained in good yields and high radiochemical purity. PET Imaging revealed a very homogenous and fast biodistribution of both substances in all regions in the body excluding the brain, as well as rapid renal excretion. Furthermore, PET imaging revealed no significant extent of in vivo defluorination of both PDRs, since no enhanced radioactivity uptake in bone was observed. High Stability of these reagents was also confirmed by metabolite analysis (radio-TLC).
Conclusion: Fluoroazidoglucoses have proven to be promising click agents for in vivo application applying SPAAC, due to homogenous and fast biodistribution, high metabolic stability as well as fast excretion. Synthesis and evaluation of further derivatives as well as in vivo click experiments are currently under investigation.

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Bioorthogonal tools for PET imaging: development of radiolabeled 1,2,4,5-Tetrazines Until recently, only few radiolabeled tetrazines mainly based on radiometals and bulky chelating agents have been reported. However, the use of short-lived PET isotopes (18F, 11C) with favorable decay characteristics and high specific activity was limited due to chemical stability and reactivity restrictions. Within this contribution an overview will be given describing the concept of bioorthogonal PET imaging. Furthermore the development of various low molecular weight radiotetrazine probes labeled with fluorine-18 and carbon-11 will be presented. Methods: In silico methods were used to investigate IEDDA ligation reactivity prior to synthesis. Tetrazines were synthesized using metal catalysis, and precursor substances (tosylates for 18F-radiochemistry, primary amines for 11C-radiochemistry) were labeled in good radiochemical yields avoiding the use of prosthetic groups. Radiochemical purity was assessed by radio-HPLC and TLC, and the identity of labeled PDRs was verified by co-injecton with non-radioactive reference materials. Biodistribution and excretion kinetics were investigated by administration into female BALB/c mice and whole body dynamic PET/MR scanning for 120 min (18F) or 60 min (11C). Furthermore blood and urine samples were analyzed for radiometabolites and gamma counting of selected organs was conducted to confirm PET results.
Conclusion: To this end a selection of promising bioorthogonal tools is available that should allow for pretargeted PET imaging of slow accumulating probes as well as rapid radiolabeling in highly complex (biological) matrices. Aim: In recent years the concept of pretargeted PET imaging using bioorthogonal chemistry has drawn a lot of attention as it allows imaging of slow accumulating probes with short-lived radionuclides leading to enhanced signal-to-noise ratios and lower patient radiation doses. The underlying idea is based on a two-step approach that includes administration of a target tissue (e.g. tumor) sensitive probe followed by a radiolabeled pull down reagent (PDR). The probe and PDR will ligate in vivo via a bioorthogonal reaction, which does not interfere with native biochemical processes and exhibits high reaction rates. The aim of this work was to investigate the biostability and -distribution of various low molecular-weight [18F]-fluoroalkylazides to evaluate their potential as PDRs in the bioorthogonal copper-free-click reaction (CFC) between azides and cyclooctynes.

A19
Methods: Precursor materials for [18F]-fluoroalkylazides were obtained via straightforward synthetic chemistry using commercially available reagents. Radiolabeling of an improved precursor (crystalline instead of liquid) was achieved in high yields and short reaction times using the Kryptofix 222/K2CO3 method. The identity of target compounds was verified by comparison of HPLC retention times with non-radioactive reference materials.
In vivo biodistribution studies were performed by administration of [18F]-radiolabeled fluoroalkylazides to female BALB/c mice and subsequent dynamic PET/MR imaging over a period of two hours. At the end of the experiment the mice were sacrificed to allow HPLC analysis for radiolabeled metabolites of plasma and urine samples. Selected organs were withdrawn and checked for radioactivity. Aim: In radiochemistry, main focus is set on time efficiency, automated syntheses as well as high chemical conversion. To meet these requirements, microfluidic devices have been tested for downsizing the precursor amount of already established radiosyntheses during the last years [1]. This approach usually enables an enhanced conversion due to a high surface-to-volume ratio [2]. Microfluidic devices have scarcely been tested for Ga-68-radiolabeling so far [3]. The aim of this study was to test the feasibility of using a fully automated microfluidic system containing a flow-through reactor for the radiosynthesis of Ga-68-PSMA-HBED-CC.
Methods: Ga-68-radiolabeling of PSMA-HBED-CC (ABX, GMP grade) was performed using an Advion NanoTek LF system containing a flow-through microreactor that consists of a silica capillary (l = 2 m, Ø100 μm, V = 15.6 μL). 68Ga3+ was obtained from a Ge-68/Ga-68 generator (3.7 GBq; Obninsk) and the eluate was collected according to a fractionized protocol. Roughly 400 μL of the peak activity were loaded into the storage loop within the NanoTek system and aliquots of different volumes were used for subsequent reactions. Conclusion: To the best of our knowledge, we were able to demonstrate for the first time the successful microfluidic Ga-68-radiolabeling of PSMA-HBED-CC. Moreover, we observed that radiochemical conversion can be further enhanced, when purging the system with all reagents prior to syntheses. This proof-of-principle might lead to increased availability of Ga-68-tracers following the dose-on-demand principle.  Conclusion: Both the somatostatin analogues 177Lu-DOTA-TATE and 177Lu-HA-DOTA-TATE for NET-treatment but also 177Lu-DOTA-PSMA for treatment of PCa could be safely produced in activities up to <16GBq (2 therapeutic doses) and excellent quality under observation of proper radioprotection and radioactive waste management. Differences in the preparations were of minor concern. Set-up for the 3 different radiotherapeutics could be easily adapted. Aim: PSMA is a most promising ligand for imaging and therapy of prostate cancer lesions. Ever since the DOTA conjugated ligand PSMA-617 is known, the DOTA ligand can be labelled with a broad range of radionuclides (1). Our aim was, on the one hand, to establish labelling of 68Ga-PSMA-617 for PET diagnosis, and on the contrary 177Lu-PSMA-617 for therapy. Both should be compliant to the GMP preparation methodology. Methods: The ligand PSMA-617 was purchased from ABX. 68Ga-PSMA-617 was prepared with a cationic purified (5 M NaCl, SCX PS-H+) 68GaCl3 (1.8 GBq Generator, IThemba). The labelling of 20 μg PSMA-617 was performed in HEPES solution at 125°C/6 min. The crude mixture was purified by C18 SPE. For 177Lu-PSMA-617, 200 μg PSMA-617 was labelled with 10 GBq 177LuCl3 (ITG) in sodium acetate/ascorbate buffer at 100°C/20 min. Then, the reaction mixture was diluted and sterile filtrated without further purification. Both kinds of synthesis was carried out with a Scintomics GRP synthesizer, sterile single use cassettes and the standard synthesis sequences for 68Ga-peptides respective therapeutic peptides.

A22
Results: 68Ga-PSMA-617 was obtained with a yield of 48 % at EOS (decay corr. 79 %). The labelling reaction was near quantitative, but 15 % (decay corr.) of 68Ga retained on the cationic exchange column during processing. The labelling to 177Lu-PSMA-617 was quantitative, there for the yield was >90 %. The radiochemical purity, determined to be HPLC was 96 % (68Ga-PSMA-617) and 92 % (177Lu-PSMA-617) due to detected impurities of labelled peptides. The detected amount of free radionuclides were always <1 %. 68Ga-PSMA-617 and 177Lu-PSMA-617 remained stable until the planned shelf live. Conclusion: The introduced preparation of 68Ga-PSMA-617 and 177Lu-PSMA-617 using Scintomics GRP synthesizer and standard synthesis sequences are robust and reliable processes, which meets the GMP rules. Aim: Liposomes (LPs) have been extensively investigated as nanocarriers for drug delivery. In this context, evaluation of their biodistribution pattern after administration into living organisms is of paramount importance. This can be achieved by incorporation of a γemitter radioisotope followed by in vivo imaging using single photon emission computed tomography (SPECT). Here, we present a method for radiolabelling LPs with the γ-emitter 67Ga. Regional distribution in the lungs after inhalation using a specially designed nebulisation chamber was determined using SPECT-CT. Methods: Gallium-67 (T1/2 = 3.26 days) was purchased from IBA-Molypharma as 67Ga-citrate complex and converted into 67GaCl3 following a well established method.1 For the radiolabelling, 10 μL 8hydroxyquinoline (10 mM in EtOH) in 100 μL sodium acetate buffer (100 mM pH 5.5, 150 mM NaCl) were added to 67GaCl3 (≈150 MBq in 0.1 M HCl). Immediately after, 100 μL of DTPA-containing LPs were added and the mixture was incubated at 37°C for 1 hour. 67Ga-liposomes were purified by size exclusion chromatography and radiochemical purity was assessed by radio-ITLC. Administration of the radiolabelled LPs was carried out under sedation using an only-nose exposition device coupled to a chamber equipped with a specially designed nebulizer. Biodistribution of 67Galiposomes was investigated by whole body SPECT-CT imaging. Dissection/gamma counting and ex vivo imaging experiments to assess the percentage of the nebulised dose deposited in the lungs and the accurate regional distribution, respectively, were also carried out.
Results: Labelling efficiencies close to 45 % were achieved. After purification, radiochemical purity exceeded 95 % in all cases. Biodistribution data showed a uniform distribution of the labelled LPs in both lungs at short times after inhalation. The percentage of the nebulised LPs reaching the lungs was close to 0.5 %.
Conclusion: Uniform distribution of the labelled LPs in the lungs is achieved with the new aerosol generator. The obtained data constitute a promising starting point for using liposomes as nanocarriers for antibiotics targeting the lungs of infected patients.

A27
Fully automated quantification of DaTscan SPECT: Integration of age and gender differences F VandeVyver, T Barclay, N Lippens, M Troch AZ St-Lucas Gent, Belgium EJNMMI Research 2016, 6(Suppl 1):A27 Aim: SPECT imaging of dopamine transporters (DaT) with FP-CIT (DaTscan) is an established method for the diagnosis of neurodegenerative parkinsonism. Quantification of DaTscan (semi-automatic or full automatic) has been shown to reduce equivocal reporting of DaTscan and can be used as an adjunct to visual assessment. The recent published "European multicentre database of healthy controls" [1] showed significant age-related effects and gender differences in DaT levels in healthy controls. We developed a tool to integrate those normal physiological variances in the quantification of a single SPECT-examination. Furthermore the tool allows to build a large database for further statistical analysis. Methods: SPECT-acquisition was done on a GE Hawkeye dual head gamma-camera. Quality control showed longitudinal uniformity and centre of rotation within limits. SPECT acquisition and reconstruction were performed in concordance with the parameters described in the ENC-DAT study. Images were reconstructed without and with attenuation correction (using Chang's method). For further calculation only the results of the AC images were used. Quantification was done using BRASS fully automated functional brain analysis (Hermes, Sweden). Using standard Excel software (Microsoft Corporation, United States) a macro enabled worksheet was developped which 1) allows easy input of relevant parameters (including quantitative output of BRASS) for an individual patient, 2) create a result page with numerical and graphical results of the DaTscan-quantification and 3) builds a database from each input session.
Results: In all patients (age ranging from 32 to 87 years; 31 male and 30 female patients) scheduled for DaTscan, quantification was performed with age and gender correction. The procedure is standardised and fully automatic and autonomously done by the medical imager. Physicians can report DaTscan with greater diagnostic confidence: all scans could be classified as normal or abnormal. A database of 61 patients is build since start of this tool: further statistical analysis will be performed in the future. Conclusion: Integreation of age and gender differences in quantification of DaTscan is feasible and applicable in clinical routine.

A28
Lesion-to-background ratio in co-registered 18F-FET PET/MR imagingis it a valuable tool to differentiate between low grade and high grade brain tumor? The Philips software Intellispace Portal (ISP) was used to co-register 18F-FET PET data with most recent MRT images with a maximum interval of 42 days. A circular background area with 5 cm diameter drawn in the contra lateral hemisphere to glioma including white and grey matter was suitable to define a LBR of 1,6 as threshold between tumor and normal tissue. For calculating the lesion-tobackground ratio (LBR), the SUV max of the lesion was divided by the SUV mean of the background area. Clinical data on surgery, histology, chemotherapy, radiotherapy and WHO grade were obtained from all patients.   Aim: SeHCAT absorption studies have gained in popularity over recent years. The capsule has a Se75 activity of only 370 kBq, therefore the gamma camera is normally used intrinsically (no collimators). However intrinsic counting leaves the crystals exposed, with the potential for anything falling onto the crystal face causing expensive damage. In addition there is the potential for sources, or for any low level (50 kBq) Tc99m contamination on the bed, to interfere with the measurement Some departments count with a LEHR collimator in place but sensitivity is then very low, so counting times are longer and the statistical error can become significant. Methods: A new concept uses a uniform 2 mm lead plate as a crystal cover, or 'collimator'. This completely blocks any effect from other Tc99m sources in the department. However the higher energy Se75 emissions (264 -400 keV) can easily penetrate the lead sheet for counting. The lead plate also provides complete protection for the crystal.
Results: The sensitivity for Se75 (in a water-filled phantom) with the lead plate is 7608 c/s/MBq. This is 10x the LEHR collimated count rate (GE-LEHR, 766c/s/MBq). Even for a large BMI patient, a 60s count with the lead plate system gives + −0.8 % (2std.dev) error on a 10 % absorption value. However the corresponding error with the LEHR collimator is + −3.5 %. An error of + −1 % would need 1100s counting time for the LEHR collimator. A point source of Se75 was counted in varying positions and depths in a water-filled phantom. The Variation Index (VI), (average modulus of %differences) was calculated. The more uniform the spread of values then the VI value is smaller. Table 1.
Conclusion: The sensitivity for Se75 (in a water-filled phantom) with the lead plate is 7608 c/s/MBq. This is 10x the LEHR collimated count rate (GE-LEHR, 766c/s/MBq). Even for a large BMI patient, a 60s count with the lead plate system gives + −0.8 % (2std.dev) error on a 10 % absorption value. However the corresponding error with the LEHR collimator is + −3.5 % . An error of + −1 % would need 1100s counting time for the LEHR collimator. A point source of Se75 was counted in varying positions and depths in a water-filled phantom. The Variation Index (VI), (average modulus of %differences) was calculated. The more uniform the spread of values then the VI value is smaller. They were scanned 50 min. past injection of (avg.) 300 MBq F-18-FDG from skull base to mid-femurs; these results were compared to diagnostic X-ray-CTs (including contrast enhancement where applicable) performed at the same visit or up to 4 weeks prior to the FDG-PET. We used microbiological findings as well as clinical and further (PET/)CT results to establish the diagnose independently.
Results: 83 patients showed no relevant uptake. In 21 we suspected a malignoma, which was proven in 9 cases by surgery and histology. The rest (105 patients) showed conspicuous focal uptake (SUV > 2.5), which was interpreted by us or after exclusion of malignant disease as inflammatory (tuberculosis, sarcoidosis and non-granulomatous). In 35 cases (18 m, 17 f, 45.4 ± 18 y) we do not only have proof of tuberculotic disease other than by FDG-PET, but also ≥ 1 follow-up PET/CTs. We stratified our results according to involved systems: lung and pleura / LN intrathor. / LN extrathor. / bones / visceral organs / other soft tissue. 1 patient remained without FDG-uptake, 15 showed 1 involved system, 13 had lesions in 2, 1 in 3 and 5 in 4. The figures extracted from Xray-CT alone are 12/0 (incl. one false negative also with FDG), 13/1, 9/2, 1/3, none with 4 or more involved systems.  Conclusion: This independent validation technique proves Poisson resampling software correctly generates expected noise characteristics even down to 1 count/pixel. This is reassuring given the increasing applications of such software, and indicates that the Poisson software can reliably be used in studies to examine the effects of reduced time or activity.

A41
Protection of PET nuclear medicine personnel: problems in satisfying dose limit requirements J Hudzietzová 1  Aim: The paper is to discuss some current specific difficulties in assessing the radiation exposure received by workers handling radiopharmaceuticals at nuclear medicine clinics or departments engaged in the PET/CT examinations. This staff is daily coming into contact with unsealed radioactive material which results in its whole-body exposure as well as in the exposure of extremities, especially the skin of hands.
Methods: The present situation in radiation exposures of extremities of radiation workers has been summarized and the specific problems in monitoring the skin dose identified. The equivalent dose to the skin of hands of workers at selected nuclear medicine departments in the Czech Republic have been measured and compared against relevant dose limits.
Results: The distribution of the dose on the surface of fingers at specified positions monitored by TLDs is presented. The relation between the readings of finger dosimeters and the maximum skin exposure was analysed and interpreted. The preliminary results have shown that about 5 % of workers handling F-18 labelled radiopharmaceuticals may exceed the current dose limit for the skin.