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Purpose: Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that modulates intracellular transport and protein quality control. Inhibition of HDAC6 deacetylase activity has shown beneficial effects in disease models, including Alzheimer's disease and amyotrophic lateral sclerosis. This first-in-human positron emission tomography (PET) study evaluated the brain binding of [ 18 F]EKZ-001 ([ 18 F]Bavarostat), a radiotracer selective for HDAC6, in healthy adult subjects., Methods: Biodistribution and radiation dosimetry studies were performed in four healthy subjects (2M/2F, 23.5 ± 2.4 years) using sequential whole-body PET/CT. The most appropriate kinetic model to quantify brain uptake was determined in 12 healthy subjects (6M/6F, 57.6 ± 3.7 years) from 120-min dynamic PET/MR scans using a radiometabolite-corrected arterial plasma input function. Four subjects underwent retest scans (2M/2F, 57.3 ± 5.6 years) with a 1-day interscan interval to determine test-retest variability (TRV). Regional volume of distribution (V T ) was calculated using one-tissue and two-tissue compartment models (1-2TCM) and Logan graphical analysis (LGA), with time-stability assessed. V T differences between males and females were evaluated using volume of interest and whole-brain voxel-wise approaches., Results: The effective dose was 39.1 ± 7.0 μSv/MBq. Based on the Akaike information criterion, 2TCM was the preferred model compared to 1TCM. Regional LGA V T were in agreement with 2TCM V T , however demonstrated a lower absolute TRV of 7.7 ± 4.9%. Regional V T values were relatively homogeneous with highest values in the hippocampus and entorhinal cortex. Reduction of acquisition time was achieved with a 0 to 60-min scan followed by a 90 to 120-min scan. Males demonstrated significantly higher V T than females in the majority of cortical and subcortical brain regions. No relevant radiotracer related adverse events were reported., Conclusion: [ 18 F]EKZ-001 is safe and appropriate for quantifying HDAC6 expression in the human brain with Logan graphical analysis as the preferred quantitative approach. Males showed higher HDAC6 expression across the brain compared to females.

Background: Peptide receptor radionuclide therapy (PRRT) is a validated treatment for somatostatin receptor overexpressing neuroendocrine tumors (NETs). The NETTER-1 trial demonstrated a pronounced positive effect on progression-free-survival compared to high dose somatostatin analogs (SSAs), with a strong tendency toward overall survival benefit. Our aim was to investigate the influence of pretreatment with everolimus and/or sunitinib on subacute hematotoxicity of PRRT. To assess the influence of prior treatment with everolimus/sunitinib might be of clinical relevance due to the link between short-term hematotoxicity and increased incidence of late hematotoxicity. Material and methods: Our single-center retrospective study enrolled all patients treated with 177 Lu-DOTATATE PRRT (1-4 cycles of 7.4 GBq), between November 2013 and July 2018. Patients were assigned to two groups according to their pretreatment: no targeted agents ( N  = 41), or targeted agents (everolimus, sunitinib or both; N  = 41). The end point was subacute hematotoxicity, defined as the nadir value between the first administration until 3 months after the last administration, using the CTCAE 4.03 classification. The impact of splenectomy was also explored. Results: Eighty percent of patients had a primary gastroenteropancreatic NET. No statistically significant differences in severe subacute hematotoxicity were seen in the pretreated group vs. the naive group for hemoglobin (grade 3/4: 12% vs. 22%), neither for leucocytes (grade 3/4: 10% vs. 7%), neutrophils (grade 3/4: 5% vs. 7%), lymphocytes (grade 3/4: 49% vs. 37%) and platelets (grade 3/4: 15% vs. 15%). Furthermore, we observed significantly lower toxicity for total white blood cells, lymphocytes and platelets in the subgroup that had splenectomy ( N  = 12). Limitations of this study include the potential bias in lack of use of targeted agents in patients more susceptible to toxicity, and the limited number of patients and events. Conclusions: In a patient cohort with NET pretreated with everolimus and/or sunitinib, we could not demonstrate a significant effect of prior/pretreatment with everolimus and/or sunitinib on the subacute hematotoxicity of 177 Lu-DOTATATE PRRT.

Purpose: The P2X7 receptor (P2X7R) is an ATP-gated ion channel predominantly expressed on activated microglia and is important in neurodegenerative diseases including Parkinson's disease (PD). In this first-in-human study, we investigated [ 11 C]JNJ54173717 ([ 11 C]JNJ717), a selective P2X7R tracer, in healthy volunteers (HV) and PD patients. Biodistribution, dosimetry, kinetic modelling and short-term test-retest variation (TRV), as well as possible genotype effects, were investigated., Methods: Biodistribution and radiation dosimetry studies were performed in three HV (mean age 30 ± 2 years, two women) using whole-body PET/CT. The most appropriate kinetic model was determined in 11 HV (mean age 62 ± 10 years, six women) and 10 PD patients (mean age 64 ± 8 years, three women; mean UPDRS motor score 21 ± 8) using 90-min dynamic simultaneous PET/MR scans. The total volume of distribution (V T ) was calculated using a one-tissue and a two-tissue compartment model (1TCM, 2TCM) and Logan graphical analysis, and its time stability was assessed. Seven subjects underwent retest scans (mean age 60 ± 13 years, four HV, one woman). A group analysis was performed to compare PD patients and HV. Finally, 13 exons of P2X7R were genotyped in all subjects included in the second part of the study., Results: The mean effective dose was 4.47 ± 0.32 μSv/MBq, with the highest absorbed doses to the gallbladder, liver and small intestine. A reversible 2TCM was the most appropriate kinetic model with relatively homogeneous V T values in the grey and white matter. Average V T values were 3.4 ± 0.8 in HV and 3.3 ± 0.7 in PD patients, with no significant difference between the groups, but a possible genotype effect (rs3751143) was identified which can affect V T . Average TRV was 10-15%. The stability of V T over time allowed a reduction in scan time to 70 min., Conclusion: [ 11 C]JNJ717 is safe and suitable for quantifying P2X7R expression in human brain. In this pilot study, no significant differences in P2X7R binding were found between HV and PD patients. The results also suggest that genotype effects need to be incorporated in future P2X7R PET analyses.

Background: Gastro-intestinal stromal tumors (GISTs) are very rare tumors of the gastro-intestinal tract, originating from the interstitial cells of Cajal or a common cell precursor which both express type III tyrosine kinase receptors. Regorafenib is an oral multi-kinase inhibitor used to treat gastro-intestinal stromal tumors. To our knowledge this is the first case in literature to show the response of regorafenib on PET., Case Presentation: A 37-year-old male with lower abdominal pain and weight loss was referred to our hospital. Abdominal ultrasound and computed tomography (CT) showed diffuse peritoneal implants. Surgical specimen histology showed a GIST with c-KIT exon 11 deletion (c.1708_1728del) and treatment with imatinib 400 mg/day was initiated. Due to disease progression illustrated on baseline versus follow-up 18 F-FDG-PET/CT scans therapy was switched to imatinib 800 mg/day and later to sunitinib 50 mg/day. Upon further disease progression 10 months later, third line treatment with regorafenib 160 mg/day was initiated. 18 F-FDG-PET/CT showed the metabolic responses after 4 months regorafenib treatment ranging from complete response to the appearance of a new lesion in the liver. The new hypermetabolic lesion was only seen on the non-attenuation-corrected images because of breathing motion artifact., Conclusion: This case illustrates that metabolic response can occur in GIST lesions without morphological response after third line regorafinib treatment. Furthermore this is the first case in literature to show regorafinib response on PET.

During the past decades, extensive efforts have been made to expand the knowledge of amyotrophic lateral sclerosis (ALS). However, clinical translation of this research, in terms of earlier diagnosis and improved therapy, remains challenging. Since more than 30% of motor neurons are lost when symptoms become clinically apparent, techniques allowing non-invasive, in vivo detection of motor neuron degeneration are needed in the early, pre-symptomatic disease stage. Furthermore, it has become apparent that non-motor signs play an important role in the disease and there is an overlap with cognitive disorders, such as frontotemporal dementia (FTD). Radionuclide imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), form an attractive approach to quantitatively monitor the ongoing neurodegenerative processes. Although [ 18 F]-FDG has been recently proposed as a potential biomarker for ALS, active targeting of the underlying pathologic molecular processes is likely to unravel further valuable disease information and may help to decipher the pathogenesis of ALS. In this review, we provide an overview of radiotracers that have already been applied in ALS and discuss possible novel targets for in vivo imaging of various pathogenic processes underlying ALS onset and progression.

(18)F-FPEB is a promising PET tracer for studying the metabotropic glutamate subtype 5 receptor (mGluR5) expression in neuropsychiatric disorders. To assess the potential of (18)F-FPEB for longitudinal mGluR5 evaluation in patient studies, we evaluated the long-term test-retest reproducibility using various kinetic models in the human brain. Nine healthy volunteers underwent consecutive scans separated by a 6-month period. Dynamic PET was combined with arterial sampling and radiometabolite analysis. Total distribution volume (V(T)) and nondisplaceable binding potential (BP(ND)) were derived from a two-tissue compartment model without constraints (2TCM) and with constraining the K(1)/k(2) ratio to the value of either cerebellum (2TCM-CBL) or pons (2TCM-PONS). The effect of fitting different functions to the tracer parent fractions and reducing scan duration were assessed. Regional absolute test-retest variability (aTRV), coefficient of repeatability (CR) and intraclass correlation coefficient (ICC) were computed. The 2TCM-CBL showed best fits. The mean 6-month aTRV of V(T) ranged from 8 to 13% (CR < 25%) with ICC > 0.6 for all kinetic models. BPND from 2TCM-CBL with a sigmoid fit for the parent fractions showed the best reproducibility, with aTRV ≤ 7% (CR < 16%) and ICC > 0.9 in most regions. Reducing the scan duration from 90 to 60 min did not affect reproducibility. These results demonstrate for the first time that (18)F-FPEB brain PET has good long-term reproducibility, therefore validating its use to monitor mGluR5 expression in longitudinal clinical studies. We suggest a 2TCM-CBL with fitting a sigmoid function to the parent fractions to be optimal for this tracer., (© 2016 Wiley Periodicals, Inc.)

Early clinical results of two tau tracers, [(18)F]T808 and [(18)F]T807, have recently been reported. In the present study, the biodistribution, radiometabolite quantification, and competition-binding studies were performed in order to acquire comparative preclinical data as well as to establish the value of T808 and T807 as benchmark compounds for assessment of binding affinities of eight new/other tau tracers. Biodistribution studies in mice showed high brain uptake and fast washout.In vivoradiometabolite analysis using high-performance liquid chromatography showed the presence of polar radiometabolites in plasma and brain. No specific binding of [(18)F]T808 was found in transgenic mice expressing mutant human P301L tau. In semiquantitative autoradiography studies on human Alzheimer disease slices, we observed more than 50% tau selective blocking of [(18)F]T808 in the presence of 1 µmol/L of the novel ligands. This study provides a straightforward comparison of the binding affinity and selectivity for tau of the reported radiolabeled tracers BF-158, BF-170, THK5105, lansoprazole, astemizole, and novel tau positron emission tomography ligands against T807 and T808. Therefore, these data are helpful to identify structural requirements for selective interaction with tau and to compare the performance of new highly selective and specific radiolabeled tau tracers., (© The Author(s) 2016.)

Unlabelled: The metabotropic glutamate receptor 5 (mGluR5) is a high-interest target for PET imaging because it plays a role in several pathologies, including addiction, schizophrenia, and fragile X syndrome., Methods: We studied the pharmacokinetics of (18)F-FPEB (3-(18)F-fluoro-5-(2-pyridinylethynyl)benzonitrile), a selective PET radioligand for mGluR5, and used it to quantify mGluR5 in rat brain. Quantification was performed using both arterial sampling in combination with compartment models and simplified reference methods. The simplified reference tissue model (SRTM), Ichise's original multi-linear reference tissue model (MRTMO), and Logan noninvasive were tested as reference models with nondisplaceable binding (BPND) as outcome parameter. Additionally, test-retest scans were obtained in 6 animals., Results: (18)F-FPEB uptake in rat brain was consistent with its known distribution. No radiometabolites were present in the brain, and binding was specific as shown in blocking experiments, which also confirmed the cerebellum as a viable reference region. A 2-tissue-compartment model was used to determine BPND for the striatum (11.7 ± 1.5), nucleus accumbens (10.6 ± 2.0), hippocampus (9.0 ± 1.2), cortex (7.2 ± 1.0), and thalamus (4.0 ± 0.9). Reference methods were able to estimate these values with small bias (<2%). Test-retest analysis showed high repeatability between scans below 6%, also for shorter scan durations of 30 and 60 min., Conclusion: Because of its favorable reversible kinetics, high specificity, and absence of brain radiometabolites (18)F-FPEB proves a highly useful tracer for in vivo visualization of the mGluR5 in rat brain. Moreover, reference tissue models allow noninvasive, rapid scanning with good test-retest., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Objectives: The amyloid imaging PET tracer [(18)F]flutemetamol was recently approved by regulatory authorities in the US and EU for estimation of β-amyloid neuritic plaque density in cognitively impaired patients. While the clinical assessment in line with the label is a qualitative visual assessment of 20 min summation images, the aim of this work was to assess the performance of various parametric analysis methods and standardized uptake value ratio (SUVR), in comparison with arterial input based compartment modeling., Methods: The cerebellar cortex was used as reference region in the generation of parametric images of binding potential (BPND) using multilinear reference tissue methods (MRTMo, MRTM, MRTM2), basis function implementations of the simplified reference tissue model (here called RPM) and the two-parameter version of SRTM (here called RPM2) and reference region based Logan graphical analysis. Regionally averaged values of parametric results were compared with the BPND of corresponding regions from arterial input compartment modeling. Dynamic PET data were also pre-filtered using a 3D Gaussian smoothing of 5mm FWHM and the effect of the filtering on the correlation was investigated. In addition, the use of SUVR images was evaluated. The accuracy of several kinetic models were also assessed through simulations of time-activity curves based on clinical data for low and high binding adding different levels of statistical noise representing regions and individual voxels., Results: The highest correlation was observed for pre-filtered reference Logan, with correction for individual reference region efflux rate constant k2' (R(2)=0.98), or using a cohort mean k2' (R(2)=0.97). Pre-processing filtered MRTM2, unfiltered SUVR over the scanning window 70-90 min and unfiltered RPM also demonstrated high correlations with arterial input compartment modeling (MRTM2 R(2)=0.97, RPM R(2)=0.96 and SUVR R(2)=0.95) Poorest agreement was seen with MRTM without pre-filtering (R(2)=0.68)., Conclusions: Parametric imaging allows for quantification without introducing bias due to selection of anatomical regions, and thus enables objective statistical voxel-based comparisons of tracer binding. Several parametric modeling approaches perform well, especially after Gaussian pre-filtering of the dynamic data. However, the semi-quantitative use of SUVR between 70 and 90 min has comparable agreement with full kinetic modeling, thus supporting its use as a simplified method for quantitative assessment of tracer uptake., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Decreased glutamatergic neurotransmission is hypothesized to be involved in the pathophysiology of schizophrenia. Inhibition of glycine transporter Type-1 (GlyT1) reuptake is expected to increase the glutamatergic neurotransmission and may serve as treatment for cognitive and negative symptoms of schizophrenia. In this article, we present human data from a novel GlyT1 PET tracer, [(18) F]MK-6577. In the process of developing a GlyT1 inhibitor therapeutic, a PET tracer can assist in determining the dose with a high probability of sufficiently testing the mechanism of action. This article reports the human PET studies with [(18) F]MK-6577 for measuring GlyT1 receptor availability at baseline in normal human subjects and occupancy with a GlyT1 inhibitor, MK-2637. Studies were also performed to measure radiation burden and the baseline test-retest (T-RT) variability of the tracer. The effective dose from sequential whole-body dosimetry scans in three male subjects was estimated to be 24.5 ± 2.9 µSV/MBq (mean ± SD). The time-activity curves from T-RT scans modeled satisfactorily using a two tissue compartmental model. The tracer uptake was highest in the pons (VT  = 6.7 ± 0.9, BPND  = 4.1 ± 0.43) and lowest in the cortex (VT  = 2.1 ± 0.5, BPND  = 0.60 ± 0.23). VT T-RT variability measured in three subjects was <12% on average. The occupancy scans performed in a cohort of 15 subjects indicated absence of a reference region. The in vivo potency (Occ50 ) of MK-2637 was determined using two methods: A: Lassen plot with a population input function (Occ50  = 106 nM, SE = 20 nM) and B: pseudo reference tissue model using cortex as the pseudo reference region (Occ50  = 141 nM, SE = 21 nM)., (© 2014 Wiley Periodicals, Inc.)

Purpose: Apart from binding to the dopamine transporter (DAT), [(123)I]FP-CIT shows moderate affinity for the serotonin transporter (SERT), allowing imaging of both monoamine transporters in a single imaging session in different brain areas. The aim of this study was to systematically evaluate extrastriatal binding (predominantly due to SERT) and its age and gender dependencies in a large cohort of healthy controls., Methods: SPECT data from 103 healthy controls with well-defined criteria of normality acquired at 13 different imaging centres were analysed for extrastriatal binding using volumes of interest analysis for the thalamus and the pons. Data were examined for gender and age effects as well as for potential influence of striatal DAT radiotracer binding., Results: Thalamic binding was significantly higher than pons binding. Partial correlations showed an influence of putaminal DAT binding on measured binding in the thalamus but not on the pons. Data showed high interindividual variation in extrastriatal binding. Significant gender effects with 31 % higher binding in women than in men were observed in the thalamus, but not in the pons. An age dependency with a decline per decade (±standard error) of 8.2 ± 1.3 % for the thalamus and 6.8 ± 2.9 % for the pons was shown., Conclusion: The potential to evaluate extrastriatal predominant SERT binding in addition to the striatal DAT in a single imaging session was shown using a large database of [(123)I]FP-CIT scans in healthy controls. For both the thalamus and the pons, an age-related decline in radiotracer binding was observed. Gender effects were demonstrated for binding in the thalamus only. As a potential clinical application, the data could be used as a reference to estimate SERT occupancy in addition to nigrostriatal integrity when using [(123)I]FP-CIT for DAT imaging in patients treated with selective serotonin reuptake inhibitors.

Purpose: Several lines of evidence strongly implicate a dysfunctional endocannabinoid system (ECS) in eating disorders. Using [(18)F]MK-9470 and small animal positron emission tomography (PET), we investigated for the first time cerebral changes in type 1 cannabinoid (CB1) receptor binding in vivo in the activity-based rat model of anorexia (ABA), in comparison to distinct motor- and food-related control conditions and in relation to gender and behavioural variables., Methods: In total, experiments were conducted on 80 Wistar rats (23 male and 57 female). Male rats were assigned to the cross-sectional conditions: ABA (n = 12) and CONTROL (n = 11), whereas female rats were divided between two settings: (1) a cross-sectional design using ABA (n = 13), CONTROL (n = 9), and two extra control conditions for each of the variables manipulated in ABA, i.e. DIET (n = 8) and WHEEL (n = 9), and (2) a longitudinal one using ABA (n = 10) and CONTROL (n = 8) studied at baseline, during the model and upon recovery. The ABA group was subjected to food restriction in the presence of a running wheel, the DIET group to food restriction without wheel, the WHEEL group to a normal diet with wheel and CONTROL animals had a normal diet and no running wheel. Parametric CB1 receptor images of each group were spatially normalized to Paxinos space and analysed voxel-wise., Results: In the ABA model, absolute [(18)F]MK-9470 binding was significantly increased in all cortical and subcortical brain areas as compared to control conditions (male +67 %; female >51%, all p cluster < 6.3×10(-6)) that normalized towards baseline values after weight gain. Additionally, relative [(18)F]MK-9470 binding was increased in the hippocampus, inferior colliculus and entorhinal cortex of female ABA (+4.6%; p cluster < 1.3×10(-6)), whereas no regional differences were observed in male subjects. Again, relative [(18)F]MK-9470 binding values normalized upon weight gain., Conclusion: These data point to a widespread transient disturbance of the endocannabinoid transmission, specifically for CB1 receptors in the ABA model. Our data also suggest (1) gender effects on regional CB1 receptor binding in the hippocampus and (2) add further proof to the validity of the ABA model to mimic aspects of human disease.

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide whose agonist interaction with the CGRP receptor (CGRP-R) in the periphery promotes vasodilation, neurogenic inflammation and trigeminovascular sensory activation. This process is implicated in the cause of migraine headaches, and CGRP-R antagonists in clinical development have proven effective in treating migraine-related pain in humans. CGRP-R is expressed on blood vessel smooth muscle and sensory trigeminal neurons and fibers in the periphery as well as in the central nervous system. However, it is not clear what role the inhibition of central CGRP-R plays in migraine pain relief. To this end, the CGRP-R positron emission tomography (PET) tracer [(11)C]MK-4232 (2-[(8R)-8-(3,5-difluorophenyl)-6,8-[6-(11)C]dimethyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]-N-[(2R)-2'-oxospiro[1,3-dihydroindene-2,3'-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide) was discovered and developed for use in clinical PET studies. In rhesus monkeys and humans, [(11)C]MK-4232 displayed rapid brain uptake and a regional brain distribution consistent with the known distribution of CGRP-R. Monkey PET studies with [(11)C]MK-4232 after intravenous dosing with CGRP-R antagonists validated the ability of [(11)C]MK-4232 to detect changes in CGRP-R occupancy in proportion to drug plasma concentration. Application of [(11)C]MK-4232 in human PET studies revealed that telcagepant achieved only low receptor occupancy at an efficacious dose (140 mg PO). Therefore, it is unlikely that antagonism of central CGRP-R is required for migraine efficacy. However, it is not known whether high central CGRP-R antagonism may provide additional therapeutic benefit.

Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and (18)F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by Δ(9)-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis). In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of Δ(9)-THC was measured in 9 healthy cannabis users (average risk psychotic disorder), 8 patients with psychotic disorder (high risk psychotic disorder) and 7 un-related first-degree relatives (intermediate risk psychotic disorder). PET data were analyzed applying the linear extension of the simplified reference region model (LSRRM), which accounts for time-dependent changes in (18)F-fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after Δ(9)-THC administration, reflecting dopamine release. While Δ(9)-THC was not associated with dopamine release in the control group, significant ligand displacement induced by Δ(9)-THC in striatal subregions, indicative of dopamine release, was detected in both patients and relatives. This was most pronounced in caudate nucleus. This is the first study to demonstrate differential sensitivity to Δ(9)-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis.

Catechol-O-methyltransferase (COMT) plays an essential role in degradation of extracellular dopamine in prefrontal regions of the brain. Although a polymorphism in this gene, COMT Val(158)Met, affects human behavior in response to stress little is known about its effect on dopaminergic activity associated with the human stress response, which may be of interest for stress-related psychiatric disorders such as psychosis. We aimed to investigate the effect of variations in COMT genotype on in vivo measures of stress-induced prefrontal cortex (PFC) dopaminergic processing and subjective stress responses. A combined sample of healthy controls and healthy first-degree relatives of psychosis patients (n = 26) were subjected to an [(18)F]fallypride Positron Emission Tomography scan. Psychosocial stress during the scan was induced using the Montreal Imaging Stress Task and subjective stress was assessed every 12 minutes. Parametric t-maps, generated using the linear extension of the simplified reference region model, revealed an effect of COMT genotype on the spatial extent of [(18)F]fallypride displacement. Detected effects of exposure to psychosocial stress were unilateral and remained restricted to the left superior and right inferior frontal gyrus, with Met-hetero- and homozygotes showing less [(18)F]fallypride displacement than Val-homozygotes. Additionally, Met-hetero- and homozygotes experienced larger subjective stress responses than Val-homozygotes. The direction of the effects remained the same when the data was analyzed separately for controls and first-degree relatives. The human stress response may be mediated in part by COMT-dependent dopaminergic PFC activity, providing speculation for the neurobiology underlying COMT-dependent differences in human behaviour following stress. Implications of these results for stress-related psychopathology and models of dopaminergic functioning are discussed.

Purpose: The aim of this study was to assess striatal dopamine transporter (DAT) availability in a large group of normal subjects., Methods: The study included 122 healthy subjects, aged 18-83 years, recruited in the multicentre 'ENC-DAT' study (promoted by the European Association of Nuclear Medicine). Brain single photon emission computed tomography (SPECT) was acquired by means of dual-head cameras 3 h after [(123)I]FP-CIT administration. Specific to nondisplaceable binding ratios (SBRs) in the basal ganglia were computed using the 'BasGan' software, allowing automatic value extraction with partial volume effect correction. Multicentre camera inhomogeneity was taken into account by calibrating values on basal ganglia phantom data. SBR in each caudate nucleus (C) and putamen (P) were the dependent variables in a repeated measures general linear model analysis; age, gender, handedness and body mass index (BMI) were the independent variables., Results: SBR values in C and P were significantly associated with age (mean rate decrease with age: 0.0306 per year, or 0.57 % of the general mean; p < 0.0001) and gender (women had higher values; p = 0.015), while no significant effect was found for handedness and BMI. A significant interaction was found between age and region (p < 0.0001) as the age-related decline was 0.028 for left C, 0.026 for right C and 0.034 for both P. P/C ratio analysis confirmed that age-related SBR decrease was stronger in P than in C (p < 0.0001). No significant effect was found for season or time of the day when the scan was acquired by analysing the residual of SBR values in C and P, after subtraction of age and gender effects., Conclusion: This study confirms the dependency of DAT on ageing and highlights the gender differences in a large sample of healthy subjects, while it does not support the dependency of DAT on BMI, handedness, circadian rhythm or season.

Purpose: Because brain death (BD)-related donor lung injury is still poorly understood, a reliable mouse model can help in understanding the immunologic mechanisms behind this lung injury. The purpose of our study was to validate BD in mice using small-animal positron emission tomography., Procedures: BD was induced in male Balb/c mice (27.1 ± 0.9 g) with an intracranial balloon catheter inflated rapidly (<1 min) [BD](R) or gradually (36 ± 5 min) [BD](G), and compared with sham-operated [SH] and control animals [C] (n = 6/group). Ten minutes after balloon insertion 10.4 ± 1.0 MBq 2-deoxy-2-[(18)F]-fluoro-D-glucose ((18)FDG) was administered intravenously and static images were performed and quantified., Results: Coronal, sagittal, and transaxial sections of cerebral (18)FDG activity revealed significant differences when comparing [BD](R) and [BD](G) with [C] and [SH] animals. No significant (18)FDG uptake was visually detectable in [BD](R) and [BD](G). The percentage injected dose showed significant differences between BD groups and [C] and [SH] (P < 0.0001). No significant difference was seen between [C] versus [SH] nor between [BD](R)versus [BD](G) (P > 0.05)., Conclusions: (18)FDG micro positron emission tomography imaging is a valuable tool to demonstrate brain functionality and can therefore be used as a surrogate test to confirm BD in mice., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Antagonism of the central opioid receptor like-1 receptor (ORL1) has been implicated in cognition, and has been a focus of drug discovery efforts to ameliorate the cognitive deficits that remain during the stable treatment of schizophrenia with current antipsychotics. In order to facilitate dose selection for phase II clinical testing an ORL1-specific PET tracer was developed to determine drug plasma concentration versus occupancy relationships in order to ensure that the doses selected and the degree of target engagement were sufficient to ensure adequate proof of concept testing. MK-0911 is a selective, high affinity antagonist for the ORL1 receptor radiolabeled with high specific activity (18)F for positron emission tomography (PET) studies. Evaluation of [(18)F]MK-0911 in rhesus monkey PET studies showed a pattern of brain uptake which was consistent with the known distribution of ORL1. In vitro autoradiography with [(18)F]MK-0911 in rhesus monkey and human brain tissue slices showed a regional distribution that was consistent with in vivo imaging results in monkey. Pre-treatment of rhesus monkeys with high doses of structurally diverse ORL1 antagonists MK-0584, MK-0337, or MK-5757 achieved blockade of [(18)F]MK-0911 in all gray matter regions. Baseline PET studies with [(18)F]MK-0911 in healthy human subjects showed tracer distribution and kinetics similar to that observed in rhesus monkey. Quantification of [(18)F]MK-0911 uptake in repeat human baseline PET studies showed a test-retest variability in volume of distribution (V(T)) averaging 3% across brain regions. Humans dosed orally with MK-5757 showed reduced [(18)F]MK-0911 tracer concentration in brain proportional with MK-5757 dose and plasma level. [(18)F]MK-0911 was useful for determining MK-5757-induced receptor occupancy of ORL1 to guide MK-5757 dose-selection for clinical proof-of-concept studies. Additionally, [(18)F]MK-0911 may be a useful tool for studying the pharmacology of ORL1 in various human populations and disease states., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Phosphodiesterase 10A (PDE10A) is a cAMP/cGMP-hydrolysing enzyme with a central role in striatal signalling and implicated in neuropsychiatric disorders such as Huntington's disease, Parkinson's disease, schizophrenia and addiction. We have developed a novel PDE10A PET ligand, (18)F-JNJ42259152, and describe here its human dynamic biodistribution, safety and dosimetry., Methods: Six male subjects (age range 23-67 years) underwent ten dynamic whole-body PET/CT scans over 6 h after bolus injection of 175.5 ± 9.4 MBq (18)F-JNJ42259152. Source organs were delineated on PET/CT and individual organ doses and effective dose were determined using the OLINDA software., Results: F-JNJ42259152 was readily taken up by the brain and showed exclusive retention in the brain, especially in the striatum with good washout starting after 20 min. The tracer was cleared through both the hepatobiliary and the urinary routes. No defluorination was observed. Organ absorbed doses were largest for the gallbladder (239 μSv/MBq) and upper large intestine (138 μSv/MBq). The mean effective dose was 24.9 ± 4.1 μSv/MBq. No adverse events were encountered., Conclusion: In humans, (18)F-JNJ42259152 has an appropriate distribution, brain kinetics and safety. The estimated effective dose was within WHO class IIb with low interindividual variability. Therefore, the tracer is suitable for further kinetic evaluation in humans.

Introduction: Up-regulation of the type 2 cannabinoid receptor (CB(2)R) has been reported in (neuro)inflammatory diseases. In this study, we report the preclinical evaluation of [(11)C]NE40 as positron emission tomography (PET) radioligand for visualization of the CB(2)R., Methods: The selectivity of NE40 for CB(2)R and its toxicity and mutagenicity were determined. [(11)C]NE40 was evaluated by biodistribution and autoradiography studies in normal rats and a microPET study in normal mice, rats and a rhesus monkey. Specific in vivo binding of [(11)C]NE40 to human CB(2)R (hCB(2)R) was studied in a rat model with hCB(2)R overexpression., Results: [(11)C]NE40 shows specific CB(2)R binding in the spleen and blood of normal rats and high brain uptake in rhesus monkey. [(11)C]NE40 showed specific and reversible binding to hCB(2)R in vivo in a rat model with local hCB(2)R overexpression., Conclusions: [(11)C]NE40 shows favorable characteristics as radioligand for in vivo visualization of the CB(2)R and is a promising candidate for hCB(2)R PET imaging., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: The most widely studied positron emission tomography ligand for in vivo beta-amyloid imaging is (11)C-Pittsburgh compound B ((11)C-PIB). Its availability, however, is limited by the need for an on-site cyclotron. Validation of the (18)F-labeled PIB derivative (18)F-flutemetamol could significantly enhance access to this novel technology., Methods: Twenty-seven patients with early-stage clinically probable Alzheimer disease (AD), 20 with amnestic mild cognitive impairment (MCI), and 15 cognitively intact healthy volunteers (HVs) above and 10 HVs below 55 years of age participated. The primary endpoint was the efficacy of blinded visual assessments of (18)F-flutemetamol scans in assigning subjects to a raised versus normal uptake category, with clinical diagnosis as the standard of truth (SOT). As secondary objectives, we determined the correlation between the regional standardized uptake value ratios (SUVRs) for (18)F-flutemetamol and its parent molecule (11)C-PIB in 20 of the AD subjects and 20 of the MCI patients. We also determined test-retest variability of (18)F-flutemetamol SUVRs in 5 of the AD subjects., Results: Blinded visual assessments of (18)F-flutemetamol scans assigned 25 of 27 scans from AD subjects and 1 of 15 scans from the elderly HVs to the raised category, corresponding to a sensitivity of 93.1% and a specificity of 93.3% against the SOT. Correlation coefficients between cortical (18)F-flutemetamol SUVRs and (11)C-PIB SUVRs ranged from 0.89 to 0.92. Test-retest variabilities of regional SUVRs were 1 to 4%., Interpretation: (18)F-Flutemetamol performs similarly to the (11)C-PIB parent molecule within the same subjects and provides high test-retest replicability and potentially much wider accessibility for clinical and research use.

These guidelines summarize the current views of the European Association of Nuclear Medicine Neuroimaging Committee (ENC). The purpose of the guidelines is to assist nuclear medicine practitioners when making recommendations, performing, interpreting, and reporting the results of brain perfusion single photon emission computed tomography (SPECT) studies using (99m)Tc-labelled radiopharmaceuticals. The aim is to achieve a high quality standard for brain perfusion SPECT imaging, which will increase the diagnostic impact of this technique in clinical practice. The present document replaces a former version of the guideline published in 2001 which was inspired by the Society of Nuclear Medicine Procedure Guideline for Brain Perfusion SPECT [1], the views of the Society of Nuclear Medicine Brain Imaging Council [2], and the individual experience of experts in European countries. The guidelines are intended to present information specifically adapted to European practice. The information provided should be taken in the context of local conditions and regulations.

Imaging agents targeting amyloid beta (Abeta) may be useful for early diagnosis and follow-up of treatment of patients with Alzheimer's disease (AD). Three of five tested 2-(4'-fluorophenyl)-1,3-benzothiazoles displayed high binding affinities for Abeta plaques in AD human brain homogenates (K(i) between 2.2 and 22.5 nM). They all contained the (18)F-label directly attached to the aromatic ring and were synthesized starting from the nitro precursor. Determination of the partition coefficient, biodistribution studies in normal mice, and in vivo microPET studies in normal rats showed that their initial brain uptake was high and brain washout was fast. The most promising compound [(18)F]5, or 6-methyl-2-(4'-[(18)F]fluorophenyl)-1,3-benzothiazole, seemed to be metabolically stable in the brain, and its plasma radiometabolites, which do not cross the blood-brain barrier, were determined. The preliminary results strongly suggest that this new fluorinated compound is a promising candidate as an Abeta plaque imaging agent for the study of patients with AD.

Introduction: The cannabinoid type 2 receptor (CB(2) receptor) is part of the endocannabinoid system and has been suggested as mediator of a number of central and peripheral inflammatory processes. In the present study, we have synthesized N-[(1s)-1-[4-[[4-methoxy-2-[(4-[(11)C]methoxyphenyl)sulfonyl)-phenyl]sulfonyl] phenyl]ethyl]methanesulfonamide ([(11)C]methoxy-Sch225336) and evaluated this new tracer agent as a potential positron emission tomography radioligand for the in vivo visualization of CB(2) receptors., Methods: Sch225336 was demethylated and the resulting phenol precursor was radiolabelled with a carbon-11 methyl group by methylation using [(11)C]methyl iodide, followed by purification by high-performance liquid chromatography. The log P of [(11)C]methoxy-Sch225336 and its biodistribution in normal mice were determined. Enhancement of brain uptake by inhibition of blood-brain barrier (BBB) efflux transporters was studied. Mouse plasma was analysed to quantify the formation of radiometabolites. The affinity of Sch225336 for the human cannabinoid type 1 and type 2 receptor was determined., Results: [(11)C]methoxy-Sch225336 was obtained with a decay corrected radiochemical yield of about 30% and a specific activity of 88.8 GBq/mumol (end of synthesis). After intravenous injection in mice, the compound is rapidly cleared from the blood through the hepatobiliary pathway and does not show particular retention in any of the major organs. Polar metabolites were found in mouse plasma. Brain uptake was low despite the favourable log P value of 2.15, which is partly due to efflux by BBB pumps., Conclusion: [(11)C]methoxy-Sch225336 is a good candidate for in vivo imaging of the CB(2) receptor, although the low blood-brain barrier penetration limits its potential for central nervous system imaging.

The endocannabinoid system (ECS) is implicated as a regulator of homeostasis of several cerebral functions and is a novel target for drug treatment of neuropyschiatric disorders. So far, the cerebral cannabinoid-type 1 receptor (CB1R) has only been studied using in vitro, animal model, electrophysiological and post-mortem data. We have used positron emission tomography (PET) using a high-affinity, subtype-selective radioligand, [(18)F]MK-9470, to assess the in vivo cerebral CB1R distribution and its variation with healthy aging and gender. Fifty healthy volunteers (25 M/25 F, 18-69 years) underwent [(18)F]MK-9470 PET. Parametric [(18)F]MK-9470 binding maps were constructed, corrected for partial volume effects and analyzed using statistical parametric mapping in a combined categorical (gender) and covariate (age) design. We found that [(18)F]MK-9470 binding to CB1R increased with aging but only in women (p(FWE)<0.05, corrected for multiple comparisons); this was most pronounced in the basal ganglia, lateral temporal cortex and limbic system, especially in the hippocampus. Men showed higher [(18)F]MK-9470 binding then women (p<0.001, uncorrected), in clusters of the limbic system and cortico-striato-thalamic-cortical circuit. Region-dependent and gender-related upregulation of [(18)F]MK-9470 binding with aging is in line with ex vivo findings in rodent studies and may be associated with a changing homeostatic capacity or compensation mechanisms in the ECS that is modulated by sex hormones. In vivo PET of the CB1R will likely improve our understanding of the ECS in several neurological and psychiatric disorders.

Cerebral cannabinoid receptor (CB1) and cannabinoid drugs constitute a vibrant field in modern medicine and pharmacology. However, the physiological and pharmacological roles played by the cannabinoid receptor in the central nervous system are still not fully understood. Positron-emission tomography (PET) is the most advanced technique for non-invasive research of cerebral receptors. Quantitative PET imaging of CB1 in animal and human brains has been limited by drawbacks of the available CB1 radioligands that manifested low specific binding, high non-specific binding and/or low brain uptake. The latest research revealed three CB1 PET radioligands ([(11)C]JHU75528, [(18)F]MK9470 and [(11)C]MePPEP) with improved imaging properties. These compounds are now being employed for the quantitative evaluation of CB1 in human subjects with PET. Molecular imaging of the CB1 receptor with these radioligands has now become possible and their application in healthy humans and in patients is underway. Despite the substantial progress in development of CB1 PET radioligands even the latest radioligands manifest certain disadvantages. Current research efforts on the development of CB1 radioligands with higher binding potential, greater brain uptake and more optimal brain kinetics.

Introduction: [2'-[(18)F]Fluoroethyl (lR-2-exo-3-exe)-8-methyl-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]-octane-2-carboxylate] ([(18)F]FECT) is a positron emission tomography (PET) tracer for imaging the dopamine transporter (DAT) in vivo. We report an improved radiosynthesis procedure and affinity data and have analyzed both brain tissue and plasma samples for the presence of radiometabolites as a function of time post intravenous injection of [(18)F]FECT to rats., Methods: The radiosynthesis of [(18)F]FECT was carried out using [(18)F]fluoroethyltriflate ([(18)F]FEtOTf) as a labeling agent. The affinity of FECT for DAT was determined in vitro by binding experiments on rat striatal membranes. Three rats were injected with [(18)F]FECT and blood samples were collected at 1 or 3 h post injection (p.i.). Plasma was separated and analyzed using reversed-phase high-performance liquid chromatography (RP-HPLC). Similarly, cerebrum and cerebellum were isolated after sacrifice of the animals at 3 h p.i. of the tracer and homogenized. HPLC analysis was performed on extracts of both samples to examine the presence of metabolites., Results: The radiochemical yield for [(18)F]FECT was 85% relative to the starting activity of [(18)F]FEtOTf. The inhibitory constant (K(i)) of FECT for DAT was found to be 6 nM. The fraction of radioactivity corresponding to intact [(18)F]FECT was 93% in plasma at both 1 and 3 h p.i. and 96% in cerebrum as well as cerebellum samples at 3 h p.i., Conclusions: FECT has a high affinity for the dopamine transporter. [(18)F]FECT was found to be stable in vivo and the amount of radiolabeled metabolites in plasma and brain at 3 h p.i. is negligible. Hence, [(18)F]FECT can be used for the in vivo quantification of DAT using PET.

Unlabelled: Automated voxel-based or predefined volume-of-interest (VOI) analysis of rodent small-animal PET data is necessary for optimal use of information because the number of available resolution elements is limited. We have mapped metabolic ((18)F-FDG), dopamine transporter (DAT) (2'-(18)F-fluoroethyl(1R-2-exo-3-exe)-8-methyl-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]-octane-2-carboxylate [(18)F-FECT]), and dopaminergic D(2) receptor ((11)C-raclopride) small-animal PET data onto a 3-dimensional T2-weighted MRI rat brain template oriented according to the rat brain Paxinos atlas. In this way, ligand-specific templates for sensitive analysis and accurate anatomic localization were created. Registration accuracy and test-retest and intersubject variability were investigated. Also, the feasibility of individual rat brain statistical parametric mapping (SPM) was explored for (18)F-FDG and DAT imaging of a 6-hydroxydopamine (6OHDA) model of Parkinson's disease., Methods: Ten adult Wistar rats were scanned repetitively with multitracer small-animal PET. Registrations and affine spatial normalizations were performed using SPM2. On the MRI template, a VOI map representing the major brain structures was defined according to the stereotactic atlas of Paxinos. (18)F-FDG data were count normalized to the whole-brain uptake, whereas parametric DAT and D(2) binding index images were constructed by reference to the cerebellum. Registration accuracy was determined using random simulated misalignments and vectorial mismatching., Results: Registration accuracy was between 0.24 and 0.86 mm. For (18)F-FDG uptake, intersubject variation ranged from 1.7% to 6.4%. For (11)C-raclopride and (18)F-FECT data, these values were 11.0% and 5.3%, respectively, for the caudate-putamen. Regional test-retest variability of metabolic normalized data ranged from 0.6% to 6.1%, whereas the test-retest variability of the caudate-putamen was 14.0% for (11)C-raclopride and 7.7% for (18)F-FECT. SPM analysis of 3 individual 6OHDA rats showed severe hypometabolism in the ipsilateral sensorimotor cortex (P

Purpose: [18F]MK-6240 is a selective, high-affinity positron emission tomography tracer for imaging neurofibrillary tangles, a key pathological signature that correlates with cognitive decline in Alzheimer disease. This report provides safety information from preclinical toxicology studies and first-in-human whole-body biodistribution and dosimetry studies of [18F]MK-6240 for its potential application in human brain imaging studies.Procedures: MK-6240 was administered intravenously (IV) in a 7-day rat toxicity study at × 50, × 100, and × 1000 dose margins relative to projected highest clinical dose of 0.333 μg/kg. The IV formulation of MK-6240 for clinical use and the formulation used in the 7-day rat toxicity study was tested for hemolysis potential in human and Wistar rat whole blood. Sequential whole-body positron emission tomography scans were performed in three healthy young subjects after IV bolus injection of 180 ± 0.3 MBq [18F]MK-6240 to characterize organ biodistribution and estimate whole-body radiation exposure (effective dose).Results: MK-6240 administered IV in a 7-day rat toxicity study did not show any test article-related changes. The no-observed-adverse-effect level in rats was ≥ 333 μg/kg/day which provides a margin 1000-fold over an anticipated maximum clinical dose of 0.333 μg/kg. Additionally, the MK-6240 formulation was not hemolytic in human or Wistar rat blood. [18F]MK-6240 activity was widely distributed to the brain and the rest of the body, with organ absorbed doses largest for the gall bladder (202 μGy/MBq). The average (±SD) effective dose was 29.4 ± 0.6 μSv/MBq, which is in the typical range for F-18 radiolabeled ligands.Conclusions: Microdoses of [18F]MK-6240 are safe for clinical positron emission tomography imaging studies. Single IV administration of 185 MBq (5 mCi) [18F]MK-6240 is anticipated to result in a total human effective dose of 5.4 mSv and thus allows multiple positron emission tomography scans of the same subject per year. [ABSTRACT FROM AUTHOR]

Purpose: Preclinical, or asymptomatic, Alzheimer's disease (AD) refers to the presence of positive AD biomarkers in the absence of cognitive deficits. This research concept is being applied to define target populations for clinical drug development. In a prospective community-recruited cohort of cognitively intact older adults, we compared two amyloid imaging markers within subjects: F-flutemetamol and C-Pittsburgh compound B (PIB). Methods: In 32 community-recruited cognitively intact older adults aged between 65 and 80 years, we determined the concordance between binary classification based on F-flutemetamol versus C-PIB according to semiquantitative assessment (standardized uptake value ratio in composite cortical volume, SUVR) and, alternatively, according to visual reads. We also determined the correlation between F-flutemetamol and C-PIB SUVR and evaluated how this was affected by the reference region chosen (cerebellar grey matter versus pons) and the use of partial volume correction (PVC) in this population. Results: Binary classification based on semiquantitative assessment was concordant between F-flutemetamol and C-PIB in 94 % of cases. Concordance of blinded binary visual reads between tracers was 84 %. The Spearman correlation between F-flutemetamol and C-PIB SUVR with cerebellar grey matter as reference region was 0.84, with a slope of 0.98. Correlations in neocortical regions were significantly lower with the pons as reference region. PVC improved the correlation in striatum and medial temporal cortex. Conclusion: For the definition of preclinical AD based on F-flutemetamol, concordance with C-PIB was highest using semiquantitative assessment with cerebellar grey matter as reference region. [ABSTRACT FROM AUTHOR]

These guidelines summarize the current views of the European Association of Nuclear Medicine Neuroimaging Committee (ENC). The aim of the guidelines is to assist nuclear medicine practitioners when making recommendations, performing, interpreting, and reporting the results of clinical dopamine transporter (DAT) single photon emission computed tomography (SPECT) studies using 123I-labelled radiopharmaceuticals. The aim is to achieve a high-quality standard of DAT SPECT imaging, which will increase the diagnostic impact of this technique in neurological practice. The present document is an update of the 2002 guidelines [] and has been guided by the views of various national societies: the Task Group Neuro-Nuclear-Medicine of the German Society of Nuclear Medicine [], a consensus statement of the imaging centres included in the “Kompetenznetz-Parkinson” sponsored by the German Federal Ministry of Education, and the Task Group of Neuro-Nuclear-Medicine of the French Society of Nuclear Medicine []. The guidelines reflect the individual experience of experts in European countries. The guidelines are intended to present information specifically adapted to European practice. The information provided should be taken in the context of local conditions and regulations. [ABSTRACT FROM AUTHOR]

The article discusses the 18-fluorodeoxyglucose-positron-emission tomography (FDG-PET) findings in female patients with an asymmetrical subtype of primary lateral sclerosis (PLS). Topics covered include the difference between PLS and amyotrophic lateral sclerosis (ALS), the correlation of the asymmetrical presentation with clear regions of hypometabolism on FDG-PET and the spread of the disease from the right arm to the right leg.

As [ 18 F]fluoride is a starting reagent in the radiosynthesis of most fluorine-18 labeled positron emission tomography (PET) tracers, its chromatographic behavior on reversed phase (RP) HPLC columns is important for the purification performance and accuracy of RP HPLC quality control methods. We have investigated the chromatographic behavior and recovery of [ 18 F]fluoride as a function of the type and brand of RP HPLC column, the pH and the composition of the mobile phase. Elution and elution profile of [ 18 F]fluoride from six RP-HPLC columns (Waters XBridge C18 3 mm × 100 mm 3.5 μm; Grace Platinum EPS C18 4.6 mm × 100 mm, 3 μm; Waters XTerra C18 4.6 mm × 250 mm, 5 μm; Phenomenex C18 4.6 mm × 150 mm, 5 μm; Hamilton PRP-1 column 4.1 mm × 150 mm, 5 μm; Merck KGaA Chromolith Performance C18 3 mm × 100 mm) eluted with mobile phase composed of phosphate or acetate buffers (pH 2, 3, 4, 5, 7.3 and 9) and acetonitrile or ethanol as organic modifier were characterized. The elution profile was determined by on-line radioactivity measurement in the column eluate and recovery was calculated by comparison of radioactivity eluted with the HPLC column present or absent in the chromatographic flow path. Interestingly, [ 18 F]fluoride recovery increased with increasing pH. At pH 3 all packed silica-based columns showed significant retention of fluorine-18, whereas almost no retention was observed on a polymeric PRP-1 column. However at pH 5, [ 18 F]fluoride recovery was above 90% for each tested column. In addition, small differences were observed when changing the composition of the mobile phase. We therefore recommend to use a mobile phase with pH > 5 for silica based C18 columns for both quality control and semi-preparative HPLC of fluorine-18 labeled PET radiopharmaceuticals. If required a lower pH can be used in combination with a polymer based HPLC column. [ABSTRACT FROM AUTHOR]