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Purpose: Florbetaben is a β-amyloid-targeted PET tracer with significant potential for augmenting the toolbox in the clinical diagnosis of Alzheimer's disease (AD). In dementia imaging, shortening of scan duration may simplify future clinical use. The aim of this retrospective study was to investigate the effect of scan duration on diagnostic accuracy. Methods: PET scans obtained from 25 AD patients and 25 healthy volunteers (HVs) were analysed. In each subject, scans of three different durations (5, 10 and 20 min; all starting 90 min after injection) were obtained, randomized, and visually assessed by three experts blinded to the subject's identity and group affiliation. Presence/absence of β-amyloid and diagnostic confidence (0-100 %) were scored, and 10 % of the scans were re-read. Further, randomly selected datasets of ten AD patients and ten HVs were quantified using an established VOI-based approach and using a voxel-based approach. Results: The sensitivity and specificity of the blinded read were 80 % and 96 %, respectively, for all scan durations. Diagnostic confidence was high (97 ± 6 %, 97 ± 6 % and 95 ± 8 % for the 20-min, 10-min and 5-min scans, respectively; n.s.), as was interreader agreement (kappa = 0.94, kappa = 0.94, kappa = 0.89; n.s.). Intrareader agreement was highest for the 20-min scan (kappa = 1.00) and lower for the 10-min scan (kappa = 0.71) and 5-min scan (kappa = 0.80; p = 0.002 and 0.003 vs. the 20-min scan). For all scan durations, composite SUVRs (Cohen's d effect size 4.5, 3.9 and 4.8 for the 5-min, 10-min and 20-min scans; p < 0.0001 each) and individual brain volumes affected by β-amyloid (Cohen's d effect size 1.6, 1.8 and 2.0 for the 5-min, 10-min and 20-min scans; p < 0.005 each) were significantly higher in AD patients than in HVs. Conclusion: Reduction in scan duration did not relevantly affect the accuracy of florbetaben PET scans in discriminating between AD patients and HVs. Thus, a reduction in scan duration seems conceivable for the future clinical use of florbetaben. [ABSTRACT FROM AUTHOR]

Purpose: [C]DASB is currently the most frequently used highly selective radiotracer for visualization and quantification of central SERT. Its use, however, is hampered by the short half-life of C, the moderate cortical test-retest reliability, and the lack of quantifying endogenous serotonin. Labelling with F allows in principle longer acquisition times for kinetic analysis in brain tissue and may provide higher sensitivity. The aim of our study was to firstly use the new highly SERT-selective F-labelled fluoromethyl analogue of (+)-McN5652 ((+)-[F]FMe-McN5652) in humans and to evaluate its potential for SERT quantification. Methods: The PET data from five healthy volunteers (three men, two women, age 39 ± 10 years) coregistered with individual MRI scans were semiquantitatively assessed by volume-of-interest analysis using the software package PMOD. Rate constants and total distribution volumes ( V) were calculated using a two-tissue compartment model and arterial input function measurements were corrected for metabolite/plasma data. Standardized uptake region-to-cerebellum ratios as a measure of specific radiotracer accumulation were compared with those of a [C]DASB PET dataset from 21 healthy subjects (10 men, 11 women, age 38 ± 8 years). Results: The two-tissue compartment model provided adequate fits to the data. Estimates of total distribution volume ( V) demonstrated good identifiability based on the coefficients of variation (COV) for the volumes of interest in SERT-rich and cortical areas (COV V <10%). Compared with [C]DASB PET, there was a tendency to lower mean uptake values in (+)-[F]FMe-McN5652 PET; however, the standard deviation was also somewhat lower. Altogether, cerebral (+)-[F]FMe-McN5652 uptake corresponded well with the known SERT distribution in humans. Conclusion: The results showed that (+)-[F]FMe-McN5652 is also suitable for in vivo quantification of SERT with PET. Because of the long half-life of F, the widespread use within a satellite concept seems feasible. [ABSTRACT FROM AUTHOR]

Purpose: Complementing clinical findings with those generated by biomarkers-such as β-amyloid-targeted positron emission tomography (PET) imaging-has been proposed as a means of increasing overall accuracy in the diagnosis of Alzheimer's disease (AD). Florbetaben ([F]BAY 94-9172) is a novel β-amyloid PET tracer currently in global clinical development. We present the results of a proof of mechanism study in which the diagnostic efficacy, pharmacokinetics, safety and tolerability of florbetaben were assessed. The value of various quantitative parameters derived from the PET scans as potential surrogate markers of cognitive decline was also investigated. Methods: Ten patients with mild-moderate probable AD (DSM-IV and NINCDS-ADRDA criteria) and ten age-matched (≥ 55 years) healthy controls (HCs) were administered a single dose of 300 MBq florbetaben, which contained a tracer mass dose of < 5 μg. The 70-90 min post-injection brain PET data were visually analysed by three blinded experts. Quantitative assessment was also performed via MRI-based, anatomical sampling of predefined volumes of interest (VOI) and subsequent calculation of standardized uptake value (SUV) ratios (SUVRs, cerebellar cortex as reference region). Furthermore, single-case, voxelwise analysis was used to calculate individual 'whole brain β-amyloid load'. Results: Visual analysis of the PET data revealed nine of the ten AD, but only one of the ten HC brains to be β-amyloid positive ( p = 0.001), with high inter-reader agreement (weighted kappa ≥ 0.88). When compared to HCs, the neocortical SUVRs were significantly higher in the ADs (with descending order of effect size) in frontal cortex, lateral temporal cortex, occipital cortex, anterior and posterior cingulate cortices, and parietal cortex ( p = 0.003-0.010). Voxel-based group comparison confirmed these differences. Amongst the PET-derived parameters, the Statistical Parametric Mapping-based whole brain β-amyloid load yielded the closest correlation with the Mini-Mental State Examination scores ( r = −0.736, p < 0.001), following a nonlinear regression curve. No serious adverse events or other safety concerns were seen. Conclusion: These results indicate florbetaben to be a safe and efficacious β-amyloid-targeted tracer with favourable brain kinetics. Subjects with AD could be easily differentiated from HCs by both visual and quantitative assessment of the PET data. The operator-independent, voxel-based analysis yielded whole brain β-amyloid load which appeared valuable as a surrogate marker of disease severity. [ABSTRACT FROM AUTHOR]

Recent imaging and neuropathological studies indicate reduced serotonin transporter (SERT) in advanced Parkinson's disease (PD). However, data on SERT in early PD patients are sparse. Following the hypothesis that the serotonergic system is damaged early in PD, the aim of our study was to investigate SERT availability by means of PET imaging. Since the loss of dopaminergic neurons is the pathologic hallmark of PD and SERT might be associated with psychiatric co-morbidity, we further sought to correlate SERT availability with the availability of dopamine transporter (DAT) and depressive or motor symptoms in early PD. We prospectively recruited nine early PD patients (4 female, 5 male; 42-76 years) and nine age matched healthy volunteers (5 female, 4 male; 42-72 years). Diagnosis of PD was confirmed by the UK brain bank criteria and DAT imaging. SERT availability was measured by means of [C]DASB PET. For neuropsychiatric assessment done on the day of PET we applied UPDRS parts I, II and III, Beck's Depression Inventory, Hamilton Rating Scale for Depression, Mini-Mental State Examination and Demtect. SERT was not reduced in any of 14 investigated regions of interest in the nine PD patients compared to healthy controls ( p > 0.13). SERT was negatively associated with DAT in the striatum ( r = −0.69; p = 0.04) but not within the midbrain. There was no correlation of SERT availability with depressive symptoms. No alteration of SERT binding in our patients suggests that the serotonergic system is remarkably preserved in early PD. Correlation with DAT might point to a compensatory regulation of the serotonergic system in early stages of PD. [ABSTRACT FROM AUTHOR]

Functional changes of nicotinic acetylcholine receptors (nAChR) are important during age-related neuronal degeneration. Recent studies demonstrate the applicability of the nAChR ligand 2-[18F]F-A-85380 for neuroimaging of patients with dementias. However, its binding kinetics demands a 7-h acquisition time limiting its practicality for clinical PET studies. Thus, the authors developed [18F]norchloro-fluoro-homoepibatidine ([18F]NCFHEB) for nAChR imaging. The kinetics of the two enantiomers of [18F]NCFHEB were compared with 2-[18F]F-A85380 in porcine brain to evaluate their potential for human neuroimaging. Twenty-four juvenile female pigs were studied with PET using [18F]NCFHEB. Nine animals received an additional i.v. injection (1 mg/kg) of the nAChR agonist A81418 before radiotracer administration followed by infusion (2 mg/kg/7h) thereafter. Several compartment models were applied for quantification. (−)- and (+)-[18F]NCFHEB showed a twofold to threefold higher brain uptake than 2-[18F]F-A-85380. All three radiotracers displayed spatially hetereogenous binding kinetics in regions with high, moderate, or low specific binding. The equilibrium of specific binding of (−)-[18F]NCFHEB was reached earlier than that of (+)-[18F]NCFHEB or 2-[18F]F-A85380. Continuous administration of the nAChR agonist A81418 inhibited the specific binding of (−)- and (+)-[18F]NCFHEB but not of 2-[18F]F-A85380. The peripheral metabolism of (+)-[18F]NCFHEB proceeded somewhat slower than that of the other radiotracers. Both enantiomers of [18F]NCFHEB are appropriate radiotracers for neuroimaging of nAChR in pigs. Their binding profile in vivo appears to be more selective than that of 2-[18F]F-A85380. (−)-[18F]NCFHEB offers a faster equilibrium of specific binding than 2-[18F]F-A85380. Synapse 62:205-218, 2008. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: 2-[18F]Fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]F-A-85380) was among the first subtype selective radioligands to visualise the in vivo distribution of α4β2-containing neuronal nicotinic acetylcholine receptors (nAChRs) in human brain. We developed a one-pot synthesis for the preparation of 2-[18F]F-A-85380 in a commercially available TRACERlab FXF−N synthesis module. The synthesis comprises a nucleophilic substitution followed by hydrolysis of a t-butyloxycarbonyl (BOC)-protected intermediate. After formulation for intravenous application up to 20GBq 2-[18F]F-A-85380 were produced from a starting activity of 100GBq [18F]fluoride in 60min with a specific activity of about 4·105 GBq/mmol and a mean radiochemical purity of more than 99%. [Copyright &y& Elsevier]

Noninvasive molecular imaging of subtypes of neuronal nicotinic acetylcholine receptors (nAChRs) will provide information on the role of these receptors in neurodegenerative diseases. The binding of the positron emission tomography ligand 2-[18F]F-A-85380 to nAChRs was investigated in the porcine brain by quantitative autoradiography in vitro. The high-affinity binding of 2-[18F]F-A-85380 to each of the investigated 12 brain areas was saturable and apparently monophasic (e.g., apparent KD value of 1.72 nM in the thalamus). The highest density of specific binding sites was observed in the thalamus (1,158 fmol/mg protein), and the lowest density was measured in the cerebellar gray matter (11 fmol/mg protein). An attempt to assess nAChR subtype specificity of 2-[18F]F-A-85380 was made by competitive autoradiography. Binding of 2-[18F]F-A-85380 coincubated with 2-F-A-85380, epibatidine, cytisine, or methyllycaconitine, respectively, indicated a specificity of 2-[18F]F-A-85380 to β2-containing nAChRs in the porcine brain. The autoradiographic data confirmed the suitability of swine as a model for the evaluation of radioligands designed for imaging of nAChR subtypes in the living brain. Synapse 59:201-210, 2006. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The present study compares the uptake of [18F]Fluoroazomycinarabinofuranoside (18FAZA), a recently developed hypoxia tracer for PET imaging of tissue hypoxia, with an established tracer [18F]Fluoromisonidazole (18FMISO) both in vitro, using Walker 256 rat carcinosarcoma cells, and in vivo in experimental rat tumors eleven to twelve days after tumor cell implantation. In vitro studies indicated that hypoxia-selective uptake of both 18FAZA and 18FMISO in tumor cells, 20 and 100 minutes post-incubation was of the same magnitude (20 min: 1.24 ± 0.4% (18FAZA); 1.19 ± 0.7% (18FMISO); 100 min: 3.6 ± 1.6% (18FAZA); 3.3 ± 1.7% (18FMISO)). PET imaging reflected a similar radiotracer distribution in rat tumors for 18FAZA and 18FMISO one h after radiotracer injection. The concentration of 18FAZA in the tumors as measured by PET, however, was lower in comparison to 18FMISO (SUVFAZA = 0.61 ± 0.2 vs. SUVFMISO = 0.92 ± 0.3, p < 0.05) although the tumor to muscle ratios for 18FAZA and 18FMISO did not differ in the PET images that were obtained after one h (SUVFAZA = 2.5 ± 0.5 vs. SUVFMISO = 2.9 ± 0.7). A comparison of PET data three h post-injection (SUVFAZA = 3.0 ± 0.5 vs. SUVFMISO = 4.6 ± 1.8, p < 0.05) demonstrated a lower 18FAZA uptake that indicates a lower sensitivity of 18FAZA in comparison to 18FMISO in detecting hypoxic regions at a longer time in this animal model. However, these data also show a faster elimination of 18FAZA from blood, viscera and muscle tissue, via the renal system. This advantage of a faster reduction of unspecific binding, in light of similar or marginally lower tumor uptake, warrants further investigation of 18FAZA as a marker of regional hypoxia in tumors. [Copyright &y& Elsevier]

A new sugar-coupled 2-nitroimidazole derivative ([18F]1) has been prepared in good radiochemical yields starting from peracetylated 2-[18F]FDG obtained from an automated 2-[18F]FDG production module. The corresponding glucose derivative 2 has proved to be able to inhibit 2-[18F]FDG uptake into tumor cells in a concentration dependent way. However, [18F]1 failed to show a retention in hypoxic tumor tissue thus excluding itself from further investigations. [Copyright &y& Elsevier]

Purpose: We hypothesized that severe tau burden in brain regions involved in direct or indirect pathways of the basal ganglia correlate with more severe striatal dopamine deficiency in four-repeat (4R) tauopathies. Therefore, we correlated [18F]PI-2620 tau-positron-emission-tomography (PET) imaging with [123I]-Ioflupane single-photon-emission-computed tomography (SPECT) for dopamine transporter (DaT) availability. Methods: Thirty-eight patients with clinically diagnosed 4R-tauopathies (21 male; 69.0 ± 8.5 years) and 15 patients with clinically diagnosed α-synucleinopathies (8 male; 66.1 ± 10.3 years) who underwent [18F]PI-2620 tau-PET and DaT-SPECT imaging with a time gap of 3 ± 5 months were evaluated. Regional Tau-PET signals and DaT availability as well as their principal components were correlated in patients with 4R-tauopathies and α-synucleinopathies. Both biomarkers and the residuals of their association were correlated with clinical severity scores in 4R-tauopathies. Results: In patients with 4R-tauopathies, [18F]PI-2620 binding in basal ganglia and midbrain regions was negatively associated with striatal DaT availability (i.e. globus pallidus internus and putamen (β = − 0.464, p = 0.006, Durbin-Watson statistics = 1.824) in a multiple regression model. Contrarily, [18F]PI-2620 binding in the dentate nucleus showed no significant regression factor with DaT availability in the striatum (β = 0.078, p = 0.662, Durbin-Watson statistics = 1.686). Patients with α-synucleinopathies did not indicate any regional associations between [18F]PI-2620-binding and DaT availability. Higher DaT-SPECT binding relative to tau burden was associated with better clinical performance (β = − 0.522, p = 0.011, Durbin-Watson statistics = 2.663) in patients with 4R-tauopathies. Conclusion: Tau burden in brain regions involved in dopaminergic pathways is associated with aggravated dopaminergic dysfunction in patients with clinically diagnosed primary tauopathies. The ability to sustain dopamine transmission despite tau accumulation may preserve motor function. [ABSTRACT FROM AUTHOR]

The EU directive 2001/83 describes the community code for medicinal products for human use including radiopharmaceuticals. In its current definition, also radionuclide precursors, such as fluorine-18, need to hold a marketing authorization before being placed on the market. The potential of novel radiopharmaceuticals for nuclear medicine is, although encouraged by European legislation and its respective guidance documents, therefore hampered by the regulatory framework. An update of EU directive 2001/83 would be beneficial for the development of novel radiopharmaceuticals and a safe advance in nuclear medicine. [ABSTRACT FROM AUTHOR]

The term of neurodegenerative diseases covers a heterogeneous group of disorders that are distinguished by progressive degeneration of the structure and function of the nervous system such as dementias, movement disorders, motor neuron disorders, as well as some prion disorders. In recent years, a paradigm shift started for the diagnosis of neurodegenerative diseases, for which successively clinical testing is supplemented by biomarker information. In research scenarios, it was even proposed recently to substitute the current syndromic by a biological definition of Alzheimer's diseases. PET examinations with various radiotracers play an important role in providing non-invasive biomarkers and co-morbidity information in neurodegeneration. Information on co-morbidity, e.g. Aβ plaques and Lewy-bodies or Aβ plaques in patients with aphasia or the absence of Aβ plaques in clinical AD patients are of interest to expand our knowledge about the pathogenesis of different phenotypically defined neurodegenerative diseases. Moreover, this information is also important in therapeutic trials targeting histopathological abnormalities. The aim of this review is to present an overview of the currently available radiotracers for imaging neurodegenerative diseases in research and in routine clinical settings. In this context, we also provide a short summary of the most frequent neurodegenerative diseases from a nuclear medicine point of view, their clinical and pathophysiological as well as nuclear imaging characteristics, and the resulting need for new radiotracers. [ABSTRACT FROM AUTHOR]

Background: In patients with prostate cancer (PCa), imaging with gastrin-releasing peptide receptor (GRPR) ligands is an alternative to PSMA-targeted tracers, particularly if PSMA expression is low or absent. [99mTc]Tc-N4-BTG is a newly developed GRPR-directed probe for conventional scintigraphy and single photon emission computed tomography (SPECT) imaging. The current study aims to investigate the safety, biodistribution and dosimetry of [99mTc]Tc-N4-BTG in patients with biochemical recurrence (BCR) of PCa. Results: No adverse pharmacologic effects were observed. Injection of [99mTc]Tc-N4-BTG resulted in an effective dose of 0.0027 ± 0.0002 mSv/MBq. The urinary bladder was the critical organ with the highest mean absorbed dose of 0.028 ± 0.001 mGy/MBq, followed by the pancreas with 0.0043 ± 0.0015 mGy/MBq, osteogenic cells with 0.0039 ± 0.0005 mGy/MBq, the kidneys with 0.0034 ± 0.0003 mGy/MBq, and the liver with 0.0019 ± 0.0004 mGy/MBq, respectively. No focal tracer uptake suggestive of PCa recurrence could be revealed for any of the patients. Conclusion: [99mTc]Tc-N4-BTG appears to be a safe diagnostic agent. Compared to GRPR-targeted PET tracers, this 99mTc-labelled SPECT agent could contribute to a broader application and better availability of this novel approach. Further research to assess its clinical value is warranted. [ABSTRACT FROM AUTHOR]

Objective: The neurobehavioral underpinnings of binge‐eating disorder (BED), co‐occurring with obesity (OB), are largely unknown. This research project conceptualizes BED as a disorder with dysfunctional emotion regulation (ER) linked with changes in central noradrenaline (NA) transmission and NA‐modulated neuronal networks. Methods: We expect abnormalities in NA activity in both BED and OB, but most pronounced in BED. We expect these abnormalities to be modifiable through state‐of‐the‐art ER intervention, specifically in BED. To assess the role of NA transmission, we will quantify changes in NA transporter (NAT) availability using the highly NAT‐specific [11C]methylreboxetin (MRB) and positron emission tomography‐magnetic resonance imaging (PET‐MRI) that allows measuring molecular and neuronal changes before and after an ER intervention. Individual 12‐session smartphone‐supported acceptance‐based behavioral therapy will be conducted to improve ER. Thirty individuals with OB and BED (OB + BED), 30 individuals with OB without BED (OB ‐ BED), and 20 individuals with normal weight will undergo assessments of NAT availability and neuronal network activity under rest and stimulated conditions, clinical interviews, self‐report questionnaires on eating behavior, ER, mental and physical health, and quality of life, and neuropsychological tests on executive function. Afterwards, in an experimental randomized‐controlled design, individuals with OB + BED and OB ‐ BED will be allocated to smartphone‐supported ER intervention versus a waitlist and re‐assessed after 10 weeks. Discussion: By obtaining biological and behavioral markers, the proposed study will disentangle the involvement of NAT and the central NA system in the modulation of emotion‐supporting neuronal networks that influence eating behavior. Neurobehavioral mechanisms of change during an ER intervention will be determined. Trial Registration: German Clinical Trials Register (DRKS): DRKS00029367. Public Significance: This study investigates the central noradrenaline system by using hybrid brain imaging in conjunction with emotion regulation as a putative core biological mechanism in individuals with obesity with or without binge‐eating disorder that is targeted by emotion regulation intervention. The results will provide a molecular signature beyond functional imaging biomarkers as a predictive biomarker toward precision medicine for tailoring treatments for individuals with binge‐eating disorders and obesity. [ABSTRACT FROM AUTHOR]

Premenstrual dysphoric disorder (PMDD) disrupts the lives of millions of people each month. The timing of symptoms suggests that hormonal fluctuations play a role in the pathogenesis. Here, we tested whether a heightened sensitivity of the serotonin system to menstrual cycle phase underlies PMDD, assessing the relationship of serotonin transporter (5-HTT) changes with symptom severity across the menstrual cycle. In this longitudinal case-control study, we acquired 118 [11C]DASB positron emission tomography scans measuring 5-HTT nondisplaceable binding potential (BP ND) in 30 patients with PMDD and 29 controls during 2 menstrual cycle phases (periovulatory, premenstrual). The primary outcome was midbrain and prefrontal cortex 5-HTT BP ND. We tested whether BP ND changes correlated with depressed mood. Linear mixed effects modeling (significant group × time × region interaction) showed a mean increase of 18% in midbrain 5-HTT BP ND (mean [SD] periovulatory = 1.64 [0.40], premenstrual = 1.93 [0.40], delta = 0.29 [0.47]: t 29 = −3.43, p =.0002) in patients with PMDD, whereas controls displayed a mean 10% decrease in midbrain 5-HTT BP ND (periovulatory = 1.65 [0.24] > premenstrual = 1.49 [0.41], delta = −0.17 [0.33]: t 28 = −2.73, p =.01). In patients, increased midbrain 5-HTT BP ND correlated with depressive symptom severity (R 2 = 0.41, p <.0015) across the menstrual cycle. These data suggest cycle-specific dynamics with increased central serotonergic uptake followed by extracellular serotonin loss underlying the premenstrual onset of depressed mood in patients with PMDD. These neurochemical findings argue for systematic testing of pre–symptom-onset dosing of selective serotonin reuptake inhibitors or nonpharmacological strategies to augment extracellular serotonin in people with PMDD. [ABSTRACT FROM AUTHOR]

Purpose: The role of dopamine D-type receptor (DR)-expressing neurons in the regulation of motivated behavior and reward prediction has not yet been fully established. As a prerequisite for future research assessing D-mediated neuronal network regulation using simultaneous PET/MRI and DR-selective [C]SCH23390, this study investigated the stability of central DR measurements between two independent PET/MRI sessions under baseline conditions. Methods: Thirteen healthy volunteers (7 female, age 33 ± 13 yrs) underwent 90-min emission scans, each after 90-s bolus injection of 486 ± 16 MBq [C]SCH23390, on two separate days within 2-4 weeks using a PET/MRI system. Parametric images of DR distribution volume ratio (DVR) and binding potential (BP) were generated by a multi-linear reference tissue model with two parameters and the cerebellar cortex as receptor-free reference region. Volume-of-interest (VOI) analysis was performed with manual VOIs drawn on consecutive transverse MRI slices for brain regions with high and low DR density. Results: The DVR varied from 2.5 ± 0.3 to 2.9 ± 0.5 in regions with high DR density (e.g. the head of the caudate) and from 1.2 ± 0.1 to 1.6 ± 0.2 in regions with low DR density (e.g. the prefrontal cortex). The absolute variability of the DVR ranged from 2.4% ± 1.3% to 5.1% ± 5.3%, while Bland-Altman analyses revealed very low differences in mean DVR (e.g. 0.013 ± 0.17 for the nucleus accumbens). Intraclass correlation (one-way, random) indicated very high agreement (0.93 in average) for both DVR and BP values. Accordingly, the absolute variability of BP ranged from 7.0% ± 4.7% to 12.5% ± 10.6%; however, there were regions with very low DR content, such as the occipital cortex, with higher mean variability. Conclusion: The test-retest reliability of DR measurements in this study was very high. This was the case not only for DR-rich brain areas, but also for regions with low DR density. These results will provide a solid base for future joint PET/MRI data analyses in stimulation-dependent mapping of DR-containing neurons and their effects on projections in neuronal circuits that determine behavior. [ABSTRACT FROM AUTHOR]

Purpose: Characteristic features of amyloid-PET (A), tau-PET (T), and FDG-PET (N) can serve for the A/T/N classification of neurodegenerative diseases. Recent studies showed that the early, perfusion-weighted phases of amyloid- or tau-PET recordings serve to detect cerebrometabolic deficits equally to FDG-PET, therefore providing a surrogate of neuronal injury. As such, two channels of diagnostic information can be obtained in the setting of a single PET scan. However, there has hitherto been no comparison of early-phase amyloid- and tau-PET as surrogates for deficits in perfusion/metabolism. Therefore, we undertook to compare [18F]flutemetamol-amyloid-PET and [18F]PI-2620 tau-PET as "one-stop shop" dual purpose tracers for the detection of neurodegenerative disease. Methods: We obtained early-phase PET recordings with [18F]PI-2620 (0.5–2.5 min p.i.) and [18F]flutemetamol (0–10 min p.i.) in 64 patients with suspected neurodegenerative disease. We contrasted global mean normalized images (SUVr) in the patients with a normal cohort of 15 volunteers without evidence of increased pathology to β-amyloid- and tau-PET examinations. Regional group differences of tracer uptake (z-scores) of 246 Brainnetome volumes of interest were calculated for both tracers, and the correlations of the z-scores were evaluated using Pearson's correlation coefficient. Lobar compartments, regions with significant neuronal injury (z-scores < − 3), and patients with different neurodegenerative disease entities (e.g., Alzheimer's disease or 4R-tauopathies) served for subgroup analysis. Additionally, we used partial regression to correlate regional perfusion alterations with clinical scores in cognition tests. Results: The z-scores of perfusion-weighted images of both tracers showed high correlations across the brain, especially in the frontal and parietal lobes, which were the brain regions with pronounced perfusion deficit in the patient group (R = 0.83 ± 0.08; range, 0.61–0.95). Z-scores of individual patients correlated well by region (R = 0.57 ± 0.15; range, 0.16–0.90), notably when significant perfusion deficits were present (R = 0.66 ± 0.15; range, 0.28–0.90). Conclusion: The early perfusion phases of [18F]PI-2620 tau- and [18F]flutemetamol-amyloid-PET are roughly equivalent indices of perfusion defect indicative of regional and lobar neuronal injury in patients with various neurodegenerative diseases. As such, either tracer may serve for two diagnostic channels by assessment of amyloid/tau status and neuronal activity. [ABSTRACT FROM AUTHOR]

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Main Body: This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. Conclusion: Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field, and include new PET-labelling methods for 11C and 18F, the importance of choosing the proper chelator for a given radioactive metal ion, implications of total body PET on use of radiopharmaceuticals, legislation issues and radionuclide therapy including the emerging role of 161Tb. [ABSTRACT FROM AUTHOR]

Purpose: Obesity is thought to arise, in part, from deficits in the inhibitory control over appetitive behavior. Such motivational processes are regulated by neuromodulators, specifically acetylcholine (ACh), via α4β2* nicotinic ACh receptors (nAChR). These nAChR are highly enriched in the thalamus and contribute to the thalamic gating of cortico-striatal signaling, but also act on the mesoaccumbal reward system. The changes in α4β2* nAChR availability, however, have not been demonstrated in human obesity thus far. The aim of our study was, thus, to investigate whether there is altered brain α4β2* nAChR availability in individuals with obesity compared to normal-weight healthy controls. Methods: We studied 15 non-smoking individuals with obesity (body mass index, BMI: 37.8 ± 3.1 kg/m2; age: 39 ± 14 years, 9 females) and 16 normal-weight controls (non-smokers, BMI: 21.9 ± 1.7 kg/m2; age: 28 ± 7 years, 13 females) by using PET and the α4β2* nAChR selective (−)-[18F]flubatine, which was applied within a bolus-infusion protocol (294 ± 16 MBq). Volume-of-interest (VOI) analysis was performed in order to calculate the regional total distribution volume (VT). Results: No overall significant difference in VT between the individuals with obesity and the normal-weight volunteers was found, while the VT in the nucleus basalis of Meynert tended to be lower in the individuals with obesity (10.1 ± 2.1 versus 11.9 ± 2.2; p = 0.10), and the VT in the thalamus showed a tendency towards higher values in the individuals with obesity (26.5 ± 2.5 versus 25.9 ± 4.2; p = 0.09). Conclusion: While these first data do not show greater brain α4β2* nAChR availability in human obesity overall, the findings of potentially aberrant α4β2* nAChR availability in the key brain regions that regulate feeding behavior merit further exploration. [ABSTRACT FROM AUTHOR]

Purpose: Radioligand therapy is an increasingly important option for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Radiohybrid ligands targeting prostate-specific membrane antigen (PSMA) are a novel group of theranostic radioligand therapy agents for which higher tumour absorbed radiation doses have been demonstrated compared to established PSMA ligands. Here, we report data from ten patients who were treated within a compassionate use program with the radiohybrid PSMA-ligand [177Lu]Lu-rhPSMA-10.1 after experiencing disease progression under treatment with [177Lu]Lu-PSMA-I&T.Ten patients with advanced PSMA-positive prostate cancer who showed progression under treatment with [177Lu]Lu-PSMA-I&T received up to three cycles of rescue therapy with [177Lu]Lu-rhPSMA-10.1 (7.4–8.1 GBq per cycle). Efficacy (PSA response according to PCWG3 and RECIP) and overall survival were evaluated. Adverse events were recorded from first application.Despite progression with [177Lu]Lu-PSMA-I&T, after the first cycle of [177Lu]Lu-rhPSMA-10.1 rescue therapy, five patients (50%) showed a decrease in serum PSA level. In imaging, three of the ten patients (30%) showed a partial radiologic response. Four of the five patients with a decrease of serum PSA under [177Lu]Lu-rhPSMA-10.1 had initially responded to treatment with [177Lu]Lu-PSMA-I&T but had become resistant. However, the remaining patient had shown continuous disease progression during [177Lu]Lu-PSMA-I&T therapy but showed an immediate response to [177Lu]Lu-rhPSMA-10.1. The additional treatment with [177Lu]Lu-rhPSMA-10.1 was generally well tolerated by all patients.Patients showing tumour progression while receiving [177Lu]Lu-PSMA-I&T radioligand therapy may benefit from rescue therapy with the novel radiohybrid PSMA ligand, [177Lu]Lu-rhPSMA-10.1. Higher tumour absorbed radiation doses with [177Lu]Lu-rhPSMA-10.1 may overcome primary and acquired radiation resistance.Methods: Radioligand therapy is an increasingly important option for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Radiohybrid ligands targeting prostate-specific membrane antigen (PSMA) are a novel group of theranostic radioligand therapy agents for which higher tumour absorbed radiation doses have been demonstrated compared to established PSMA ligands. Here, we report data from ten patients who were treated within a compassionate use program with the radiohybrid PSMA-ligand [177Lu]Lu-rhPSMA-10.1 after experiencing disease progression under treatment with [177Lu]Lu-PSMA-I&T.Ten patients with advanced PSMA-positive prostate cancer who showed progression under treatment with [177Lu]Lu-PSMA-I&T received up to three cycles of rescue therapy with [177Lu]Lu-rhPSMA-10.1 (7.4–8.1 GBq per cycle). Efficacy (PSA response according to PCWG3 and RECIP) and overall survival were evaluated. Adverse events were recorded from first application.Despite progression with [177Lu]Lu-PSMA-I&T, after the first cycle of [177Lu]Lu-rhPSMA-10.1 rescue therapy, five patients (50%) showed a decrease in serum PSA level. In imaging, three of the ten patients (30%) showed a partial radiologic response. Four of the five patients with a decrease of serum PSA under [177Lu]Lu-rhPSMA-10.1 had initially responded to treatment with [177Lu]Lu-PSMA-I&T but had become resistant. However, the remaining patient had shown continuous disease progression during [177Lu]Lu-PSMA-I&T therapy but showed an immediate response to [177Lu]Lu-rhPSMA-10.1. The additional treatment with [177Lu]Lu-rhPSMA-10.1 was generally well tolerated by all patients.Patients showing tumour progression while receiving [177Lu]Lu-PSMA-I&T radioligand therapy may benefit from rescue therapy with the novel radiohybrid PSMA ligand, [177Lu]Lu-rhPSMA-10.1. Higher tumour absorbed radiation doses with [177Lu]Lu-rhPSMA-10.1 may overcome primary and acquired radiation resistance.Results: Radioligand therapy is an increasingly important option for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Radiohybrid ligands targeting prostate-specific membrane antigen (PSMA) are a novel group of theranostic radioligand therapy agents for which higher tumour absorbed radiation doses have been demonstrated compared to established PSMA ligands. Here, we report data from ten patients who were treated within a compassionate use program with the radiohybrid PSMA-ligand [177Lu]Lu-rhPSMA-10.1 after experiencing disease progression under treatment with [177Lu]Lu-PSMA-I&T.Ten patients with advanced PSMA-positive prostate cancer who showed progression under treatment with [177Lu]Lu-PSMA-I&T received up to three cycles of rescue therapy with [177Lu]Lu-rhPSMA-10.1 (7.4–8.1 GBq per cycle). Efficacy (PSA response according to PCWG3 and RECIP) and overall survival were evaluated. Adverse events were recorded from first application.Despite progression with [177Lu]Lu-PSMA-I&T, after the first cycle of [177Lu]Lu-rhPSMA-10.1 rescue therapy, five patients (50%) showed a decrease in serum PSA level. In imaging, three of the ten patients (30%) showed a partial radiologic response. Four of the five patients with a decrease of serum PSA under [177Lu]Lu-rhPSMA-10.1 had initially responded to treatment with [177Lu]Lu-PSMA-I&T but had become resistant. However, the remaining patient had shown continuous disease progression during [177Lu]Lu-PSMA-I&T therapy but showed an immediate response to [177Lu]Lu-rhPSMA-10.1. The additional treatment with [177Lu]Lu-rhPSMA-10.1 was generally well tolerated by all patients.Patients showing tumour progression while receiving [177Lu]Lu-PSMA-I&T radioligand therapy may benefit from rescue therapy with the novel radiohybrid PSMA ligand, [177Lu]Lu-rhPSMA-10.1. Higher tumour absorbed radiation doses with [177Lu]Lu-rhPSMA-10.1 may overcome primary and acquired radiation resistance.Conclusions: Radioligand therapy is an increasingly important option for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Radiohybrid ligands targeting prostate-specific membrane antigen (PSMA) are a novel group of theranostic radioligand therapy agents for which higher tumour absorbed radiation doses have been demonstrated compared to established PSMA ligands. Here, we report data from ten patients who were treated within a compassionate use program with the radiohybrid PSMA-ligand [177Lu]Lu-rhPSMA-10.1 after experiencing disease progression under treatment with [177Lu]Lu-PSMA-I&T.Ten patients with advanced PSMA-positive prostate cancer who showed progression under treatment with [177Lu]Lu-PSMA-I&T received up to three cycles of rescue therapy with [177Lu]Lu-rhPSMA-10.1 (7.4–8.1 GBq per cycle). Efficacy (PSA response according to PCWG3 and RECIP) and overall survival were evaluated. Adverse events were recorded from first application.Despite progression with [177Lu]Lu-PSMA-I&T, after the first cycle of [177Lu]Lu-rhPSMA-10.1 rescue therapy, five patients (50%) showed a decrease in serum PSA level. In imaging, three of the ten patients (30%) showed a partial radiologic response. Four of the five patients with a decrease of serum PSA under [177Lu]Lu-rhPSMA-10.1 had initially responded to treatment with [177Lu]Lu-PSMA-I&T but had become resistant. However, the remaining patient had shown continuous disease progression during [177Lu]Lu-PSMA-I&T therapy but showed an immediate response to [177Lu]Lu-rhPSMA-10.1. The additional treatment with [177Lu]Lu-rhPSMA-10.1 was generally well tolerated by all patients.Patients showing tumour progression while receiving [177Lu]Lu-PSMA-I&T radioligand therapy may benefit from rescue therapy with the novel radiohybrid PSMA ligand, [177Lu]Lu-rhPSMA-10.1. Higher tumour absorbed radiation doses with [177Lu]Lu-rhPSMA-10.1 may overcome primary and acquired radiation resistance.Graphical Abstract: Radioligand therapy is an increasingly important option for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Radiohybrid ligands targeting prostate-specific membrane antigen (PSMA) are a novel group of theranostic radioligand therapy agents for which higher tumour absorbed radiation doses have been demonstrated compared to established PSMA ligands. Here, we report data from ten patients who were treated within a compassionate use program with the radiohybrid PSMA-ligand [177Lu]Lu-rhPSMA-10.1 after experiencing disease progression under treatment with [177Lu]Lu-PSMA-I&T.Ten patients with advanced PSMA-positive prostate cancer who showed progression under treatment with [177Lu]Lu-PSMA-I&T received up to three cycles of rescue therapy with [177Lu]Lu-rhPSMA-10.1 (7.4–8.1 GBq per cycle). Efficacy (PSA response according to PCWG3 and RECIP) and overall survival were evaluated. Adverse events were recorded from first application.Despite progression with [177Lu]Lu-PSMA-I&T, after the first cycle of [177Lu]Lu-rhPSMA-10.1 rescue therapy, five patients (50%) showed a decrease in serum PSA level. In imaging, three of the ten patients (30%) showed a partial radiologic response. Four of the five patients with a decrease of serum PSA under [177Lu]Lu-rhPSMA-10.1 had initially responded to treatment with [177Lu]Lu-PSMA-I&T but had become resistant. However, the remaining patient had shown continuous disease progression during [177Lu]Lu-PSMA-I&T therapy but showed an immediate response to [177Lu]Lu-rhPSMA-10.1. The additional treatment with [177Lu]Lu-rhPSMA-10.1 was generally well tolerated by all patients.Patients showing tumour progression while receiving [177Lu]Lu-PSMA-I&T radioligand therapy may benefit from rescue therapy with the novel radiohybrid PSMA ligand, [177Lu]Lu-rhPSMA-10.1. Higher tumour absorbed radiation doses with [177Lu]Lu-rhPSMA-10.1 may overcome primary and acquired radiation resistance. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine, 5-HT) as well as noradrenaline (NA) are key modulators of various fundamental brain functions including the control of appetite. While manipulations that alter brain serotoninergic signaling clearly affect body weight, studies implicating 5-HT transporters and NA transporters (5-HTT and NAT, respectively) as a main drug treatment target for human obesity have not been conclusive. The aim of this positron emission tomography (PET) study was to investigate how these central transporters are associated with changes of body weight after 6 months of dietary intervention or Roux-en-Y gastric bypass (RYGB) surgery in order to assess whether 5-HTT as well as NAT availability can predict weight loss and consequently treatment success. The study population consisted of two study cohorts using either the 5-HTT-selective radiotracer [11C]DASB to measure 5-HTT availability or the NAT-selective radiotracer [11C]MRB to assess NAT availability. Each group included non-obesity healthy participants, patients with severe obesity (body mass index, BMI, >35 kg/m2) following a conservative dietary program (diet) and patients undergoing RYGB surgery within a 6-month follow-up. Overall, changes in BMI were not associated with changes of both 5-HTT and NAT availability, while 5-HTT availability in the dorsal raphe nucleus (DRN) prior to intervention was associated with substantial BMI reduction after RYGB surgery and inversely related with modest BMI reduction after diet. Taken together, the data of our study indicate that 5-HTT and NAT are involved in the pathomechanism of obesity and have the potential to serve as predictors of treatment outcomes. [ABSTRACT FROM AUTHOR]

Background: Alterations of hypothalamic–pituitary–adrenal (HPA) axis activity and serotonergic signaling are implicated in the pathogenesis of human obesity and may contribute to its metabolic and mental complications. The association of these systems has not been investigated in human obesity. Objective: To investigate the relation of HPA responsiveness and serotonin transporter (5-HTT) availability in otherwise healthy individuals with obesity class II or III (OB) compared to non-obesity controls (NO). Study participants: Twenty-eight OB (21 females; age 36.6 ± 10.6 years; body mass index (BMI) 41.2 ± 5.1 kg/m2) were compared to 12 healthy NO (8 females; age 35.8 ± 7.4 years; BMI 22.4 ± 2.3 kg/m2), matched for age and sex. Methods: HPA axis responsiveness was investigated using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test, and curve indicators were derived for cortisol and adrenocorticotropic hormone (ACTH). The 5-HTT selective tracer [11C]DASB was applied, and parametric images of the binding potentials (BPND) were calculated using the multilinear reference tissue model and evaluated by atlas-based volume of interest (VOI) analysis. The self-questionnaires of behavioral inhibition system/behavioral activation system (BIS/BAS) with subscales drive, fun-seeking and reward were assessed. Results: OB showed significant positive correlations of ACTH curve parameters with overall 5-HTT BPND (ACTHAUC: r = 0.39, p = 0.04) and 5-HTT BPND of the caudate nucleus (ACTHAUC: r = 0.54, p = 0.003). In NO, cortisol indicators correlated significantly with BPND in the hippocampus (cortisolAUC: r = 0.59, p = 0.04). In OB, BAS reward was inversely associated with the ACTHAUC (r = −0.49, p = 0.009). Conclusion: The present study supports a serotonergic-neuroendocrine association, which regionally differs between OB and NO. In OB, areas processing emotion and reward seem to be in-volved. The finding of a serotonergic HPA correlation may have implications for other diseases with dysregulated stress axis responsiveness, and for potential pharmacologic interven-tions. [ABSTRACT FROM AUTHOR]

This document is intended as a supplement to the EANM "Guidelines on current Good Radiopharmacy Practice (cGRPP)" issued by the Radiopharmacy Committee of the EANM (Gillings et al. in EJNMMI Radiopharm Chem. 6:8, 2021). The aim of the EANM Radiopharmacy Committee is to provide a document that describes how to manage risks associated with small-scale "in-house" preparation of radiopharmaceuticals, not intended for commercial purposes or distribution. [ABSTRACT FROM AUTHOR]

Background: The role of the norepinephrine transporter (NET) has received increased focus in recent studies on the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). The predictive value for pharmacological treatment and its link to other health or social limitations has been little-studied. This follow-up research on adult patients with ADHD aimed to explore whether the therapy response and health and social impairments depend on baseline individual NET availability. Methods: Data were collected from 10 patients on personal, family and professional situations, mental and physical health and treatments received after baseline via online and telephone surveys and were compared to baseline data to evaluate treatment-related changes. Results: The majority of our ADHD patients did not show therapy responses but showed improvements due to pharmacological treatment. There was no evidence of relationships between pre-treatment NET availability and therapy response or health/social limitations. Conclusions: Pharmacological monotherapy was insufficient to promote symptom remission, especially for participants with extreme insufficiency in NET availability, but improved outcomes in academic and social functioning. Psychotherapy should be considered as an add-on to the standard treatment approach due to its positive outcome in reducing social limitations. The prognostic value of individual NET availability in predicting the response to therapy needs further studies with large sample sizes. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease and depression can start with combined cognitive and depressive symptoms [1, 2]. Accurate differential diagnosis is desired to initiate specific treatment.Objective: We investigated whether amyloid-β PET imaging can discriminate both entities.Methods: This retrospective observational study included 39 patients (20 female, age = 70±11years) with both cognitive and depressive symptoms who underwent amyloid-β PET imaging and in whom clinical follow-up data was available. Amyloid-β PET was carried out applying [18F]Florbetaben or [11C]PiB. The PET images were analyzed by standardized visual and relative-quantitative evaluation. Based on clinical follow-up (median of 2.4 years [range 0.3 to 7.0 years, IQR = 3.7 years] after amyloid PET imaging which was not considered in obtaining a definite diagnosis), discrimination ability between AD-related depression and pseudo-dementia in depression/depression with other comorbidities was determined.Results: Visually, all 10 patients with pseudo-dementia in depression and all 15 patients with other depression were rated as amyloid-β-negative; 2 of 14 patients with AD-related depression were rated amyloid-β-negative. ROC curve analysis of the unified composite standardized uptake value ratios (cSUVRs) was able to discriminate pseudo-dementia in depression from AD-related depression with high accuracy (AUC = 0.92). Optimal [18F]Florbetaben discrimination cSUVR threshold was 1.34. In congruence with the visual PET analysis, the resulting sensitivity of the relative-quantitative analysis was 86% with a specificity of 100%.Conclusion: Amyloid-β PET can differentiate AD-related depression and pseudo-dementia in depression. Prospective clinical studies are warranted to confirm this result and to potentially broaden the spectrum of clinical applications for amyloid-β PET imaging. [ABSTRACT FROM AUTHOR]

The theranostics concept using the same target for both imaging and therapy dates back to the middle of the last century, when radioactive iodine was first used to treat thyroid diseases. Since then, radioiodine has become broadly established clinically for diagnostic imaging and therapy of benign and malignant thyroid disease, worldwide. However, only since the approval of SSTR2-targeting theranostics following the NETTER-1 trial in neuroendocrine tumours and the positive outcome of the VISION trial has theranostics gained substantial attention beyond nuclear medicine. The roll-out of radioligand therapy for treating a high-incidence tumour such as prostate cancer requires the expansion of existing and the establishment of new theranostics centres. Despite wide global variation in the regulatory, financial and medical landscapes, this guide attempts to provide valuable information to enable interested stakeholders to safely initiate and operate theranostics centres. This enabling guide does not intend to answer all possible questions, but rather to serve as an overarching framework for multiple, more detailed future initiatives. It recognizes that there are regional differences in the specifics of regulation of radiation safety, but common elements of best practice valid globally. [ABSTRACT FROM AUTHOR]

The EANM herewith clearly expresses its commitment and support to the non-commercial in-house preparation of radiopharmaceuticals for direct use in accordance with European and national regulations. [ABSTRACT FROM AUTHOR]

Abstract: 2-[18F]fluoro-A-85380 (2-[18F]FA) is a new radioligand for noninvasive imaging of α4β2* nicotinic acetylcholine receptors (nAChRs) by positron emission tomography (PET) in human brain. In most cases, quantification of 2-[18F]FA receptor binding involves measurement of free nonmetabolized radioligand concentration in blood. This requires an efficient and reliable method to separate radioactive metabolites from the parent compound. In the present study, three analytical methods, thin layer chromatography (TLC), high-performance liquid chromatography (HPLC) and solid phase extraction (SPE) have been tested. Reversed-phase TLC of deproteinized aqueous samples of plasma provides good estimates of 2-[18F]FA and its metabolites. However, because of the decreased radioactivity in plasma samples, this method can be used in humans over the first 2 h after radioligand injection only. Reliable quantification of the parent radioligand and its main metabolites was obtained using reversed-phase HPLC, followed by counting of eluted fractions in a well gamma counter. Three main and five minor metabolites of 2-[18F]FA were detected in human blood using this method. On average, the unchanged 2-[18F]FA fraction in plasma of healthy volunteers measured at 14, 60, 120, 240 and 420 min after radioligand injection was 87.3±2.2%, 74.4±3%, 68.8±5%, 62.3±8% and 61.0±8%, respectively. In patients with neurodegenerative disorders, the values corresponding to the three last time points were significantly lower. The fraction of nonmetabolized 2-[18F]FA in plasma determined using SPE did not differ significantly from that obtained by HPLC (+gamma counting) (n=73, r=.95). Since SPE is less time-consuming than HPLC and provides comparable results, we conclude that SPE appears to be the most suitable method for measurement of 2-[18F]FA parent fraction during PET investigations. [Copyright &y& Elsevier]

Purpose: Pulmonary hypertension (PH) is characterized by a progressive remodelling of the pulmonary vasculature resulting in right heart failure and eventually death. The serotonin transporter (SERT) may be involved in the pathogenesis of PH in patients with chronic-obstructive pulmonary disease (COPD). This study investigated for the first time the SERT in vivo availability in the lungs of patients with COPD and PH (COPD+PH). Methods: SERT availability was assessed using SERT-selective [11C]DASB and positron emission tomography/computed tomography (PET/CT) with dynamic acquisition over 30 min in 4 groups of 5 participants each: COPD, COPD+PH, pulmonary arterial hypertension, and a healthy control (HC). Time activity curves were generated based on a volume of interest within the middle lobe. Tissue-to-blood concentration ratios after 25 to 30 min (TTBR25–30) served as receptor parameter for group comparison and were corrected for lung tissue attenuation. Participants underwent comprehensive pulmonary workup. Statistical analysis included group comparisons and correlation analysis. Results: [11C]DASB uptake peak values did not differ among the cohorts after adjusting for lung tissue attenuation, suggesting equal radiotracer delivery. Both the COPD and COPD+PH cohort showed significantly lower TTBR25–30 values after correction for lung attenuation than HC. Attenuation corrected TTBR25–30 values were significantly higher in the COPD+PH cohort than those in the COPD cohort and higher in non-smokers than in smokers. They positively correlated with invasively measured severity of PH and inversely with airflow limitation and emphysema. Considering all COPD patients ± PH, they positively correlated with right heart strain (NT-proBNP). Conclusion: By applying [11C]DASB and PET/CT, semiquantitative measures of SERT availability are demonstrated in the lung vasculature of patients with COPD and/or PH. COPD patients who developed PH show increased pulmonary [11C]DASB uptake compared to COPD patients without PH indicating an implication of pulmonary SERT in the development of PH in COPD patients. [ABSTRACT FROM AUTHOR]

Purpose: Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [18F] fluspidine and [18F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD. Methods: Using [18F] fluspidine PET (300 MBq, 0–90 min), 11 male HVs (pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (pridopidine 90 mg) were investigated twice, without and 2 h after single dose of pridopidine. Using [18F] fallypride PET (200 MBq, 0–210 min), four male HVs were studied without and 2 h following pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot. Results: S1R occupancy as function of pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg pridopidine. In contrast, at 90 mg pridopidine, the D2/D3R occupancy was only minimal (~ 3%). Conclusions: Our PET findings indicate that at clinically relevant single dose of 90 mg, pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of pridopidine to the S1R. Our findings provide significant clarification about pridopidine's mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41. [ABSTRACT FROM AUTHOR]

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Results: This commentary of highlights has resulted in 23 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. Conclusion: Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry. [ABSTRACT FROM AUTHOR]

Purposes: We present the first in-human brain PET imaging data of the new α4β2 nicotinic acetylcholine receptor (nAChR)–targeting radioligand (+)-[18F]Flubatine. Aims were to develop a kinetic modeling-based approach to quantify (+)-[18F]Flubatine and compare the data of healthy controls (HCs) and patients with Alzheimer's disease (AD); to investigate the partial volume effect (PVE) on regional (+)-[18F]Flubatine binding; and whether (+)-[18F]Flubatine binding and cognitive test data respective β-amyloid radiotracer accumulation were correlated. Methods: We examined 11 HCs and 9 mild AD patients. All subjects underwent neuropsychological testing and [11C]PiB PET/MRI examination. (+)-[18F]Flubatine PET data were evaluated using full kinetic modeling and regional as well as voxel-based analyses. Results: With 270-min p.i., the unchanged parent compound amounted to 97 ± 2%. Adequate fits of the time-activity curves were obtained with the 1 tissue compartment model (1TCM). (+)-[18F]Flubatine distribution volume (binding) was significantly reduced in bilateral mesial temporal cortex in AD patients compared with HCs (right 10.6 ± 1.1 vs 11.6 ± 1.4, p = 0.049; left 11.0 ± 1.1 vs 12.2 ± 1.8, p = 0.046; one-sided t tests each). PVE correction increased not only (+)-[18F]Flubatine binding of approximately 15% but also standard deviation of 0.4–70%. Cognitive test data and (+)-[18F]Flubatine binding were significantly correlated in the left anterior cingulate, right posterior cingulate, and right parietal cortex (r > 0.5, p < 0.05 each). In AD patients, (+)-[18F]Flubatine binding and [11C]PiB standardized uptake value ratios were negatively correlated in several regions; whereas in HCs, a positive correlation between cortical (+)-[18F]Flubatine binding and [11C]PiB accumulation in the white matter was found. No adverse event related to (+)-[18F]Flubatine occurred. Conclusion: (+)-[18F]Flubatine is a safe and stable PET ligand. Full kinetic modeling can be realized by 1TCM without metabolite correction. (+)-[18F]Flubatine binding affinity was high enough to detect group differences. Of interest, correlation between white matter β-amyloid PET uptake and (+)-[18F]Flubatine binding indicated an association between white matter integrity and availability of α4β2 nAChRs. Overall, (+)-[18F]Flubatine showed favorable characteristics and has therefore the potential to serve as α4β2 nAChR–targeting PET ligand in further clinical trials. [ABSTRACT FROM AUTHOR]

This guideline on current good radiopharmacy practice (cGRPP) for small-scale preparation of radiopharmaceuticals represents the view of the Radiopharmacy Committee of the European Association of Nuclear Medicine (EANM). The guideline is laid out in the format of the EU Good Manufacturing Practice (GMP) guidelines as defined in EudraLex volume 4. It is intended for non-commercial sites such as hospital radiopharmacies, nuclear medicine departments, research PET centres and in general any healthcare establishments. In the first section, general aspects which are applicable to all levels of operations are discussed. The second section discusses the preparation of small-scale radiopharmaceuticals (SSRP) using licensed generators and kits. Finally, the third section goes into the more complex preparation of SSRP from non-licensed starting materials, often requiring a purification step and sterile filtration. The intention is that the guideline will assist radiopharmacies in the preparation of diagnostic and therapeutic SSRP's safe for human administration. [ABSTRACT FROM AUTHOR]

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to describe trends in the field. Results: This commentary of highlights has resulted in 19 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. Conclusion: Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry. [ABSTRACT FROM AUTHOR]

The current study aimed to investigate whether the in vivo availability of central serotonin reuptake transporters (5-HTT) is associated with plasma levels of glycosylated hemoglobin (HbA1c) in non-diabetic humans with obesity. 5-HTT availability was measured by using positron emission tomography (PET) imaging with the 5-HTT selective radiotracer [11C]DASB in 23 non-diabetic individuals with obesity and 14 healthy, non-obesity controls. Parametric images of binding potential BPND were generated from the PET data and analyzed together with HbA1c levels by using volume of interest analysis for brain areas relevant to appetite control. Voxel-based morphometry (VBM) of individual magnetic resonance imaging data was further performed to correlate grey matter density (GMD) maps with HbA1c. We found significant negative correlations between HbA1c levels and BPND in right and left hippocampus in obesity (r = − 0.717, p < 0.001, and r = − 0.557, p = 0.006, respectively). VBM analyses revealed that higher HbA1c levels were associated with GMD in the right para-hippocampal area. Our results indicate that chronically high blood glucose levels may evoke changes in hippocampal 5-HTT levels that are in part tied to local microstructure. [ABSTRACT FROM AUTHOR]

Background: To fulfil good manufacturing requirements, analytical methods for the analysis of pharmaceuticals for human and vetinary use must be validated. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has published guidance documents on the requirements for such validation activities and these have been adopted by the European Medicines Agency, The U.S. Food and Drug Administration (FDA) and other regulatory bodies. These guidance documents do not, however, fully address all the specific tests required for the analysis of radiopharmaceuticals. This guideline attempts to rectify this shortcoming, by recommending approaches to validate such methods. Results: Recommedations for the validation of analytical methods which are specific for radiopharmaceutials are presented in this guideline, along with two practical examples. Conclusions: In order to comply with good manufacturing practice, analytical methods for radiopharmaceuticals for human use should be validated. [ABSTRACT FROM AUTHOR]

Purpose: In recent years, several [F]-labeled amyloid-PET tracers have been developed and have obtained clinical approval. Despite their widespread scientific use, studies in routine clinical settings are limited. We therefore investigated the impact of [F]-florbetaben (FBB)-PET on the diagnostic management of patients with suspected dementia that was still unclarified after [F]-fluordeoxyglucose (FDG)-PET. Methods: All subjects were referred in-house with a suspected dementia syndrome due to neurodegenerative disease. After undergoing an FDG-PET exam, the cases were discussed by the interdisciplinary dementia board, where the most likely diagnosis as well as potential differential diagnoses were documented. Because of persistent diagnostic uncertainty, the patients received an additional FBB-PET exam. Results were interpreted visually and classified as amyloid-positive or amyloid-negative, and we then compared the individual clinical diagnoses before and after additional FBB-PET. Results: A total of 107 patients (mean age 69.4 ± 9.7y) were included in the study. The FBB-PET was rated as amyloid-positive in 65/107. In 83% of the formerly unclear cases, a final diagnosis was reached through FBB-PET, and the most likely prior diagnosis was changed in 28% of cases. The highest impact was observed for distinguishing Alzheimer's dementia (AD) from fronto-temporal dementia (FTLD), where FBB-PET altered the most likely diagnosis in 41% of cases. Conclusions: FBB-PET has a high additive value in establishing a final diagnosis in suspected dementia cases when prior investigations such as FDG-PET are inconclusive. The differentiation between AD and FTLD was particularly facilitated by amyloid-PET, predicting a considerable impact on patient management, especially in the light of upcoming disease-modifying therapies. [ABSTRACT FROM AUTHOR]

The brain noradrenaline (NA) system, particularly NA transporters (NAT), are thought to play an important role in modulating impulsive behavior. Impaired impulsivity is implicated in a variety of neuropsychiatric conditions; however, an in vivo link between central NAT availability and human impulsivity has not been shown. Using positron emission tomography (PET) and S,S-[ 11 C]O-methylreboxetine (MRB), we tested whether NAT availability is associated with this basic behavioral trait based on the Barratt Impulsiveness Scale (BIS-11) in twenty healthy individuals (12 females, 33.8±9.3, 21–52 years of age) with a body mass index (BMI) ranging from 21.7 kg/m 2 to 47.8 kg/m 2 . Applying both voxel-wise and volume-of-interest (VOI) based analyses, we found that distribution volume ratios (DVR) used as PET outcome measures negatively correlated with BIS-11 total scores in the orbitofrontal cortex (OFC) and in the hippocampus as well as in parts of the cerebellar cortex. These associations however did not remain after correction for multiple testing. Thus, although it appears that low NAT availability is associated with greater scores of impaired behavioral control, this needs to be confirmed in a larger series of individuals with highly impulsive behavior. [ABSTRACT FROM AUTHOR]

Purpose: The brain noradrenaline (NA) system plays an important role in the central nervous control of energy balance and is thus implicated in the pathogenesis of obesity. The specific processes modulated by this neurotransmitter which lead to obesity and overeating are still a matter of debate. Methods: We tested the hypothesis that in vivo NA transporter (NAT) availability is changed in obesity by using positron emission tomography (PET) and S,S-[C]O-methylreboxetine (MRB) in twenty subjects comprising ten highly obese (body mass index BMI > 35 kg/m), metabolically healthy, non-depressed individuals and ten non-obese (BMI < 30 kg/m) healthy controls. Results: Overall, we found no significant differences in binding potential (BP) values between obese and non-obese individuals in the investigated brain regions, including the NAT-rich thalamus (0.40 ± 0.14 vs. 0.41 ± 0.18; p = 0.84) though additional discriminant analysis correctly identified individual group affiliation based on regional BP in all but one (control) case. Furthermore, inter-regional correlation analyses indicated different BP patterns between both groups but this did not survive testing for multiple comparions. Conclusions: Our data do not find an overall involvement of NAT changes in human obesity. However, preliminary secondary findings of distinct regional and associative patterns warrant further investigation. [ABSTRACT FROM AUTHOR]