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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 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.

An EU legal analysis of the European Central Bank's Pandemic Emergency Purchase Programme (PEPP), originally published in March 2020 in EULawLive, updated to include more references to the ECB's pandemic responses (prudential, monetary policy) and the EU's NextGenerationEU Recovery and Resilience Facility, and to the Bundesverfassungsgericht's decision on the Public Sector Purchasing Programme (PSPP) and the Court of Justice of the European Union's judgment on the subject (Weiss).

Positron emission tomography (PET) imaging of misfolded protein aggregates that form in neurodegenerative processes of the brain is key to providing a robust marker for improved diagnosis and evaluation of treatments. We report the development of advanced radiotracer candidates based on the sulfoxide scaffold found in proton pump inhibitors (lansoprazole, prevacid) with inherent affinity to neurofibrillary tangles in Alzheimer’s disease and related disorders (e.g., dementia with Lewy bodies and the frontotemporal degeneration syndrome). First-in-man results obtained with [18F]lansoprazole and N-methyl-[18F]lansoprazole were used to guide the design of a set of 24 novel molecules with suitable properties for neuroimaging with PET. Compounds were synthesized and characterized pharmacologically, and the binding affinity of the compounds to synthetic human tau-441 fibrils was determined. Selectivity of binding was assessed using α-synuclein and β-amyloid fibrils to address the key misfolded proteins of relevance in dementia. To complete the pharmacokinetic profiling in vitro, plasma protein binding and lipophilicity were investigated. Highly potent and selective new radiotracer candidates were identified for further study.

Whether α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) expression is reduced in early Alzheimer’s disease is controversial. Using (-)-[18F]Flubatine PET, Sabri, Meyer et al. report α4β2-nAChR deficiency in mild Alzheimer’s dementia, especially within the basal forebrain-cortical and septohippocampal cholinergic projections. Reduced α4β2-nAChR availability correlates with impaired episodic memory and executive function/working memory., In early Alzheimer’s dementia, there is a need for PET biomarkers of disease progression with close associations to cognitive dysfunction that may aid to predict further cognitive decline and neurodegeneration. Amyloid biomarkers are not suitable for that purpose. The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) are widely abundant in the human brain. As neuromodulators they play an important role in cognitive functions such as attention, learning and memory. Post-mortem studies reported lower expression of α4β2-nAChRs in more advanced Alzheimer’s dementia. However, there is ongoing controversy whether α4β2-nAChRs are reduced in early Alzheimer’s dementia. Therefore, using the recently developed α4β2-nAChR-specific radioligand (−)-18F-flubatine and PET, we aimed to quantify the α4β2-nAChR availability and its relationship to specific cognitive dysfunction in mild Alzheimer’s dementia. Fourteen non-smoking patients with mild Alzheimer’s dementia, drug-naïve for cholinesterase therapy, were compared with 15 non-smoking healthy controls matched for age, sex and education by applying (−)-18F-flubatine PET together with a neuropsychological test battery. The one-tissue compartment model and Logan plot method with arterial input function were used for kinetic analysis to obtain the total distribution volume (VT) as the primary, and the specific binding part of the distribution volume (VS) as the secondary quantitative outcome measure of α4β2-nAChR availability. VS was determined by using a pseudo-reference region. Correlations between VT within relevant brain regions and Z-scores of five cognitive functions (episodic memory, executive function/working memory, attention, language, visuospatial function) were calculated. VT (and VS) were applied for between-group comparisons. Volume of interest and statistical parametric mapping analyses were carried out. Analyses revealed that in patients with mild Alzheimer’s dementia compared to healthy controls, there was significantly lower VT, especially within the hippocampus, fronto-temporal cortices, and basal forebrain, which was similar to comparisons of VS. VT decline in Alzheimer’s dementia was associated with distinct domains of impaired cognitive functioning, especially episodic memory and executive function/working memory. Using (−)-18F-flubatine PET in patients with mild Alzheimer’s dementia, we show for the first time a cholinergic α4β2-nAChR deficiency mainly present within the basal forebrain-cortical and septohippocampal cholinergic projections and a relationship between lower α4β2-nAChR availability and impairment of distinct cognitive domains, notably episodic memory and executive function/working memory. This shows the potential of (−)-18F-flubatine as PET biomarker of cholinergic α4β2-nAChR dysfunction and specific cognitive decline. Thus, if validated by longitudinal PET studies, (−)-18F-flubatine might become a PET biomarker of progression of neurodegeneration in Alzheimer’s dementia.

Recent case law on the scope of professional secrecy for the supervisory authorities in the financial sector and on the measure of openness of their files highlights the lack of coordination among the silos of supervision and the absence of clear and uniform professional secrecy rules across the financial sector. The introduction of the Single Supervisory Mechanism (SSM) makes this situation more acute: notwithstanding a centralised system of banking supervision, different approaches may exist in respect of access to files, even when based on EU legislation. This contribution addresses the accountability of supervisory authorities and, notably the European Central Bank (ECB), from the perspective of access to supervisory files, as a prelude to possible follow-up proceedings for failing supervision. Recent judgments in the Altmann, Baumeister, Buccioni, and UBS Europe cases slowly move the case law on supervisory secrecy towards more openness, long after Hillegom/Hillenius (1984). The judgments lead us to wonder whether the absence of legislative coordination and questionable drafting is being remedied by the judiciary. The variety of legislative provisions and relevant recent case law form the backdrop of our proposal to adopt a Regulation on professional secrecy for supervisory authorities in the financial sector, which would institute a single standard that is directly applicable across Member States and supervisory authorities.

Radiolabeled tracers targeting the prostate-specific membrane antigen (PSMA) have become important radiopharmaceuticals for the PET-imaging of prostate cancer. In this connection, we recently developed the fluorine-18-labelled PSMA-ligand [18F]PSMA-1007 as the next generation radiofluorinated Glu-ureido PSMA inhibitor after [18F]DCFPyL and [18F]DCFBC. Since radiosynthesis so far has been suffering from rather poor yields, novel procedures for the automated radiosyntheses of [18F]PSMA-1007 have been developed. We herein report on both the two-step and the novel one-step procedures, which have been performed on different commonly-used radiosynthesisers. Using the novel one-step procedure, the [18F]PSMA-1007 was produced in good radiochemical yields ranging from 25 to 80% and synthesis times of less than 55 min. Furthermore, upscaling to product activities up to 50 GBq per batch was successfully conducted. All batches passed quality control according to European Pharmacopoeia standards. Therefore, we were able to disclose a new, simple and, at the same time, high yielding production pathway for the next generation PSMA radioligand [18F]PSMA-1007. Actually, it turned out that the radiosynthesis is as easily realised as the well-known [18F]FDG synthesis and, thus, transferable to all currently-available radiosynthesisers. Using the new procedures, the clinical daily routine can be sustainably supported in-house even in larger hospitals by a single production batch.

This article examines the administrative remedy provided by the Administrative Board of Review (ABoR) of the European Central Bank (ECB), as part of the broader issue of the right of defence of natural and legal persons vis-Ã -vis ECB supervisory decisions within the Single Supervisory Mechanism (SSM). After presenting an overview of the review panels established in the financial sector in the EU, the article describes the experience with the ABoR by analysing its composition, its mandate and scope of review, the main procedural aspects and the relationship with judicial proceedings before the European Court of Justice. Particular attention is given to the substantial issues dealt with by the ABoR in its Opinions and to some of the major challenges faced in the first 2Â years of practice. Among them is the assessment of the correct application of national laws implementing EU legislation by the ECB. The paper identifies two aspects giving particular cause for concern and requiring legislative reforms: (1) the assessment of the suitability of the members of management bodies (fit and proper assessment) and (2) the inclusion of bank holding companies within the scope of banking supervision.

Radiolabeled tracers targeting the prostate-specific membrane antigen (PSMA) have become important radiopharmaceuticals for the PET-imaging of prostate cancer. In this connection, we recently developed the fluorine-18-labelled PSMA-ligand [18F]PSMA-1007 as the next generation radiofluorinated Glu-ureido PSMA inhibitor after [18F]DCFPyL and [18F]DCFBC. Since radiosynthesis so far has been suffering from rather poor yields, novel procedures for the automated radiosyntheses of [18F]PSMA-1007 have been developed. We herein report on both the two-step and the novel one-step procedures, which have been performed on different commonly-used radiosynthesisers. Using the novel one-step procedure, the [18F]PSMA-1007 was produced in good radiochemical yields ranging from 25 to 80% and synthesis times of less than 55 min. Furthermore, upscaling to product activities up to 50 GBq per batch was successfully conducted. All batches passed quality control according to European Pharmacopoeia standards. Therefore, we were able to disclose a new, simple and, at the same time, high yielding production pathway for the next generation PSMA radioligand [18F]PSMA-1007. Actually, it turned out that the radiosynthesis is as easily realised as the well-known [18F]FDG synthesis and, thus, transferable to all currently-available radiosynthesisers. Using the new procedures, the clinical daily routine can be sustainably supported in-house even in larger hospitals by a single production batch.

Introduction (−)-[ 18 F]Flubatine is a PET tracer with high affinity and selectivity for the nicotinic acetylcholine α 4 β 2 receptor subtype. A clinical trial assessing the availability of this subtype of nAChRs was performed. From a total participant number of 21 Alzheimer's disease (AD) patients and 20 healthy controls (HCs), the following parameters were determined: plasma protein binding, metabolism and activity distribution between plasma and whole blood. Methods Plasma protein binding and fraction of unchanged parent compound were assessed by ultracentrifugation and HPLC, respectively. The distribution of radioactivity (parent compound+metabolites) between plasma and whole blood was determined ex vivo at different time-points after injection by gamma counting after separation of whole blood by centrifugation into the cellular and non-cellular components. In additional experiments in vitro , tracer distribution between these blood components was assessed for up to 90min. Results A fraction of 15%±2% of (−)-[ 18 F]Flubatine was found to be bound to plasma proteins. Metabolic degradation of (−)-[ 18 F]Flubatine was very low, resulting in almost 90% unchanged parent compound at 90min p.i. with no significant difference between AD and HC. The radioactivity distribution between plasma and whole blood changed in vivo only slightly over time from 0.82±0.03 at 3min p.i. to 0.87±0.03 at 270min p.i. indicating the contribution of only a small amount of metabolites. In vitro studies revealed that (−)-[ 18 F]Flubatine was instantaneously distributed between cellular and non-cellular blood parts. Discussion (−)-[ 18 F]Flubatine exhibits very favourable characteristics for a PET radiotracer such as slow metabolic degradation and moderate plasma protein binding. Equilibrium of radioactivity distribution between plasma and whole blood is reached instantaneously and remains almost constant over time allowing both convenient sample handling and facilitated fractional blood volume contribution assessment.

Both enantiomers of the epibatidine analogue flubatine display high affinity towards the α4β2 nicotinic acetylcholine receptor (nAChR) in vitro, accompanied by negligible interactions with diverse off-target proteins. Extended single dose toxicity studies in rodent indicated a NOEL (No Observed Effect Level) of 6.2μg/kg for (-)-flubatine and 1.55μg/kg for (+)-flubatine. We developed syntheses for both flubatine enantiomers and their corresponding precursors for radiolabeling. The newly synthesized trimethylammonium precursors allowed for highly efficient (18)F-radiolabelling in radiochemical yields >60% and specific activities >750GBq/μmol, thus making the radioligands practical for clinical investigation.

Key points:- When the Cyprus rescue was announced, the initial idea was to have depositors contribute to the banks' rescue. This did not happen but depositors across Europe became concerned. The question arose whether small deposits at EU banks are safe.- This article examines the safety of deposits of natural persons and small and medium-sized enterprises (SMEs) under four legal texts: three documents adopted in the context of 'banking union' and a fourth text on state aid to the banking sector. These documents contain provisions on the so-called 'bail-in': contributions by a bank's creditors towards a bank's rescue ahead of public assistance.- The legal acts concerned are the latest available on the Single Resolution Mechanism, the third element of 'banking union', the Bank Recovery & Resolution Directive, the Eurogroup Agreement on direct bank recapitalization from the European Stability Mechanism, and the Commission's 2013 Banking Communication.- On the basis of the latest texts available at end-2013, it is concluded that deposits covered by deposit insurance will be free from 'bail-in': natural persons and most (in the future: all) SMEs will see their deposits up to €100,000 legally secured.

(−)-[18F]flubatine is a promising agent for visualization by PET of cerebral α4β2 nicotinic acetylcholine receptors (nAChRs), which are implicated in psychiatric and neurodegenerative disorders. Here, we describe a substantially improved two-step radiosynthesis strategy for (−)-[18F]flubatine, based on the nucleophilic radiofluorination of an enantiomerically pure precursor followed by deprotection of the intermediate. An extensive leaving group/protecting group library of precursors was tested. Application of a trimethylammonium-iodide precursor with a Boc-protecting group provided the best results: labeling efficiencies of 80–95%, RCY of 60±5%, radiochemical purity of >98%, and a specific activity of >350 GBq/μmol. The radiosynthesis is easily transferable to an automated synthesis module.

This contribution, based on a Paper for the International Conference on The Democratic Principle and the Economic and Monetary Union, held in Rome (Italy) on 22 January 2016, sketches the development of the role of the European Commission in EMU affairs, discusses, in the context of EMU, issues of democracy and legitimacy and puts forward ideas on fostering accountability, representation and transparency, as well as humane outcomes of policies.

This paper, a draft of which was presented at the Conference Judicial review in the Banking Union and in the EU financial architecture, jointly organized by the Banca d’Italia and the European Banking Institute in Rome on 21 November 2017, discusses the contours of administrative review of prudential decisions of the European Central Bank (ECB) and the main issues facing the Administrative Board of Review (ABoR) of the ECB, of which the author is an alternate member. The paper continues with a discussion of limited options to enhance transparency on review, both administrative and judicial, followed by a discussion of the main cases pending at the European Court of Justice in the area of banking union: the French banking industry against the ECB; Credit Mutuel Arkea against the ECB; and Credit Agricole against the ECB. The L-Bank Case (T-122/15) and the Order in the Trasta Case (T-698/16) are summarised. The paper concludes with a call for more transparency and a possible alignment of financial sector review mechanisms. A postscript added after the Conference discusses developments since: judgments of 13 December 2017 in the Arkea cases (Cases T-712/15 and Case T-52/16) and the appeals lodged against the Order in the Trasta case by the bank and its shareholders (Case C-669/17 P), by the ECB (Case C-663/17 P) and by the Commission (Case C-665/17 P), promising a landmark judgment on admissibility of bank shareholders acting against the withdrawal of a banking authorisation. Also, references to the list of banking union-related judicial cases at the website of the European Banking Institute were added.

Reflections on context, transparency, review and culture of the Single Supervisory Mechanism (SSM), the Euro Area system of prudential supervision of banks, three years after its start. The paper discusses the 'cascade' of banking regulation (from global standards through EU legislation and harmonising technical regulations of the Commission to national laws, central bank acts and guidance) and suggests five ways to strengthen the Single Rulebook in the financial sector. The paper further explores transparency in the SSM, inter alia, discussing the public availability of Memoranda of Understanding among supervisory authorities, the ECB's Banking Supervision Manual, and information on administrative and judicial review of ECB acts, suggesting minor steps forward on the latter. The paper concludes with considerations on the context of banking union, highlighting the incidence of the often forgotten cultural aspect of integration of Europe.

Background Both enantiomers of [18F]flubatine are new radioligands for neuroimaging of α4β2 nicotinic acetylcholine receptors with positron emission tomography (PET) exhibiting promising pharmacokinetics which makes them attractive for different clinical questions. In a previous preclinical study, the main advantage of (+)-[18F]flubatine compared to (−)-[18F]flubatine was its higher binding affinity suggesting that (+)-[18F]flubatine might be able to detect also slight reductions of α4β2 nAChRs and could be more sensitive than (−)-[18F]flubatine in early stages of Alzheimer’s disease. To support the clinical translation, we investigated a fully image-based internal dosimetry approach for (+)-[18F]flubatine, comparing mouse data collected on a preclinical PET/MRI system to piglet and first-in-human data acquired on a clinical PET/CT system. Time-activity curves (TACs) were obtained from the three species, the animal data extrapolated to human scale, exponentially fitted and the organ doses (OD), and effective dose (ED) calculated with OLINDA. Results The excreting organs (urinary bladder, kidneys, and liver) receive the highest organ doses in all species. Hence, a renal/hepatobiliary excretion pathway can be assumed. In addition, the ED conversion factors of 12.1 μSv/MBq (mice), 14.3 μSv/MBq (piglets), and 23.0 μSv/MBq (humans) were calculated which are well within the order of magnitude as known from other 18F-labeled radiotracers. Conclusions Although both enantiomers of [18F]flubatine exhibit different binding kinetics in the brain due to the respective affinities, the effective dose revealed no enantiomer-specific differences among the investigated species. The preclinical dosimetry and biodistribution of (+)-[18F]flubatine was shown and the feasibility of a dose assessment based on image data acquired on a small animal PET/MR and a clinical PET/CT was demonstrated. Additionally, the first-in-human study confirmed the tolerability of the radiation risk of (+)-[18F]flubatine imaging which is well within the range as caused by other 18F-labeled tracers. However, as shown in previous studies, the ED in humans is underestimated by up to 50 % using preclinical imaging for internal dosimetry. This fact needs to be considered when applying for first-in-human studies based on preclinical biokinetic data scaled to human anatomy. Electronic supplementary material The online version of this article (doi:10.1186/s40658-016-0160-5) contains supplementary material, which is available to authorized users.

Methods for the radiolabeling molecules of interest with [18F]-fluoride need to be rapid, convenient, and efficient. Numerous [18F]-labeled prosthetic groups, e.g., N-succinimidyl 4 [18F]-fluorobenzoate ([18F]-SFB), 4-azidophenacyl-[18F]-fluoride ([18F]-APF), and 1-(3-(2-[18F]fluoropyridin-3-yloxy)propyl)pyrrole-2,5-dione ([18F]-FpyMe), for conjugating to biomolecules have been developed. As the synthesis of these prosthetic groups usually requires multistep procedures, there is still a need for direct methods for the nucleophilic [18F]-fluorination of biomolecules. We report here on the development of a procedure based on the trimethylammonium (TMA) leaving group attached to an aromatic ring and activated with different electron-withdrawing groups (EWGs). A series of model compounds containing different electron-withdrawing substituents, a trimethylammonium leaving group, and carboxylic functionality for subsequent coupling to peptides were designed and synthesized. The optimal model compound, 2-cyano-4-(methoxycarbonyl)-N,N,N-trimethylbenzenaminium trifluoromethanesulfonate, was converted to carboxylic acid and coupled to peptides. The results of the one-step [18F]-fluorination of tetrapeptides and bombesin peptides show that the direct 18F-labeling of peptides is feasible under mild conditions and in good radiochemical yields.

With the aim of imaging and quantification of oxytocin receptors (OTRs) in living brain using positron emission tomography (PET), we developed a (18)F-labeled small molecule radiotracer and investigated its in vivo pharmacokinetics in mice and pig. [(18)F]6b (KD = 12.3 nM) was radiolabeled by a two-step procedure using a microwave system with radiochemical yields of 26.9 ± 4.7%. Both organ distribution and small animal PET studies revealed limited brain uptake of [(18)F]6b in mouse (mean SUV of 0.04 at 30 min pi). Besides, significant radioactivity uptake in the pituitary gland was observed (SUV of 0.7 at 30 min pi). In a dynamic PET study in one piglet, we detected a higher uptake of [(18)F]6b in the olfactory bulb (SUV of 0.34 at 30 min pi) accompanied by a low uptake in the whole brain. In vitro autoradiographic studies on porcine brain sections indicated interaction of [(18)F]6b with several off-target receptors.

International audience; [18F]FMTEB, [18F]FPEB, [18F]flumazenil, [18F]DAA1106, [18F]MFBG, [18F]FDOPA, [18F]FMT and [18F]FDA are prepared from the corresponding arylboronic esters and [18F]KF/K222 in the presence of Cu(OTf)2py4. The method was successfully applied using three radiosynthetic platforms, and up to 26 GBq of non-carrier added starting activity of 18F-fluoride.

The asymmetric dihydroxylation reaction of early stage and advanced Bryostatin C-ring precursors was evaluated. For homoallylic ethers and alcohols, several AD ligands were investigated including a novel class of quinidine-alkynes.

The WP analyses the changes to the law of Economic and Monetary Union (EMU) in response to the crisis, and discusses these major changes, their legal form, and the judicial challenges to them. The adaption of economic governance of the EU resulted in incisive regulation of Member States’ budgetary soundness and prudence, and further EU oversight of national economic policies. The European Central Bank (ECB) introduced unconventional monetary policy measures and played a novel role in economic policy setting under the ‘conditionality’ of emergency funding to Member States. The ECB also became the central supervisor in a Single Supervisory Mechanism for the Euro Area’s commercial banks under ‘banking union’. The ‘no bail-out’ clause of the Treaty on the Functioning of the European Union (TFEU) did not prevent the creation of arrangements for the provision of funding to Member States (ESFS, EFSM, ESM). At Union and at Member State level, there were numerous judicial challenges to the crisis response of policy makers. The WP critically analyses the crisis innovations. It calls for further study on the interplay between Member State and Union law, and on international and EU law.

The racemic title compound has been transformed into both cyclic and acyclic segments of bioactive natural products, including the C10−C17 segment of pederin, the C12−C19 (C12′−C19′) segment of disorazole and the C1−C9 segment of auriside. A methodology for the opening of six-membered ring acetals, containing gem-dimethyl groups, to δ-hydroxy-1,3-dithianes has been developed. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

(−)-18F-flubatine is a promising tracer for neuroimaging of nicotinic acetylcholine receptors (nAChRs), subtype α4β2, using PET. Radiation doses after intravenous administration of the tracer in mice and piglets were assessed to determine the organ doses (ODs) and the effective dose (ED) to humans. The results were compared with subsequent clinical investigations in human volunteers. Methods: Twenty-seven female CD1 mice (weight ± SD, 28.2 ± 2.1 g) received intravenous injection of 0.75 ± 0.33 MBq of (−)-18F-flubatine. Up to 240 min after injection, 3 animals per time point were sacrificed and the organs harvested, weighed, and counted in a γ counter to determine mass and activity, respectively. Furthermore, whole-body PET scans of 5 female piglets (age ± SD, 44 ± 3 d; weight ± SD, 13.7 ± 1.7 kg) and 3 humans (2 men and 1 woman; age ± SD, 59.6 ± 3.9 y; weight ± SD, 74.3 ± 3.1 kg) were obtained up to 236 min (piglets) and 355 min (humans) after injection of 186.6 ± 7.4 and 353.7 ± 10.2 MBq of (−)-18F-flubatine, respectively, using a PET/CT scanner. The CT was used for delineation of the organs. Exponential curves were fitted to the time–activity-data, and time and mass scales were adapted to the human anatomy. The ODs were calculated using OLINDA/EXM (version 1.0); EDs were calculated with the tissue-weighting factors of ICRP103. Results: After the injection of (−)-18F-flubatine, there were no adverse or clinically detectable pharmacologic effects in any of the subjects. The highest activities after injection were found in the kidneys, urinary bladder, and liver. The urinary bladder receives the highest OD in all investigated species, followed by the kidneys and the liver for animals and humans, respectively. On the basis of mouse, piglet, and human kinetic data, the projected human ED of (−)-18F-flubatine was estimated to be 12.5 μSv/MBq in mice, 14.7 ± 0.7 μSv/MBq in piglets, and 23.4 ± 0.4 μSv/MBq in humans. Conclusion: As has been demonstrated for other PET radiotracers, preclinical (i.e., animal-derived) dosimetry underestimates the ED to humans, in the current case of (−)-18F-flubatine by 34%–44%.

A fully automatized radiosynthesis of (+)- and (−)-[ 18 F]Flubatine ((+)- and (−)NCFHEB) by means of a commercially available synthesis module (TRACERlab FX FN) under GMP conditions is reported. Radiochemical yields of 30% within an overall synthesis time of 40 min were achieved in more than 70 individual syntheses. Specific activities were approximately 3000 GBq/μmol and radiochemical purity was determined to be at least 97%.

In this article the legal and institutional issues surrounding the transition to a European Central Bank (ECB) will be discussed. The transition to a single currency entails many legal and institutional issues, both at the European level and at member State level. I will focus on a few main themes.

The combination of the unique physical and chemical properties of fluorine with proteinogenic amino acids represents a new approach to the design of biologically active compounds including peptides with improved pharmacological parameters. Therefore, the development of routine synthetic methods which enable the effective and selective introduction of fluorine into the desired amino acids from readily available starting materials is of significant synthetic importance. The scope of this critical review is to summarize the most frequently employed strategies for the synthesis of alpha-difluoromethyl and alpha-trifluoromethyl substituted alpha-amino acids (114 references).

An array of 2-alkoxy-2,3-dihydro-2-aryl-1,4-benzodioxane derivatives and 2-amino-1,3-thiazoles were prepared in high yield using a straightforward three-step and two- step sequence of polymer-supported reagents, respectively and other polymer-supported sequestering reagents without any chromatographic purification step. A key step involves clean and efficient bromination of acetophenones using polymer-supported pyridinium bromide perbromide (PSPBP) and subsequent cyclisation reaction.

Combination of the unique physical and chemical properties of fluorine with proteinogenic amino acids represents a new approach for the design of biologically active peptides with improved pharmacological parameters that carry a powerful label for spectroscopic analysis. However, the general consequences of amino acid fluorination on structure and activity of peptides and proteins are still controversially discussed. Studying the interaction of fluorinated amino acids with enzyme active sites provides valuable information on how fluoroalkyl groups of peptide-based drugs might interact with target proteins or receptors. Therefore, different enzymatic approaches including proteolysis studies, enzymatic resolutions and peptide bond couplings were studied by our group.