Cyclotrons Operated for Nuclear Medicine and Radiopharmacy in the German Speaking D-A-CH Countries: An Update on Current Status and Trends

Background: Cyclotrons form a central infrastructure and are a resource of medical radionuclides for the development of new radiotracers as well as the production and supply of clinically established radiopharmaceuticals for patient care in nuclear medicine. Aim: To provide an updated overview of the number and characteristics of cyclotrons that are currently in use within radiopharmaceutical sciences and for the development of radiopharmaceuticals to be used for patient care in Nuclear Medicine in Germany (D), Austria (A) and Switzerland (CH). Methods: Publicly available information on the cyclotron infrastructure was (i) consolidated and updated, (ii) supplemented by selective desktop research and, last but not least, (iii) validated by members of the committee of the academic “Working Group Radiochemistry and Radiopharmacy” (AGRR), consisting of radiochemists and radiopharmacists of the D-A-CH countries and belonging to the German Society of Nuclear Medicine (DGN), as well as the Radiopharmaceuticals Committee of the DGN. Results: In total, 42 cyclotrons were identified that are currently being operated for medical radionuclide production for imaging and therapy in Nuclear Medicine clinics, 32 of them in Germany, 4 in Austria and 6 in Switzerland. Two thirds of the cyclotrons reported (67%) are operated by universities, university hospitals or research institutions close to a university hospital, less by/in cooperation with industrial partners (29%) or a non-academic clinic/ PET-center (5%). Most of the cyclotrons (88%) are running with up to 18 MeV proton beams, which is sufficient for the production of the currently most common cyclotron-based radionuclides for PET imaging. Discussion: The data presented provide an academically-updated overview of the medical cyclotrons operated for the production of radiopharmaceuticals and their use in Nuclear Medicine in the D-A-CH countries. In this context, we discuss current developments and trends with a view to the cyclotron infrastructure in these countries, with a specific focus on organizational aspects

Excitatory-inhibitory balance within EEG microstates and resting-state fMRI networks: assessed via simultaneous trimodal PET-MR-EEG imaging

The symbiosis of neuronal activities and glucose energy metabolism is reflected in the generation of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) signals. However, their association with the balance between neuronal excitation and inhibition (E/I-B), which is closely related to the activities of glutamate and γ-aminobutyric acid (GABA) and the receptor availability (RA) of GABAA and mGluR5, remains unexplored. This research investigates these associations during the resting state (RS) condition using simultaneously recorded PET/MR/EEG (trimodal) data. The trimodal data were acquired from three studies using different radio-tracers such as, [11C]ABP688 (ABP) (N = 9), [11C]Flumazenil (FMZ) (N = 10) and 2-[18F]fluoro-2-deoxy-D-glucose (FDG) (N = 10) targeted to study the mGluR5, GABAA receptors and glucose metabolism respectively. Glucose metabolism and neuroreceptor binding availability (non-displaceable binding potential (BPND)) of GABAA and mGluR5 were found to be significantly higher and closely linked within core resting-state networks (RSNs). The neuronal generators of EEG microstates and the fMRI measures were most tightly associated with the BPND of GABAA relative to mGluR5 BPND and the glucose metabolism, emphasising a predominance of inhibitory processes within in the core RSNs at rest. Changes in the neuroreceptors leading to an altered coupling with glucose metabolism may render the RSNs vulnerable to psychiatric conditions. The paradigm employed here will likely help identify the precise neurobiological mechanisms behind these alterations in fMRI functional connectivity and EEG oscillations, potentially benefitting individualised healthcare treatment measures

mGluR5 receptor availability is associated with lower levels of negative symptoms and better cognition in male patients with chronic schizophrenia

Consistent findings postulate disturbed glutamatergic function (more specifically a hypofunction of the ionotropic NMDA receptors) as an important pathophysiologic mechanism in schizophrenia. However, the role of the metabotropic glutamatergic receptors type 5 (mGluR5) in this disease remains unclear. In this study, we investigated their significance (using [11 C]ABP688) for psychopathology and cognition in male patients with chronic schizophrenia and healthy controls. In the patient group, lower mGluR5 binding potential (BPND ) values in the left temporal cortex and caudate were associated with higher general symptom levels (negative and depressive symptoms), lower levels of global functioning and worse cognitive performance. At the same time, in both groups, mGluR5 BPND were significantly lower in smokers (F[27,1] = 15.500; p = .001), but without significant differences between the groups. Our findings provide support for the concept that the impaired function of mGluR5 underlies the symptoms of schizophrenia. They further supply a new perspective on the complex relationship between tobacco addiction and schizophrenia by identifying glutamatergic neurotransmission-in particularly mGluR5-as a possible connection to a shared vulnerability. Keywords: chronic schizophrenia; cognition; mGluR5 receptor; negative symptoms; positron emission tomography

Treating a GAD65 Antibody-Associated Limbic Encephalitis with Basiliximab: A Case Study

Background: Antibodies (ABs) against the 65-kDa isoform of the intracellular enzymeglutamate decarboxylase (GAD65) have been found in limbic encephalitis (LE) andother neurological conditions. The direct significance of anti-GAD65-ABs for epilepsyis unclear. However, in histological preparations from biopsies of resective epilepsysurgeries, predominantly cytotoxic T-lymphocytes were detected making close contactsto neurons. Activated T-lymphocytes can, in turn, be selectively controlled by therapeuticinterleukin-2 receptor Abs, such as basiliximab.Case presentation: We report of a 25-year-old male patient with epilepsy since theage of 18 and displaying clinical signs of LE and a high titer of GAD65 ABs in cerebro-spinal fluid (CSF) and serum. Monthly, repetitive, intravenous cortisone pulse therapiesthat were initially administered for 6 months failed to improve his condition. Subsequentflow-cytometry analysis of CSF showed especially an increased fraction of activatedHLA-DR+CD8+T-lymphocytes (fCD8+TL) when compared to controls. Thus, a second,intravenous cortisone pulse therapy with an additional basiliximab dose of 20 mg/monthwas started. After 3 months, the fCD8+TL in the CSF normalized; after 6 months, thepsychological impulse-control deficits normalized; and after 11 months the patientwas seizure free. However, 7 weeks later, seizures and, later on, psychological deficitsrecurred and fCD8+TL was once again present in the CSF. Flumazenil PET, magneticresonance imaging-volumetry, and neuropsychological changes during therapy aredescribed.Conclusion: The correlation of the fCD8+TL in the CSF with clinical and paraclinical measures of disease activity combined with the unambiguous response to basiliximabstrongly argues in favor of the putative pathogenic role fCD8+TL in anti-GAD65 LE. The clinical relapse at the end of the observation period might be due to the formation ofhuman anti-drug ABs, a well-known complication of therapy with chimeric ABs

18 F-Labelled Intermediates for Radiosynthesis by Modular Build-Up Reactions: Newer Developments

This brief review gives an overview of newer developments in 18F-chemistry with the focus on small 18F-labelled molecules as intermediates for modular build-up syntheses. The short half-life (<2 h) of the radionuclide requires efficient syntheses of these intermediates considering that multistep syntheses are often time consuming and characterized by a loss of yield in each reaction step. Recent examples of improved synthesis of 18F-labelled intermediates show new possibilities for no-carrier-added ring-fluorinated arenes, novel intermediates for tri[18F]fluoromethylation reactions, and 18F-fluorovinylation method

Zur trägerarmen Markierung von Arylalkylaminen mit n.c.a. [18F] Fluorid am Beispiel von Norephedrin und Metaraminol

A new pathway for the no carrier added (n.c.a.) l'F-labelling of biogenic arylalkylamines such as C"Flfluoronorephedrine and [l'F]fluorometaraminol (FMR) via nucleophilic aromatic substitution was developed. To overcome the problem of low specific activity, not to avoid with previous electrophilic fluorination, l'F-labelled arylalkylamines were synthesized by direct nucleophilic exchange with n.c.a. C8F]fluoride starting with a keto-activated aromatic system and consecutive chiral reduction of the ketofunction. With regard to a stereosclective reduction of the carbonyl group, several N-protected cc-aminopropiophenones were prepared as model compounds in order to examine the influence of the protecting group on the radiochemical yield of a l'F-for-X substitution (X= F, Cl, NO" "N(CH3),) . Good radiochemical yields could be achieved using the N-dibenzyl- or acetyl-protected compounds. The para-position of the leaving group provided higher radiochemical yields than the ortho-position in the case of the l'F-forY'F substitution. It has been shown that the less basic oxalate/cryptate system does not increase the radiochemical yields

Labelling with positron emitters of pnicogens and chalcogens

The increasing importance of the positron emission tomography (PET) in clinical diagnosis led to the development of a multitude of radiotracers labelled with positron-emitting radionuclides of groups 15 (pnicogens) and 16 (chalcogens) of the periodic table of elements. The positron emitters of the endogenous occurring elements nitrogen, phosphorus, oxygen, and sulphur are characterized by very short half-lives compared with the most commonly used PET radionuclides carbon-11 or fluorine-18. Therefore, the potential of their synthesis and possible applications in PET is challenging and limited. On the other hand, the nonstandard positron emitters arsenic-72, arsenic-74, and selenium-73 have half-lives in the range of hours to days and, thus, are of interest for PET studies of processes with long biological half-lives, but novel methods have to be developed for their application, especially in the no-carrier-added state. This review summarizes recent research concerning the positron emitters of pnicogens and chalcogens for radiolabelling applications

Optimizing transfer of [18F]fluoride from aqueous to organic solvents by interim electrodeposition using different electrode materials

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Radiotracer in Kombination mit Magnetresonanz-Kontrastmittel für die simultane MR-PET-Bildgebung

Moderne bildgebende Verfahren der medizinischen Diagnostik, wie die Magnetresonanz-Tomographie (MRT) und die Positronen-Emissions-Tomographie (PET), erlauben eine immer präzisere und differenziertere Untersuchung von Krankheiten. Neben dem reinen PET- bzw. MRT-Ansatz befassen sich neue Methoden mit der simultanen PET-MR-Bildgebung, die erst durch die Entwicklung hybrider PET-MRT-Scanner ermöglicht wurde. Diese komplementären Bildgebungsverfahren kombinieren dabei in synergistischer Weise die hohe Auflösung durch MRT mit der großen Sensitivität durch die PET-Methode. Eine Möglichkeit, die Synergie beider Techniken zu nutzen, besteht darin, bereits klinisch etablierte PET-Radiopharmaka mit zugelassenen, paramagnetischen MR-Kontrastmitteln zu kombinieren. Diese Methode wurde in zahlreichen präklinischen und klinischen Studien untersucht. Eine alternative und elegantere Möglichkeit ist die Einführung beider Modalitäten in einer einzigen Kontrastsonde für die nicht-invasive bimodale Bildgebung. Hier sind verschiedene Ansätze entwickelt worden, die jedoch umfangreichere Entwicklungsarbeit erfordern. Diese multifunktionellen Kontrastsonden wurden daher bislang nur in präklinischen Studien eingesetzt