Assessment of serotonin release capacity in the human brain using dexfenfluramine challenge and [18F]altanserin positron emission tomography.

Although alterations of serotonin (5-HT) system functioning have been proposed for a variety of psychiatric disorders, a direct method quantitatively assessing 5-HT release capacity in the living human brain is still lacking. Therefore, we evaluated a novel method to assess 5-HT release capacity in vivo using dexfenfluramine challenge and [(18)F]altanserin positron emission tomography (PET). Thirteen healthy male subjects received placebo and single oral doses of 40 mg (n = 6) or 60 mg (n = 7) of the potent 5-HT releaser dexfenfluramine separated by an interval of 14 days.

Guidance on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals.

This guidance is meant as a guidance to Part B of the EANM "Guidelines on Good Radiopharmacy Practice (GRPP)" issued by the Radiopharmacy Committee of the EANM (see www.eanm.org ), covering the small-scale "in house" preparation of radiopharmaceuticals which are not kit procedures.

GMP-compliant radiosynthesis of [18F]altanserin and human plasma metabolite studies.

[(18)F]altanserin is the preferred radiotracer for in-vivo labeling of serotonin 2A receptors by positron emission tomography (PET). We report a modified synthesis procedure suited for reliable production of multi-GBq amounts of [(18)F]altanserin useful for application in humans. We introduced thermal heating for drying of [(18)F]fluoride as well as for the reaction instead of microwave heating.

Homology modeling and dynamics of the extracellular domain of rat and human neuronal nicotinic acetylcholine receptor subtypes alpha4beta2 and alpha7.

In recent years, it has become clear that the neuronal nicotinic acetylcholine receptor (nAChR) is a valid target in the treatment of a variety of diseases, including Alzheimer's disease, anxiety, and nicotine addiction. As with most membrane proteins, information on the three-dimensional (3D) structure of nAChR is limited to data from electron microscopy, at a resolution that makes the application of structure-based design approaches to develop specific ligands difficult. Based on a high-resolution crystal structure of AChBP, homology models of the extracellular domain of the neuronal rat and human nAChR subtypes alpha4beta2 and alpha7 (the subtypes most abundant in brain) were built, and their stability assessed with molecular dynamics (MD).

Automated no-carrier-added synthesis of [1-11C]-labeled D- and L-enantiomers of lactic acid.

The first purely chemical method for automated no-carrier-added synthesis of [1-(11)C]-labeled d(R)- and l(S)-2-hydroxypropanoic acid (lactic acid) was developed for experimental neurophysiology studies and position emission tomography (PET) diagnosis. Starting from sodium 1-hydroxyethanesulfonate and [(11)C]HCN (trapped as [(11)C]KCN) the intermediate dl-(R,S)-[1-(11)C]-2-hydroxypropanenitrile was prepared. Its rapid acid hydrolysis gave dl-(R,S)-[1-(11)C]lactic acid, which was isolated by preparative reversed phase HPLC and automatically injected on a second preparative C(18) HPLC column coated with a chiral selector, where both [1-(11)C]lactic acid enantiomers were separated by chiral ligand-exchange chromatography.

Synthesis and binding studies of epibatidine analogues as ligands for the nicotinic acetylcholine receptors.

Neuronal nicotinic acetylcholine receptors (nAChRs) are transmembrane ligand-gated ion channels. Recent research demonstrated that selective nAChR ligands may have therapeutic potential in a number of CNS diseases and disorders. The alkaloid epibatidine is a highly potent non-opioid analgesic and nAChR agonist, but too toxic to be a useful ligand.

Uptake of 18F-fluorocholine, 18F-fluoro-ethyl-L: -tyrosine and 18F-fluoro-2-deoxyglucose in F98 gliomas in the rat.

Introduction: The positron emission tomography (PET) tracers (18)F-fluoro-ethyl-L: -tyrosine (FET), (18)F-fluorocholine (N,N-dimethyl-N-[(18)F]fluoromethyl-2-hydroxyethylammonium (FCH]) and (18)F-fluoro-2-deoxyglucose (FDG) are used in the diagnosis of brain tumours. The aim of this study was threefold: (a) to assess the uptake of the different tracers in the F98 rat glioma, (b) to evaluate the impact of blood-brain barrier (BBB) disruption and microvessel density (MVD) on tracer uptake and (c) to compare the uptake in the tumours to that in the radiation injuries (induced by proton irradiation of healthy rats) of our previous study.

Methods: F98 gliomas were induced in 26 rats.

Ligand selectivity for the acetylcholine binding site of the rat alpha4beta2 and alpha3beta4 nicotinic subtypes investigated by molecular docking.

The homology models of the extracellular domains of the neuronal alpha4beta2 (pdb code: 1ole) and ganglionic alpha3beta4 (pdb code: 1olf) rat nicotinic acetylcholine receptor (nAChR) subtypes were refined and energetically minimized. In this work, a series of nAChR ligands (1-15) were docked into the modeled binding cavity of both receptors. High-affinity, toxic ligands such as epibatidine (1) and dechloroepibatidine (2) docked into cluster 1 with the charged tertiary amino group, forming a pi-cation interaction with Trp 147 on the (+) side of the alpha4 subunit and establishing a characteristic H-bond with the Lys 77 on the (-) side of the beta2 subunit.

Fluorocholine PET/CT in patients with prostate cancer: initial experience.

Institutional review board approval and written informed consent were obtained. Patients with newly diagnosed prostate cancer and patients suspected of having recurrent prostate cancer were prospectively evaluated with fluorine 18 fluorocholine (FCH) combined in-line positron emission tomography (PET) and computed tomography (CT). In 19 patients (mean age, 67 years +/- 8; range, 57-85 years), standardized uptake values of FCH in 17 different tissues were determined by using volumes of interest.

Uptake of 18F-fluorocholine, 18F-fluoroethyl-L-tyrosine, and 18F-FDG in acute cerebral radiation injury in the rat: implications for separation of radiation necrosis from tumor recurrence.

Unlabelled: Differentiation between posttherapy radiation necrosis and recurrent tumor in humans with brain tumor is still a difficult diagnostic task. The new PET tracers (18)F-fluoro-ethyl-l-tyrosine (FET) and (18)F-fluorocholine (N,N-dimethyl-N-(18)F-fluoromethyl-2-hydroxyethylammonium [FCH]) have shown promise for improving diagnostic accuracy. This study assessed uptake of these tracers in experimental radiation injury.

A-186253, a specific antagonist of the alpha 4 beta 2 nAChRs: its properties and potential to study brain nicotinic acetylcholine receptors.

Imaging the living brain and the distribution of the ligand gated channels that participate in the neurotransmission is one of the challenges that is hoped to bring new insights for the treatment of neurological diseases. Herein, we probed a new nicotinic derivative, A-186253 as a potential molecule to discriminate with high resolution the different neuronal nicotinic receptor subtypes that are expressed in distinct brain areas. Binding with a high affinity of 440 pM at the major brain alpha4beta2 receptor subtype and presenting an excellent safety margin, properties of the A-186253 were thoroughly evaluated.

Constant-infusion H(2)15O PET and acetazolamide challenge in the assessment of cerebral perfusion status.

Unlabelled: Assessing the baseline perfusion and perfusion reserve after acetazolamide (ACZ) challenge is a common method for the evaluation of patients with cerebrovascular disease. Most previous studies using H(2)(15)O PET applied the bolus injection technique. There is considerable discrepancy regarding the optimal time point of imaging after ACZ injection.

18F-choline in experimental soft tissue infection assessed with autoradiography and high-resolution PET.

For each oncological tracer it is important to know the uptake in non-tumorous lesions. The purpose of this study was to measure the accumulation of fluorine-18 choline (FCH), a promising agent for the evaluation of certain tumour types, in infectious tissue. Unilateral thigh muscle abscesses were induced in five rats by intramuscular injection of 0.

Functional imaging of physiological processes by positron emission tomography.

Tracer technology makes it possible to observe physiological and biochemical processes in the living organism in a dynamic mode. Positron emission tomography adds the use of chemically unchanged biomolecules and of quantification. This opens up fascinating possibilities for both fundamental research and routine diagnostic applications.

(18)F-FDG and (18)F-FET uptake in experimental soft tissue infection.

The aim of this study was to compare the uptake of (18)F-fluoroethyl- L-tyrosine ((18)F-FET) with that of (18)F-fluorodeoxyglucose ((18)F-FDG) in activated inflammatory white blood cells. Unilateral thigh muscle abscesses were induced in 11 rats by intramuscular inoculation of 0.1 ml of a bacterial suspension ( S.

Synthesis and in vivo studies of the stereoisomers of N-[11C]methyl-homoepibatidine.

The carbon-11 labeled enantiomers of nicotinic acetylcholine receptor (nAChR) ligand N-[11C]methyl-homoepibatidine have been synthesized to study the neuronal nicotinic acetylcholine receptors (nAChRs). In vivo evaluations were performed in mice and pig using positron emission tomography (PET). The radioligands displayed a strong enantioselectivity.

Similarity and robustness of PET and SPECT binding parameters for benzodiazepine receptors.

The single photon emission computed tomography (SPECT) radiotracer [123I]iomazenil is used to assess benzodiazepine receptor binding parameters. These measurements are relative indices of benzodiazepine receptor concentration (B'max). To evaluate the ability of such indices in accurately accessing the B'max the authors compared them with absolute values of B'max, measured using positron emission tomography (PET).

Chemical modification of epibatidine causes a switch from agonist to antagonist and modifies its selectivity for neuronal nicotinic acetylcholine receptors.

Background: Studies of ligand gated channels strongly rely on the availability of compounds that can activate or inhibit with high selectivity one set or a subset of defined receptors. The alkaloid epibatidine (EPB), originally isolated from the skin of an Ecuadorian poison frog, is a very specific agonist for the neuronal nicotinic acetylcholine receptors (nAChRs). We used EPB derivatives to investigate the pharmacophore of nAChR subtypes.

Comparison of N-[(11)C]methyl-norchloroepibatidine and N-[(11)C]methyl-2-(2-pyridyl)-7-azabicyclo[2.2.1]heptane with N-[(11)C]methyl-epibatidine in small animal PET studies.

Structural variations of the nicotinic acetylcholine receptor radioligand N-[(11)C]methyl-epibatidine were made to form (11)C-labeled N-methyl-norchloroepibatidine (N-methyl-NorchloroEPB) and N-methyl-2-(2-pyridyl)-7-azabicyclo[2.2.1]heptane (N-methyl-2PABH).

A new look at the neuronal nicotinic acetylcholine receptor pharmacophore.

Interest in the field of nicotinic receptors has been recently stimulated both by the discovery of the potential therapeutic effects of new agonists, and by the discovery of an association between nicotinic receptor mutations and human neurological diseases. Expression of human receptors in an exogenous system allows their study in isolation. Receptors reconstituted by pairwise injection of either alpha4 or alpha3 with beta2 or beta4 subunits displayed important differences between the resulting receptor subtypes.

Neuronal nAChR stereoselectivity to non-natural epibatidine derivatives.

The frog toxin epibatidine is one of the most powerful ligands of the neuronal nicotinic receptors and derivatives show promising possibilities for labeling in positron emission tomography studies. In an attempt to reduce epibatidine toxicity, new methyl derivatives were synthesized, tested in positron emission tomography imaging and in electrophysiology. labeling as well as physiological experiments highlighted the differences in sensitivity of the neuronal nicotinic acetylcholine receptors between two methyl enantiomers and the reduction in sensitivity caused by introducing the methyl group.

Synthesis and in Vivo studies of [C-11]N-methylepibatidine: comparison of the stereoisomers.

The carbon-11-labelled nicotinic acetylcholine receptor (nAChR) agonist N-methylepibatidine was evaluated in vitro and in vivo as a possible positron emission tomography (PET)-tracer for nicotinic receptors in the central nervous system (CNS). The racemic mixture and both enantiomers of N-methylepibatidine were compared. Biodistribution and metabolites for blood and brain of [C-11]N-methylepibatidine were determined in mice.

Synthesis and electrophysiological studies of a novel epibatidine analogue.

The new epibatidine analogue exo-2-(2-pyridyl)-7-azabicyclo[2.2.1]heptane (2PABH) was synthesised.