Fully-automated production of [68Ga]Ga-PentixaFor on the module Modular Lab-PharmTracer.

BACKGROUND: PentixaFor is a promising radiopharmaceutical for positron emission tomography in the detection of different tumor entities and other diseases. Until now, the synthesis of [68Ga]Ga-PentixaFor was reported for the automated synthesis module from Scintomics® only. Our aim was to evaluate the automated synthesis of this radiopharmaceutical on a different module in order to make it available for a broader community. RESULTS: The synthesis of [68Ga]Ga-PentixaFor with different amounts of PentixaFor (50 µg, 30 µg and 20 µg) on the Modular Lab PharmTracer (MLPT) from Eckert & Ziegler with the already established synthesis template for [68Ga]Ga-DOTATOC yielded best results with 50 µg PentixaFor for clinical multi-dose application. All different quality control parameters tested (e.g. sterility, stability and radiochemical purity) were in accordance with the European Pharmacopoeia. CONCLUSIONS: [68Ga]Ga-PentixaFor was successfully synthesized fully-automated on the synthesis module Modular Lab PharmTracer and can be used for multi-dose application in clinical settings.

Inhibition of serotonin transport by (+)McN5652 is noncompetitive.

INTRODUCTION: Imaging of the serotonergic innervation of the brain using positron emission tomography (PET) with the serotonin transporter (SERT) ligand [11C] (+)McN5652 might be affected by serotonin in the synaptic cleft if there is relevant interaction between [11C] (+)McN5652 and serotonin at the SERT. The aim of the present study therefore was to pharmacologically characterize the interaction of [11C] (+)McN5652 and serotonin at the SERT. METHODS: In vitro saturation analyses of [3H]serotonin uptake into HEK293 cells stably expressing the human SERT were performed in the absence and presence of unlabelled (+)McN5652. Data were evaluated assuming Michaelis-Menten kinetics. RESULTS: Unlabelled (+)McN5652 significantly reduced the maximal rate of serotonin transport V(max) of SERT without affecting the Michaelis-Menten constant K(M). CONCLUSIONS: This finding indicates that (+)McN5652 inhibits serotonin transport through the SERT in a noncompetitive manner. This might suggest that [11C] (+)McN5652 PET is not significantly affected by endogenous serotonin.

Is correction for age necessary in SPECT or PET of the central serotonin transporter in young, healthy adults?

UNLABELLED: PET and SPECT have suggested that there is an age-related decline of up to 10% per decade in the availability of brain serotonin transporter (SERT) in healthy subjects, starting as early as the age of 20 y. The aim of the present study was to verify these findings in young subjects. METHODS: The equilibrium specific-to-nonspecific partition coefficient V''(3) of the SERT ligand (11)C-(+)McN5652 was obtained for 29 healthy subjects aged 18-33 y. V''(3) was tested for age dependence by linear regression analysis using both a volumes-of-interest approach and voxel-based statistical parametric mapping. The sex of the subject and the season of year were considered nuisance variables. RESULTS: Age had no significant effect on V''(3). The power for the detection of an age-related decline in V''(3) of the magnitude reported previously was 0.917. CONCLUSION: These findings indicate that age is not a relevant confounding factor for SERT availability as measured by (11)C-(+)McN5652 PET in healthy adults up to the age of about 35 y.

Convenient preparation of 3,5-anhydro- and 2,5-anhydropentofuranosides, and 5,6-anhydro-D-glucofuranose by use of the Mitsunobu reaction.

Methyl 3,5-anhydro-alpha-D-xylofuranosides are obtained by use of the Mitsunobu reaction from 2-O-protected methyl alpha-D-xylofuranosides, which are easily prepared from D-xylose. The Mitsunobu reaction of methyl 3-N-benzylamino-3-deoxy- and 3-azido-3-deoxyarabinofuranosides, which are prepared from the conveniently available methyl 2,3-anhydro-alpha-D- and 2,3-anhydro-alpha-l-lyxofuranosides by nucleophilic ring opening, yields the corresponding methyl 2,5-anhydro-alpha-D- and 2,5-anhydro-alpha-l-arabinofuranosides. Ring opening of 3,5-anhydro-1,2-O-isopropylidene-alpha-D-xylofuranose with azide yields the corresponding 5-azido derivative. The structure and configuration of the products is confirmed by NMR spectroscopy. 5,6-Anhydro-1,2-O-isopropylidene-alpha-D-glucofuranose is formed by the Mitsunobu reaction of 1,2-O-isopropylidene-alpha-D-glucofuranose. Its structure is verified by single-crystal X-ray diffraction analysis.

Thiosugars. XII. Synthesis of new 3'-O-substituted 2',5'-anhydro-2'-thio-alpha-D-pentofuranosyl nucleoside analogues.

Methyl 2,5-anhydro-3-O-(2-methoxyethyl)-2-thio-beta-D-arabinofuranoside and methyl 2,5-anhydro-3-O-(2-fluorobenzyl)-2-thio-alpha-D-lyxofuranoside were transformed into the corresponding uridine, thymidine, cytidine and adenosine analogues, which exclusively exhibited the alpha-configuration irrespective of the anomeric configuration of the donor. The structure, configuration, and conformation of the products was elucidated by X-ray structure analyses. The nucleoside analogues were tested for antiviral activities.

A voxel-based PET investigation of the long-term effects of "Ecstasy" consumption on brain serotonin transporters.

OBJECTIVE: Recent functional imaging studies have reported evidence of alterations in the serotonergic system induced by 3,4-methylenedioxymethamphetamine (MDMA), or "Ecstasy." However, these studies have often been limited by small sample size, lack of tracer selectivity, unreliable assessment of MDMA doses, insufficiently matched comparison groups, or region-of-interest analysis. METHOD: Positron emission tomography (PET) using the specific serotonin transporter ligand [(11)C](+)McN5652 was performed in 117 subjects: 30 current MDMA users, 29 former MDMA users, 29 drug-naive comparison subjects, and 29 users of drugs other than MDMA (polydrug comparison subjects). Self-assessment of drug history was checked by analyzing hair samples. Local serotonin transporter availability was computed by a regularized reference tissue approach. Voxel-based comparison of serotonin transporter availability was performed using statistical parametric mapping (SPM 99). RESULTS: Serotonin transporter availability in current MDMA users was significantly reduced in the mesencephalon, thalamus, left caudate, hippocampus, occipital cortex, temporal lobes, and posterior cingulate gyrus compared with all other groups. Reduction was more pronounced in female than in male subjects. There was no significant difference of serotonin transporter availability among former MDMA users and the drug-naive and polydrug comparison subjects. A negative correlation between serotonin transporter availability and mean MDMA dose was found in occipital visual areas and in the left precentral sulcus of current MDMA users. In addition, there was a significant positive correlation between the serotonin transporter availability and the MDMA abstention period in brainstem and in the basal forebrain in all MDMA users. CONCLUSIONS: These findings support the hypothesis of MDMA-induced protracted alterations of the serotonergic system and indicate that the reduced availability of serotonin transporter, as measured by PET, might be reversible. Women appear to be more susceptible than men to MDMA-induced alterations of the serotonergic system.

The thio-Mitsunobu reaction: a useful tool for the preparation of 2,5-anhydro-2-thio- and 3,5-anhydro-3-thiopentofuranosides.

The unprotected methyl L-arabinofuranosides, D-ribofuranosides and D-xylofuranosides are transformed into the corresponding S-acetyl-5-thio derivatives by the thio-Mitsunobu reaction. Mesylation and subsequent reaction with sodium hydrogen carbonate led, depending on the configuration of the intermediate, to 2,5-anhydro-2-thio- or 3,5-anhydro-3-thiopentofuranosides. Due to inversion at C-3 or C-2 during the intramolecular nucleophilic displacement the products exhibit L-lyxo-, D-arabino- or D-lyxo-configuration. Analogously, the methyl 2,3-anhydro-D-ribofuranosides yielded 5-thio-S-acetates with intact 2,3-oxirane groups, which were cyclised with sodium hydrogen carbonate by epoxide ring opening and concomitant ring closure to form exclusively 3,5-anhydro-3-thio-D-xylofuranosides. A related 3,5-anhydro-3-seleno-D-lyxofuranoside was obtained by reaction of a 3,5-di-O-mesyl-D-arabinofuranoside with sodium hydrogen selenide. Several X-ray diffraction analyses proved the structures of the products.

Synthesis and biological evaluation of isonucleosides derived from methyl 3,5-anhydro-2-O-(2-fluorobenzyl)-D-xylofuranosides.

New isonucleosides [methyl 5-(1-pyrimidinyl)furanosides] are prepared by nucleophilic opening of the oxetane ring of methyl 3,5-anhydro-2-O-(2-fluorobenzyl)-D-xylofuranoside with silylated pyrimidine bases in the presence of trimethylsilyl triflate. Structures, configurations and conformations were determined by NMR techniques and several X-ray diffraction analyses, seven of the isonucleosides were tested for cytotoxicity and activity against HIV, HSV and several other viruses.