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Cu‐mediated radiofluorination is a versatile tool for the preparation of 18F‐labeled (hetero)aromatics. In this work, we systematically evaluated a series of complexes and identified several generally applicable mediators for highly efficient radiofluorination of aryl boronic and stannyl substrates. Utilization of these mediators in nBuOH/DMI or DMI significantly improved 18F‐labeling yields despite use of lower precursor amounts. Impressively, application of 2.5 μmol aryl boronic acids was sufficient to achieve 18F‐labeling yields of up to 75 %. The practicality of the novel mediators was demonstrated by efficient production of five PET‐tracers and transfer of the method to an automated radiosynthesis module. In addition, (S)‐3‐[18F]FPhe and 6‐[18F]FDOPA were prepared in activity yields of 23±1 % and 30±3 % using only 2.5 μmol of the corresponding boronic acid or trimethylstannyl precursor. [ABSTRACT FROM AUTHOR]

Based on the contribution of the endocannabinoid system to the pathophysiology of schizophrenia, the primary pro-psychotic ingredient of Cannabis sativa, Δ-9-tetrahydrocannabinol (Δ-9-THC), is used in preclinical as well as clinical research to mimic schizophrenia-like symptoms. While it is common to administer lipid-based formulations of Δ-9-THC in human studies orally, intraperitoneal injections of water-based solutions are used in animal models. Because of the poor water solubility of Δ-9-THC, solubilizers such as ethanol and/or emulsifiers are needed for these preparations. In order to test whether a lipid-based solvent would be superior over a water-based vehicle in rats, we compared the effects on locomotor activity and prepulse inhibition (PPI) of the acoustic startle reaction, as well as pharmacokinetic data obtained from rats' serum and brain tissue samples. Up to 50 mg/kg Δ-9-THC in the lipid-based formulation was not able to induce any behavioral alterations, while already 5 mg/kg of the water-based Δ-9-THC preparation significantly reduced locomotor activity. This also induced a small but significant PPI reduction, which was prepulse intensity dependent. Interestingly, the reflexive motor response to the startle stimulus was not affected by the water-based Δ-9-THC solution. Analysis of serum and brain Δ-9-THC levels by high-performance liquid chromatography/mass spectrometry revealed that although the final concentration reached in the brain was comparable for both pharmaceutical preparations, the water-based formulation achieved a faster kinetic. We, therefore, conclude that the slope of the Δ-9-THC concentration-time curve and the resulting cannabinoid receptor type 1 activation per time unit are responsible for the induction of behavioral alterations. [ABSTRACT FROM AUTHOR]

Recently a novel method for the preparation of 18F-labeled arenes via oxidative [18F]fluorination of easily accessible and sufficiently stable nickel complexes with [18F]fluoride under exceptionally mild reaction conditions was published. The suitability of this procedure for the routine preparation of clinically relevant positron emission tomography (PET) tracers, 6-[18F]fluorodopamine (6-[18F]FDA), 6-[18F]fluoro- l-DOPA (6-[18F]FDOPA) and 6-[18F]fluoro- m-tyrosine (6-[18F]FMT), was evaluated. The originally published base-free method was inoperative. However, a 'low base' protocol afforded protected radiolabeled intermediates in radiochemical conversions (RCCs) of 5-18 %. The subsequent deprotection step proceeded almost quantitatively (>95 %). The simple one-pot two-step procedure allowed the preparation of clinical doses of 6-[18F]FDA and 6-[18F]FDOPA within 50 min (12 and 7 % radiochemical yield, respectively). In an unilateral rat model of Parkinsons disease, 6-[18F]FDOPA with high specific activity (175 GBq μmol−1) prepared using the described nickel-mediated radiofluorination was compared to 6-[18F]FDOPA with low specific activity (30 MBq μmol−1) produced via conventional electrophilic radiofluorination. Unexpectedly both tracer variants displayed very similar in vivo properties with respect to signal-to-noise ratio and brain distribution, and consequently, the quality of the obtained PET images was almost identical. [ABSTRACT FROM AUTHOR]

Two novel methods for copper-mediated aromatic nucleophilic radiofluorination were recently reported. Evaluation of these methods reveals that, although both are efficient in small-scale experiments, they are inoperative for the production of positron emission tomography (PET) tracers. Since high base content turned out to be responsible for low radiochemical conversions, a 'low base' protocol has been developed which affords 18F-labeled arenes from diaryliodonium salts and aryl pinacol boronates in reasonable yields. Furthermore, implementation of our 'minimalist' approach to the copper-mediated [18F]-fluorination of (mesityl)(aryl)iodonium salts allows the preparation of 18F-labeled arenes in excellent RCCs. The novel radiofluorination method circumvents time-consuming azeotropic drying and avoids the utilization of base and other additives, such as cryptands. Furthermore, this procedure enables the production of clinically relevant PET tracers; [18F]FDA, 4-[18F]FPhe, and [18F]DAA1106 are obtained in good isolated radiochemical yields. Additionally, [18F]DAA1106 has been evaluated in a rat stroke model and demonstrates excellent potential for visualization of translocator protein 18 kDa overexpression associated with neuroinflammation after ischemic stroke. [ABSTRACT FROM AUTHOR]

We investigated the effects of dopamine depletion on acoustically guided behavior of anurans by conducting phonotaxis experiments with female gray treefrogs ( Hyla versicolor) before and 90 min after bilateral injections of 3, 6, or 12 μg 6-hydroxydopamine (6-OHDA) into the telencephalic ventricles. In experiments with one loudspeaker playing back a standard artificial mating call, we analyzed the effects of 6-OHDA on phonotactic response time. In choice tests we measured the degree of distraction from the standard call (20 pulses/s) by three different variants with altered pulse-rate (30/s, 40/s, 60/s). Five days after experiments, brains were immunostained for tyrosine hydroxylase. Labeled neurons were counted in the suprachiasmatic nucleus, posterior tuberculum, interpeduncular nucleus, and locus coeruleus, and correlation between neuronal numbers and behavioral scores was tested. Response times increased together with 6-OHDA concentrations, which was mainly due to longer immobile periods before the animals started movement. In choice tests the most irrelevant stimulus (60/s) distracted 6-OHDA injected females from the standard stimulus, while sham injected controls were undistracted. The number of catecholaminergic neurons decreased with increasing 6-OHDA concentration in the suprachiasmatic nucleus, posterior tuberculum, and interpeduncular nucleus. The normalized number of immunoreactive neurons in the posterior tuberculum was positively correlated with phonotaxis scores in the one-speaker test, demonstrating that motor deficits are a function of tubercular cell loss. We conclude that bilateral 6-OHDA lesions in anuran amphibians cause motor (difficulty to start movements) as well as cognitive symptoms (higher distraction by irrelevant stimuli) that have also been described for human Parkinson patients. © 2004 Wiley Periodicals, Inc. J Neurobiol 60: 395-410, 2004 [ABSTRACT FROM AUTHOR]

The cover picture shows the differences in brain metabolism of a healthy young and a healthy old subject, as well as a patient suffering from Parkinsons disease (left to right) uncovered by 6‐[18F]FDOPA‐positron emission tomography (PET). Morbus Parkinson occurs when nerve cells that produce dopamine begin to die. The shortage of dopamine leads to movement problems in affected individuals. 6‐[18F]FDOPA is extensively used to evaluate the progression of Parkinsons disease. Bold stick projections of this PET tracer, as well as a neuronal network, are seen in the background. Unfortunately, conventional procedures to produce 6‐[18F]FDOPA are cumbersome. Thus, several recent developments aim at the simplification of this radiosynthesis. In our work, we studied the applicability of the recently reported Ni‐mediated radiofluorination approach for daily routine production of 6‐[18F]FDOPA. For more details, see the Full Paper on p. 457 ff. [ABSTRACT FROM AUTHOR]

Based on the contribution of the endocannabinoid system to the pathophysiology of schizophrenia, the primary pro-psychotic ingredient of Cannabis sativa, Δ-9-tetrahydrocannabinol (Δ-9-THC), is used in preclinical as well as clinical research to mimic schizophrenia-like symptoms. While it is common to administer lipid-based formulations of Δ-9-THC in human studies orally, intraperitoneal injections of water-based solutions are used in animal models. Because of the poor water solubility of Δ-9-THC, solubilizers such as ethanol and/or emulsifiers are needed for these preparations. In order to test whether a lipid-based solvent would be superior over a water-based vehicle in rats, we compared the effects on locomotor activity and prepulse inhibition (PPI) of the acoustic startle reaction, as well as pharmacokinetic data obtained from rats' serum and brain tissue samples. Up to 50 mg/kg Δ-9-THC in the lipid-based formulation was not able to induce any behavioral alterations, while already 5 mg/kg of the water-based Δ-9-THC preparation significantly reduced locomotor activity. This also induced a small but significant PPI reduction, which was prepulse intensity dependent. Interestingly, the reflexive motor response to the startle stimulus was not affected by the water-based Δ-9-THC solution. Analysis of serum and brain Δ-9-THC levels by high-performance liquid chromatography/mass spectrometry revealed that although the final concentration reached in the brain was comparable for both pharmaceutical preparations, the water-based formulation achieved a faster kinetic. We, therefore, conclude that the slope of the Δ-9-THC concentration-time curve and the resulting cannabinoid receptor type 1 activation per time unit are responsible for the induction of behavioral alterations., (© 2019 Society for the Study of Addiction.)