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Introduction: Present data indicate that merging beneficial structural elements from previously published DAT-ligands highest DAT affinity, selectivity and a suitable metabolic profile should be achieved. This combination led to the development of IPCIT and FE@IPCIT., Methods: Precursor synthesis was done starting from cocaine in a six step reaction. O-[(11)C]-methylation was established using [(11)C]methyl iodide, optimized and subsequently automated. Small scale (18)F-fluroroethylation as well as optimization of reaction parameters and automation were performed. Affinity and selectivity of the candidate substances were tested in standard binding experiments on human membranes. Metabolic stability and blood-brain-barrier (BBB) penetration were determined., Results: Precursor compound, IPCITacid, and reference compounds, IPCIT and FE@IPCIT, were obtained in 4.9%, 12.7% and 4.1% yield, respectively. Automated radiosynthesis of [(11)C]IPCIT yielded 1.9 ± 0.7 GBq (12.5 ± 4%, corrected for decay). Optimum parameters for (18)F-fluoroethylation were 110 °C for 15 min under TBAH catalysis, yielding 67 ± 16 % radiochemical incorporation. Affinity was determined as 1.7 ± 0.6 nM for IPCIT, 1.3 ± 0.2 nM for FE@IPCIT and 37 ± 13 nM for the precursor molecule, IPCIT-acid. Results from in vitro and in silico evaluations revealed high stability but also high lipophilicity., Conclusion: Present data indicate high affinity and stability of both IPCIT and FE@IPCIT. Radiolabelling, optimization of reaction parameters and automation succeeded. On the other hand, data concerning BBB-penetration are not promising., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Aim of this work was the implementation of a generalized in-loop synthesis for (11)C-carboxylations and subsequent (11)C-acylations on the TRACERlab FxC Pro platform. The set-up was tested using [carbonyl-(11)C]WAY-100635 and, for the first time, [(11)C]-(+)-PHNO. Its general applicability could be demonstrated and both [carbonyl-(11)C]WAY-100635 and [(11)C]-(+)-PHNO were prepared with high reliability and satisfying outcome., (© 2013 The Authors. Published by Elsevier Ltd. All rights reserved.)

Introduction: Image-derived input functions (IDIFs) represent a promising non-invasive alternative to arterial blood sampling for quantification in positron emission tomography (PET) studies. However, routine applications in patients and longitudinal designs are largely missing despite widespread attempts in healthy subjects. The aim of this study was to apply a previously validated approach to a clinical sample of patients with major depressive disorder (MDD) before and after electroconvulsive therapy (ECT)., Methods: Eleven scans from 5 patients with venous blood sampling were obtained with the radioligand [carbonyl-(11)C]WAY-100635 at baseline, before and after 11.0±1.2 ECT sessions. IDIFs were defined by two different image reconstruction algorithms 1) OSEM with subsequent partial volume correction (OSEM+PVC) and 2) reconstruction based modelling of the point spread function (TrueX). Serotonin-1A receptor (5-HT1A) binding potentials (BPP, BPND) were quantified with a two-tissue compartment (2TCM) and reference region model (MRTM2)., Results: Compared to MRTM2, good agreement in 5-HT1A BPND was found when using input functions from OSEM+PVC (R(2)=0.82) but not TrueX (R(2)=0.57, p<0.001), which is further reflected by lower IDIF peaks for TrueX (p<0.001). Following ECT, decreased 5-HT1A BPND and BPP were found with the 2TCM using OSEM+PVC (23%-35%), except for one patient showing only subtle changes. In contrast, MRTM2 and IDIFs from TrueX gave unstable results for this patient, most probably due to a 2.4-fold underestimation of non-specific binding., Conclusions: Using image-derived and venous input functions defined by OSEM with subsequent PVC we confirm previously reported decreases in 5-HT1A binding in MDD patients after ECT. In contrast to reference region modeling, quantification with image-derived input functions showed consistent results in a clinical setting due to accurate modeling of non-specific binding with OSEM+PVC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Electroconvulsive therapy (ECT) is a potent therapy in severe treatment-refractory depression. Although commonly applied in psychiatric clinical routine since decades, the exact neurobiological mechanism regarding its efficacy remains unclear. Results from preclinical and clinical studies emphasize a crucial involvement of the serotonin-1A receptor (5-HT(1A)) in the mode of action of antidepressant treatment. This includes associations between treatment response and changes in 5-HT(1A) function and density by antidepressants. Further, alterations of the 5-HT(1A) receptor are consistently reported in depression. To elucidate the effect of ECT on 5-HT(1A) receptor binding, 12 subjects with severe treatment-resistant major depression underwent three positron emission tomography (PET) measurements using the highly selective radioligand [carbonyl-(11)C]WAY100635, twice before (test-retest variability) and once after 10.08±2.35 ECT sessions. Ten patients (~83%) were responders to ECT. The voxel-wise comparison of the 5-HT(1A) receptor binding (BP(ND)) before and after ECT revealed a widespread reduction in cortical and subcortical regions (P<0.05 corrected), except for the occipital cortex and the cerebellum. Strongest reductions were found in regions consistently reported to be altered in major depression and involved in emotion regulation, such as the subgenual part of the anterior cingulate cortex (-27.5%), the orbitofrontal cortex (-30.1%), the amygdala (-31.8%), the hippocampus (-30.6%) and the insula (-28.9%). No significant change was found in the raphe nuclei. There was no significant difference in receptor binding in any region comparing the first two PET scans conducted before ECT. This PET study proposes a global involvement of the postsynaptic 5-HT(1A) receptor binding in the effect of ECT.

[Carbonyl-(11)C]WAY-100635 is a potent and effective antagonist for the 5-HT(1A) receptor subtype. We aimed to assess the status of [carbonyl-(11)C]WAY-100635 and its main radio-metabolites, [carbonyl-(11)C]desmethyl-WAY-100635 and [carbonyl-(11)C]cyclohexanecarboxylic acid, on the basis of an improved radio-HPLC method. Common methods were characterized by preparative HPLC columns with long runtimes and/or high flow rates. Considering the short half-life of C-11, we developed a more rapid and solvent saving HPLC assay, allowing a fast, efficient and reliable quantification of these major metabolites., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Animal models revealed that the serotonin-1A (5-HT(1A)) receptor modulates gray matter structure. However, there is a lack of evidence showing the relationship between 5-HT(1A) receptor concentration and gray matter in the human brain in vivo. Here, to demonstrate an association between the 5-HT(1A) receptor binding potential, an index for receptor concentration, and the local gray matter volume (GMV), an index for gray matter structure, we measured 35 healthy subjects with both positron emission tomography (PET) and structural magnetic resonance imaging (MRI). We found that regional heteroreceptor binding was positively associated with GMV in distinctive brain regions such as the hippocampi and the temporal cortices in both hemispheres (R(2) values ranged from 0.308 to 0.503, p<0.05 cluster-level FDR-corrected). Furthermore, autoreceptor binding in the midbrain raphe region was positively associated with GMV in forebrain projection sites (R(2)=0.656, p=0.001). We also observed a broad range between 5-HT(1A) receptor binding and GMV. Given the congruence of altered 5-HT(1A) receptor concentrations and GMV reduction in depression or Alzheimer's disease as reported by numerous studies, these results might provide new insights towards understanding the mechanisms behind GMV alterations observed in these brain disorders., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The intention for the present study was to implement a microfluidic set-up for N-(11)C-methylations in a flow-through microreactor device with [(11)C]DASB as model-compound and [(11)C]CH(3)I and [(11)C]CH(3)OTf, respectively, as (11)C-methylation agents. Due to an observed "aging" effect of the (11)C-methylation agents' solution, this goal was not achieved. Nevertheless, based on these observations, the time consumption for the vessel-based routine production of [(11)C]DASB was reduced (34±1 min) and RCY was increased to 45.1±4.6% (EOB; 5.2±0.95 GBq EOS)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The highly diverse serotonergic system with at least 16 different receptor subtypes is implicated in the pathophysiology of most neuropsychiatric disorders including affective and anxiety disorders, obsessive compulsive disorder, post-traumatic stress disorder, eating disorders, sleep disturbance, attention deficit/hyperactivity disorder, drug addiction, suicidal behavior, schizophrenia, Alzheimer, etc. Alterations of the interplay between various pre- and postsynaptic receptor subtypes might be involved in the pathogenesis of these disorders. However, there is a lack of comprehensive in vivo values using standardized procedures. In the current PET study we quantified 3 receptor subtypes, including the major inhibitory (5-HT(1A) and 5-HT(1B)) and excitatory (5-HT(2A)) receptors, and the transporter (5-HTT) in the brain of healthy human subjects to provide a database of standard values. PET scans were performed on 95 healthy subjects (age=28.0 ± 6.9 years; 59% males) using the selective radioligands [carbonyl-(11)C]WAY-100635, [(11)C]P943, [(18)F]altanserin and [(11)C]DASB, respectively. A standard template in MNI stereotactic space served for region of interest delineation. This template follows two anatomical parcellation schemes: 1) Brodmann areas including 41 regions and 2) AAL (automated anatomical labeling) including 52 regions. Standard values (mean, SD, and range) for each receptor and region are presented. Mean cortical and subcortical binding potential (BP) values were in good agreement with previously published human in vivo and post-mortem data. By means of linear equations, PET binding potentials were translated to post-mortem binding (provided in pmol/g), yielding 5.89 pmol/g (5-HT(1A)), 23.5 pmol/g (5-HT(1B)), 31.44 pmol/g (5-HT(2A)), and 11.33 pmol/g (5-HTT) being equivalent to the BP of 1, respectively. Furthermore, we computed individual voxel-wise maps with BP values and generated average tracer-specific whole-brain binding maps. This knowledge might improve our interpretation of the alterations taking place in the serotonergic system during neuropsychiatric disorders., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Changes in the expression of the melanin concentrating hormone receptor 1 (MCHR1) are involved in a variety of pathologies, especially obesity and anxiety disorders. To monitor these pathologies in-vivo positron emission tomography (PET) is a suitable method. After the successful radiosynthesis of [(11)C]SNAP-7941-the first PET-Tracer for the MCHR1, we aimed to synthesize its [(18)F]fluoroethylated analogue: [(18)F]FE@SNAP. Therefore, microfluidic and vessel-based approaches were tested. [(18)F]fluoroethylation was conducted via various [(18)F]fluoroalkylated synthons and direct [(18)F]fluorination. Only the direct [(18)F]fluorination of a tosylated precursor using a flow-through microreactor was successful, affording [(18)F]FE@SNAP in 44.3 ± 2.6%., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: Our aim was the optimization of radiochemical parameters for the microfluidic preparation of [(18)F]altanserin. The four main parameters evaluated were (1) precursor concentration, (2) reaction temperature, (3) bolus flow rate through the microreactor and (4) bolus volume., Methods: For the determination of optimal reaction conditions within a flow-through microreactor synthesizer, 5-400 μL of precursor and dried [(18)F]fluoride solution were simultaneously pushed through the temperature-controlled reactor (180-220°C) with defined bolus flow rates of 10-60 μL/min. Radiochemical incorporation yields (RCIYs) were examined using a thin layer chromatography (TLC) set-up and radio- high-performance liquid chromatography (HPLC)., Results: Optimum reaction parameters for the microfluidic set-up were determined as following: 220°C, 5-10 μL/min pump rate per reactant (10-20 μL/min reaction overall flow rate) and 2mg/mL precursor concentration in the reaction mixture. Applying these optimized conditions, RCIYs of 53.7 ± 7.9 were observed for scaled-up preparations. A positive "bolus effect" was observed: applying higher reaction volume resulted in increased RCIYs., Conclusion: This study proved that the reaction bolus volume is an essential parameter influencing the RCIY of [(18)F]altanserin. A possible explanation is the inhomogeneous distribution within the reaction volume probably caused by diffusion at the bolus interface. This important finding should be considered an important variable for the evaluation of all novel radiotracers labeled using a flow-through reactor device., (Copyright © 2012 Elsevier Inc. All rights reserved.)

18F radiolabelling of peptides bearing two different prosthetic groups was successfully conducted in a continuous flow microfluidic device for the first time. Radiochemical yields were dependent on precursor concentration, reaction temperature and flow rate. The choice of leaving group had a dramatic influence on the reaction outcome. Rapid reaction optimization was possible.

[(11)C]PIB is still the standard PET compound for Alzheimer imaging targeting beta-amyloid plaques. We aimed to establish a fully-automated procedure for the synthesis and purification of [(11)C]PIB with a high degree of reliability and improved specific activity as well as a suitable and fast quality control assay. The optimum reaction conditions were 75°C, 4 mg/mL precursor yielding at 48.0±2.7% (EOS, based on [(11)C]CH(3)OTf, corrected for decay), 183±14 GBq/μmol specific activity and >99% radiochemical purity. Time consumption was kept to a minimum (40 min from EOB) and overall yields were enough to serve 2 consecutive patients with a single preparation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Introduction: Recently, first applications of microfluidic principles for radiosyntheses of positron emission tomography compounds were presented, but direct comparisons with conventional methods were still missing. Therefore, our aims were (1) the set-up of a microfluidic procedure for the preparation of the recently developed adenosine A(3)-receptor tracers [(18)F]FE@SUPPY [5-(2-[(18)F]fluoroethyl)2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] and [(18)F]FE@SUPPY:2 [5-ethyl-2,4-diethyl-3-((2-[(18)F]fluoroethyl)sulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] and (2) the direct comparison of reaction conditions and radiochemical yields of the no-carrier-added nucleophilic substitution with [(18)F]fluoride between microfluidic and conventional methods., Methods: For the determination of optimal reaction conditions within an Advion NanoTek synthesizer, 5-50 μl of precursor and dried [(18)F]fluoride solution were simultaneously pushed through the temperature-controlled reactor (26 °C-180 °C) with defined reactant bolus flow rates (10-50 μl/min). Radiochemical incorporation yields (RCIYs) and overall radiochemical yields for large-scale preparations were compared with data from conventional batch-mode syntheses., Results: Optimal reaction parameters for the microfluidic set-up were determined as follows: 170 °C, 30-μl/min pump rate per reactant (reaction overall flow rate of 60 μl/min) and 5-mg/ml precursor concentration in the reaction mixture. Applying these optimized conditions, we observed a significant increase in RCIY from 88.2% to 94.1% (P < .0001, n ≥ 11) for [(18)F]FE@SUPPY and that from 42.5% to 95.5% (P<.0001, n ≥ 5) for [(18)F]FE@SUPPY:2 using microfluidic instead of conventional heating. Precursor consumption was decreased from 7.5 and 10 mg to 1 mg per large-scale synthesis for both title compounds, respectively., Conclusion: The direct comparison of radiosyntheses data applying a conventional method and a microfluidic approach revealed a significant increase of RCIY using the microfluidic approach., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: Recently, [(18)F]FE@SUPPY and [(18)F]FE@SUPPY:2 were introduced as the first positron emission tomography (PET) tracers for the adenosine A(3) receptor. Thus, aim of the present study was the metabolic characterization of the two adenosine A(3) receptor PET tracers., Methods: In vitro carboxylesterase (CES) experiments were conducted using incubation mixtures containing different concentrations of the two substrates, porcine CES and phosphate-buffered saline. Enzymatic reactions were stopped by adding acetonitrile/methanol (10:1) after various time points and analyzed by a high-performance liquid chromatography (HPLC) standard protocol. In vivo experiments were conducted in male wild-type rats; tracers were injected through a tail vein. Rats were sacrificed after various time points (n=3), and blood and brain samples were collected. Sample cleanup was performed by an HPLC standard protocol., Results: The rate of enzymatic hydrolysis by CES demonstrated Michaelis-Menten constants in a micromolar range (FE@SUPPY, 20.15 microM, and FE@SUPPY:2, 13.11 microM) and limiting velocities of 0.035 and 0.015 microM/min for FE@SUPPY and FE@SUPPY:2, respectively. Degree of metabolism in blood showed the following: 15 min pi 47.7% of [(18)F]FE@SUPPY was intact compared to 33.1% of [(18)F]FE@SUPPY:2; 30 min pi 30.3% intact [(18)F]FE@SUPPY was found compared to 15.6% [(18)F]FE@SUPPY:2. In brain, [(18)F]FE@SUPPY:2 formed an early hydrophilic metabolite, whereas metabolism of [(18)F]FE@SUPPY was not observed before 30 min pi, Conclusion: Knowing that metabolism in rats is several times faster than in human, we conclude that [(18)F]FE@SUPPY should be stable for the typical time span of a clinical investigation. As a consequence, from a metabolic point of view, one would tend to decide in favor of [(18)F]FE@SUPPY., ((c) 2010 Elsevier Inc. All rights reserved.)

[(11)C]DASB combines all major prerequisites for a successful SERT-ligand, providing excellent biological properties and in-vivo behaviour. Thus, we aimed to establish a fully automated procedure for the synthesis and purification of [(11)C]DASB with a high degree of reliability reducing the overall synthesis time while conserving high yields and purity. The optimized [(11)C]DASB synthesis was applied in more than 60 applications with a very low failure rate (3.2%). We obtained yields up to 8.9 GBq (average 5.3+/-1.6 GBq). Radiochemical yields based on [(11)C]CH(3)I, (corrected for decay) were 66.3+/-6.9% with a specific radioactivity (A(s)) of 86.8+/-24.3 GBq/micromol (both at the end of synthesis, EOS). Time consumption was kept to a minimum, resulting in 43 min from end of bombardment to release of the product after quality control. From our data, it is evident that the presented method can be implemented for routine preparations of [(11)C]DASB with high reliability.