Karem Shanab

Green Solvents in Organic Synthesis: An Overview

Research concerning green solvents is focused on reducing environmental damages due to the use of toxic solvents in organic chemistry. Hence, there have been developed a lot of solvent-free processes as well as more efficient recycling protocols in the last dec- ades. Unfortunately, these approaches have their limitations. Therefore, the authors review different environmentally benign solvent al- ternatives. This report highlights reactions using water, fluorous solvents, ionic liquids, organic carbonates, supercritical carbon dioxide, as well as biosolvents instead of conventional organic solvents.

Microfluidic preparation of [18F]FE@SUPPY and [18F]FE@SUPPY:2 — comparison with conventional radiosyntheses

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.

[18F]FE@SNAP—A new PET tracer for the melanin concentrating hormone receptor 1 (MCHR1): Microfluidic and vessel-based approaches

Graphical abstract SNAP-7941 derivatives 1–4 (1: SNAP-7941; 2: [18F]FE@SNAP; 3: SNAP-acid; 4: Tos@SNAP).

Preclinical in vitro & in vivo evaluation of [11C]SNAP-7941 – the first PET tracer for the melanin concentrating hormone receptor 1

INTRODUCTION Due to its involvement in a variety of pathologies (obesity, diabetes, gut inflammation and depression), the melanin concentrating hormone receptor 1 (MCHR1) is a new target for the treatment of these lifestyle diseases. We previously presented the radiosynthesis of [(11)C]SNAP-7941, the first potential PET tracer for the MCHR1. METHODS We herein present its in vitro and in vivo evaluation, including binding affinity, plasma stability, stability against liver mircrosomes and carboxylesterase, lipohilicity, biodistribution, in vivo metabolism and small-animal PET. RESULTS [(11)C]SNAP-7941 evinced high stability against liver microsomes, carboxylesterase and in human plasma. The first small-animal PET experiments revealed a 5 fold increased brain uptake after Pgp/BCRP inhibition. Therefore, it can be assumed that [(11)C]SNAP-7941 is a Pgp/BCRP substrate. No metabolites were found in brain. CONCLUSION On the basis of these experiments with healthy rats, the suitability of [(11)C]SNAP-7941 for the visualisation of central and peripheral MCHR1 remains speculative.

[18F]FE@SUPPY and [18F]FE@SUPPY:2 — metabolic considerations

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.

Radiosynthesis of [11C]SNAP-7941--the first PET-tracer for the melanin concentrating hormone receptor 1 (MCHR1).

The melanin concentrating hormone (MCH) system is a new target to treat human disorders. Our aim was the preparation of the first PET-tracer for the MCHR1. [11C]SNAP-7941 is a carbon-11 labeled analog of the published MCHR1 antagonist SNAP-7941. The optimum reaction conditions were 2 min reaction time, ≤25 °C reaction temperature, and 2 mg/mL precursor (SNAP-acid) in acetonitrile, using [11C]CH3OTf as methylation agent. [11C]SNAP-7941 was prepared in a reliable and feasible manner with high radiochemical yields (2.9±1.6 GBq; 11.5±6.4% EOB, n=15).

Synthesis and biological evaluation of new cytotoxic azanaphthoquinone pyrrolo-annelated derivatives

A series of azanaphthoquinone pyrrolo-annelated derivatives attached to basic side chains have been synthesized. The antiproliferative activities of all compounds were evaluated on at least four different cell lines. The effects on cell cycle and intercalation were investigated.

Synthesis and antiproliferative activity of new cytotoxic azanaphthoquinone pyrrolo-annelated derivatives: Part II.

A series of 6-azanaphthoquinone pyrrolo-annelated derivatives carrying different basic side chains have been synthesized. The antiproliferative activities of all compounds were evaluated on at least four different cell lines with Mitoxantrone as reference compound. Cytotoxic effects and DNA intercalation behavior were investigated.

Radiosynthesis of the adenosine A3 receptor ligand 5-(2-[18F]fluoroethyl) 2,4-diethyl-3-(ethylsulfanylcarbonyl)- 6-phenylpyridine-5-carboxylate ([18F]FE@SUPPY)

Summary Since to date very limited information on the distribution and function of the adenosine A3 receptor is available, the development of a suitable radioligand is needed. Such a selective radioligand can then be used for quantitative autoradiography, preclinical studies in animals and subsequent human PET applications. Recently, a promising candidate compound, 5-(2-fluoroethyl) 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (FE@SUPPY), has been presented. The successful preparation of a suitable labelling precursor and the evaluation and optimization of the radiosynthesis of [18F] FE@SUPPY is presented herewith. For satisfactory yields, a reaction temperature of 75 °C has to be applied for at least 20 min using 8–10 mg of precursor. Until now, 15 complete high-scale radiosyntheses were performed. Starting from an average of 51±12 GBq (average ±SD; range: 30–67 GBq) [18F]fluoride, 9.4–3.6 GBq of formulated [18F]FE@SUPPY (32.3±12.4%, based on [18F]fluoride, corrected for decay) were prepared in <105 min.

Radiosynthesis of a novel potential adenosine A3 receptor ligand, 5-ethyl 2,4-diethyl-3-((2-[18F]fluoroethyl)sulfanylcarbonyl)-6-phenylpyridine-5-carboxylate ([18F]FE@SUPPY:2)

Abstract Since, to date very limited information on the distribution and function of the adenosine A3 receptor is available, the development of suitable radioligands is needed. Recently, we introduced [ 18F]FE@SUPPY (5-(2-[ 18F]fluoroethyl) 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate) as the first PET-ligand for the A3R. Regarding the metabolic profile – this class of dialkylpyridines comprises two ester functions within one molecule, one carboxylic and one thiocarboxylic – one could expect carboxylesterases significantly contributing to cleavage and degradation. Therefore, our aim was the development of [ 18F]FE@SUPPY:2 (5-ethyl 2,4-diethyl-3-((2-[ 18F]fluoroethyl)sulfanylcarbonyl)-6-phenylpyridine-5-carboxylate), the functional isomer containing the label at the thiocarboxylic moiety. For satisfactory yields in high scale radiosyntheses, a reaction temperature of 75 °C has to be applied for at least 20 min using 20 mg/mL of precursor. So far, 6 complete high-scale radiosyntheses were performed. Starting from an average of 51.2±21.8 GBq (mean±SD) [ 18F]fluoride, 5.8±4.1 GBq of formulated [ 18F]FE@SUPPY:2 (12.0±5.4%, based on [ 18F]fluoride, not corrected for decay) were prepared in 75±8 min.