A Wittig reaction employing Li(CD₃)₂CP(C₆H₅)₃ was used to prepare d₆-farnesol and d₆-geranylgeraniol. Reductive amination of aniline-2,3,4,5,6-d₅ was used to prepare the unnatural isoprenoid analogues d₅-anilinogeraniol and d₅-anilinofarnesol. All of these deuterated isoprenols were elaborated into their diphosphate and cysteine thioether derivatives suitable for use as stable-isotope labeled standards for quantitative mass spectrometric analysis.

[¹⁸F]2-Fluoroethyl-p-toluenesulfonate also called [¹⁸F]2-fluoroethyl tosylate has been widely used for labeling radioligands for positron emission tomography (PET). [¹⁸F]2-Fluoroethyl-4-bromobenzenesulfonate, also called [¹⁸F]2-fluoroethyl brosylate ([¹⁸F]F(CH₂)₂OBs), was used as an alternative radiolabeling agent to prepare [¹⁸F]FEOHOMADAM, a fluoroethoxy derivative of HOMADAM, by O-fluoroethylating the phenolic precursor. Purified by reverse-phase HPLC, the no-carrier-added [¹⁸F]F(CH₂)₂OBs was obtained in an average radiochemical yield (RCY) of 35%. The reaction of the purified and dried [¹⁸F]F(CH₂)₂OBs with the phenolic precursor was performed by heating in DMF and successfully produced [¹⁸F]FEOHOMADAM, after HPLC purification, in RCY of 21%.

Automated synthetic procedures of [¹⁸F]fluoro-[di-deutero]methyl tosylate on a GE TRACERlab FX F-N module and a non-commercial synthesis module have been developed. The syntheses included azeotropic drying of the [¹⁸F]fluoride, nucleophilic ¹⁸F-fluorination of bis(tosyloxy)-[di-deutero]methane, HPLC purification and subsequent formulation of the synthesized [¹⁸F]fluoro-[di-deutero]methyl tosylate (d₂-[¹⁸F]FMT) in organic solvents. Automation shortened the total synthesis time to 50 min, resulting in an average radiochemical yield of about 50% and high radiochemical purity (>98%). The possible application of this procedure to commercially available synthesis modules might be of significance for the production of deuterated ¹⁸F-fluoromethylated imaging probes in the future. Copyright © 2013 John Wiley & Sons, Ltd.

Methods for the preparation of deuterium-labeled analogs to six prominent biotransformation products of the explosive 2,4,6-trinitrotoluene were developed. These are useful as reference standards for stable isotope dilution techniques and for solid state ²H NMR spectroscopic studies. Although syntheses for most of the target compounds in protiated form had been reported in the past, most of those were found to be poorly suited for the preparation of the deuterated materials. Selective reduction of [²H₅]trinitrotoluene furnished [²H₅]-4,6-dinitro-2-hydroxylaminotoluene, [²H₅]-2,6-dinitro-4-hydroxylaminotoluene, [²H₅]-2-amino-4,6-dinitrotoluene, and [²H₅]-4-amino-2,6-dinitrotoluene. The syntheses of [²H₁₀]-2,2′-azo-4,4′,6,6′-tetranitrotoluene and [²H₁₀]-4,4′-azo-2,2′,6,6′-tetranitrotoluene were accomplished by selective oxidation of [²H₅]-2-amino-4,6-dinitrotoluene and [²H₅]-4-amino-2,6-dinitrotoluene, respectively.

The development of new efficient syntheses of labeled reagents is a great challenge. Avoidance of overcomplicated procedures, availability and cost of starting materials are important considerations in choosing the synthetic route. In this report, we describe a facile and rapid preparation of labeled cyanate by ozonation of cyanide, a basic precursor. The crude cyanate was used without purification for the synthesis of various [¹³C] or [¹⁴C]ureidocarboxylic acids (20-68% yield from potassium cyanide). According to these results, cyanide ozonation may prove to be a promising alternative to traditional preparations of labeled cyanate.

The cocaine-derived dopamine reuptake inhibitors FE-β-CIT (8-(2-fluoroethyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester) (1) and PR04.MZ(8-(4-fluorobut-2-ynyl)-3-p-tolyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester) (2) were labelled with ¹⁸F-fluorine using a two-step route. 2-[¹⁸F]Fluoroethyltosylate and 4-[¹⁸F]fluorobut-2-yne-1-yl tosylate were used as labelling reagents, respectively. Radiochemically pure (>98%) [¹⁸F]FE-β-CIT and [¹⁸F]PRD04.MZ (32–86 GBq/µmol) were obtained after a synthesis time of 100 min in about 25% non-decay-corrected overall yield.

Introduction

In support of a program to identify toxic metabolites of the antimalarial, primaquine, its [¹³C₆] analog was prepared from [¹³C₆] anisole in seven steps.

Deuterium labeled 2,2-dimethyl-[²H₆]-succinic anhydride by a sequence of reactions involving Knoevenagel condensation of [²H₆]-acetone with ethyl cyanoacetate in the presence of piperidine, Michael addition of cyanide, HCl hydrolysis, simultaneous decarboxylation, and subsequent dehydration using acetic anhydride in an overall yield of 34.23% based on [²H₆]-acetone utilized in the reaction is reported. The title compounds were characterized and confirmed spectroscopically by Fourier transform infrared, ¹H-NMR, and Mass. The chemical purity as determined by HPLC was 99%. To the best of our knowledge, the synthesis of these specifically deuterium labeled compounds has not been reported so far. Copyright © 2013 John Wiley & Sons, Ltd.

Cytochrome P450 (P450) enzymes account for ~75% of the metabolism of drugs. Most of the reactions catalyzed by P450s are mixed-function oxidations, and a C–H bond is (usually) broken. The rate-limiting nature of this step can be analyzed using the kinetic isotope effect (KIE) approach. The most relevant type of KIE is one termed intermolecular non-competitive, indicative of rate-limiting C–H bond breaking. A plot of KIE versus k_cat for several P450s showed a correlation coefficient (r²) of 0.62. Deuterium substitution has been considered as a potential means of slowing drug metabolism or redirecting sites of metabolism in some cases, and several general points can be made regarding the potential for application of deuterium in drug design/development based on what is known about P450 KIEs. Copyright © 2013 John Wiley & Sons, Ltd.

[¹⁸F]ML10 is a promising novel low molecular weight positron emission tomography probe for apoptosis. As part of the quality control to support clinical studies for cancer therapy monitoring in the GSK Clinical Imaging Centre, a simple and sensitive liquid chromatography mass spectrometry method has been developed and validated for the quantification of total ML10 and impurity content in the final product. Chromatographic separation of ML10 and its radiolabelling precursor and impurities was achieved. Mass curves were constructed from a concentration range of ML10 and known impurities and were linear. Quantification was achieved by comparison of the area under the curve for ML10 content (m/z = 205) and the mass curve. The method was validated over a concentration range of 0.1-1 µg/ml. Copyright © 2013 John Wiley & Sons, Ltd.

Isotopologues of l-histidine and its N-methylderivatives labeled with deuterium and tritium at the 5-position in the imidazole ring were obtained using the isotope exchange method. The deuterium-labeled isotopologues [5-²H]-l-histidine, [5-²H]-N^τ-methyl-l-histidine, [5-²H]-N^π-methyl-l-histidine, and [2,5-²H₂]-l-histidine were synthesized by isotope exchange method carried out in a fully deuterated medium with. The same reaction conditions were applied to synthesize [5-³H]-N^τ-methyl-l-histidine, [5-³H]-N^π-methyl-l-histidine, and [5-³H]-l-histidine with specific activity of 2.0, 5.0, and 2.6 MBq/mmol, respectively. The N^π-[methyl-¹⁴C]-histamine was obtained with specific activity of 0.23 MBq/mmol in a one-step reaction by the direct methylation of histamine by [¹⁴C]iodomethane.

A method for the preparation of [3′-³H]-4-(2′-chloro-6′-hydroxyphenyl)-2-thioxo-3,4-dihydro-1H-indeno[1,2-d]pyrimidin-5(2H)-one (1), a TRPA1 inhibitor, was developed for the evaluation of imaging properties of a class of TRPA1 inhibitors. 1 was prepared via tritiation of a protected benzaldehyde followed by a tetrachlorosilane catalyzed multicomponent one-step fusion and was obtained at a specific activity of 0.9 TBq/mmol. A ³H-NMR spectrum on 13.5 MBq at 75 μM was recorded. Copyright © 2013 John Wiley & Sons, Ltd.

In support of a metabolite study, the β-amyloid plaque neuroimaging positron-emission tomography radioligand AZD4694 was labeled with carbon-14 in 10 radiosynthetic steps starting from radiolabeled carbon dioxide. [¹⁴C]AZD4694 was labeled in the benzofuran heterocycle with a specific activity of 2.1 GBq/mmol and with a radiochemical purity of >99%. The described synthesis constitutes a general method to carbon-14-labeled substituted benzofurans. Copyright © 2013 John Wiley & Sons, Ltd.

A novel phosphonium salt bearing a fluorine-18 labelled triazole has been designed as a potential imaging agent for apoptosis. The radiosynthesis of [1-(2-[¹⁸F]fluoroethyl),1H[1,2,3]triazole 4-ethylene] triphenylphosphonium bromide ([¹⁸F]MitoPhos_01) has been carried out on a fully automated system in a two-step reaction. Radiolabelling an ethyl azide and then carrying out a copper-mediated 1,3-cycloaddition reaction has allowed for total synthesis time to be slightly more than 1 h from aqueous [¹⁸F]fluoride. After purification by HPLC, the average radiochemical yield was determined to be 9% (not decay corrected); the specific activity was on average 70 GBq/µmol at the end of synthesis, and the radiochemical purity was >99%. Copyright © 2013 John Wiley & Sons, Ltd.

[³H]Fluoroethyl tosylate, a novel alkylating tritium labelling agent, was synthesized from tritium gas with high specific activity and with 99% radiochemical purity. [³H]Fluoroethyl tosylate was applied in the tritium labelling of the dopamine transporter radioligand [³H]FE-PE2I. Copyright © 2013 John Wiley & Sons, Ltd.

Positron emission tomography (PET) imaging of receptor integrin α_vβ₃ expression may play a key role in the early detection of cancer and cardiovascular diseases, monitoring disease progression, evaluating therapeutic response, and aiding anti-angiogenic drugs discovery and development. The last decade has seen the development of new PET tracers for in vivo imaging of integrin α_vβ₃ expression along with advances in PET chemistry. In this review, we will focus on the radiochemistry development of PET tracers based on arginine–glycine–aspartic acid (RGD) peptide, present an overview of general strategies for preparing RGD-based PET tracers, and review the recent advances in preparations of ¹⁸F-labeled, ⁶⁴Cu-labeled, and ⁶⁸Ga-labeled RGD tracers, RGD-based PET multivalent probes, and RGD-based PET multimodality probes for imaging receptor integrin α_vβ₃ expression.

Microfluidics technology has emerged as a powerful tool for the radiosynthesis of positron emission tomography (PET) and single-photon emission computed tomography radiolabeled compounds. In this work, we have exploited a continuous flow microfluidic system (Advion, Inc., USA) for the [¹⁸F]-fluorine radiolabeling of the malonic acid derivative, [¹⁸F] 2-(5-fluoro-pentyl)-2-methyl malonic acid ([¹⁸F]-FPMA), also known as [¹⁸F]-ML-10, a radiotracer proposed as a potential apoptosis PET imaging agent. The radiosynthesis was developed using a new tosylated precursor. Radiofluorination was initially optimized by manual synthesis and served as a basis to optimize reaction parameters for the microfluidic radiosynthesis. Under optimized conditions, radio-thin-layer chromatography analysis showed 79% [¹⁸F]-fluorine incorporation prior to hydrolysis and purification. Following hydrolysis, the [¹⁸F]-FPMA was purified by C18 Sep-Pak, and the final product was analyzed by radio-HPLC (high-performance liquid chromatography). This resulted in a decay-corrected 60% radiochemical yield and ≥98% radiochemical purity. Biodistribution data demonstrated rapid blood clearance with less than 2% of intact [¹⁸F]-FPMA radioactivity remaining in the circulation 60 min post-injection. Most organs showed low accumulation of the radiotracer, and radioactivity was predominately cleared through kidneys (95% in 1 h). Radio-HPLC analysis of plasma and urine samples showed a stable radiotracer at least up to 60 min post-injection.

We have developed an ethanol-free formulation method of [¹⁸F]florbetapir ([¹⁸F]AV-45) using a commercially available automated JFE multi-purpose synthesizer. We have also evaluated the radiochemical stability in an ethanol-free solution of [¹⁸F]AV-45 under visible light irradiation and dark conditions by comparison with a conventional 10% ethanol solution of [¹⁸F]AV-45. [¹⁸F]AV-45 was obtained with a radiochemical yield of 55.1 ± 2.2% (decay-corrected to end of bombardment), specific activity of 591.6 ± 90.3 GBq/µmol and radiochemical purity of >99% within a total synthesis time of about 73 min. The radiochemical purity of [¹⁸F]AV-45 formulated by dissolving the ethanol-free solution was found to decrease as a function of the period of exposure to visible light. In contrast, the visible light photolysis could be suppressed by adding 10% ethanol to the formulation or by avoiding exposure to visible light. In the radiosynthesis of [¹⁸F]AV-45 formulated by dissolving the ethanol-free solution, [¹⁸F]AV-45 could be obtained with high radiochemical purity and high stability by avoiding exposure to visible light. Copyright © 2013 John Wiley & Sons, Ltd.

Background

Atrazine is a long-lasting herbicide that has been shown to affect hormone levels in amphibians. Using the C-13 labeled atrazine to detect its residue is effective and essential. This study presents three steps for the synthesis of [¹³C₃]atrazine, which starts from [¹³C]urea, and results in the incorporation of C-13 atoms at the 1, 3 and 5 positions of the S-triazine ring of atrazine. The method prepares the product in an overall yield of 57.6% and chemical purity of 98.6%, for use as an internal standard. Copyright © 2013 John Wiley & Sons, Ltd.

[¹¹C]MENET, a promising norepinephrine transporter imaging agent, was prepared by Suzuki cross coupling of 1 mg N-t-Boc pinacolborate precursor with [¹¹C]CH₃I in DMF using palladium complex generated in situ from Pd₂(dba)₃ and (o-CH₃C₆H₄)₃P together with K₂CO₃ as the co-catalyst, followed by deprotection with trifluoroacetic acid. This improved radiolabeling method provided [¹¹C]MENET in high radiochemical yield at end of synthesis (EOS, 51 ± 3%, decay-corrected from end of ¹¹CH₃I synthesis, n = 6), moderate specific activity (1.5–1.9 Ci/µmol at EOS), and high radiochemical (>98%) and chemical purity (>98%) in a synthesis time of 60 ± 5 min from the end of bombardment. Copyright © 2013 John Wiley & Sons, Ltd.

The two step synthesis of [15, 16-³H] beta-funaltrexamine is described.