Stability of L-[S-methyl-11C]methionine solutions

For clinical PET studies L-[S-methyl-¹¹C]methionine ([¹¹C]MET) solutions have been prepared in both high doses and specific activities (up to 48.1 GBq and 370 GBq/mmol, respectively) with high radiochemical purity (>99%). The stability of these preparations was investigated by HPLC to ensure the radiopharmaceutical efficacy during the usable shelf life. Under our routine conditions the observed radiochemical purity loss never exceeded 3.5% one hour after EOS. The decomposition rate was affected by total activity and chemical composition of the solutions.     

Synthesis of 15-(4-[11C]methylphenyl)pentadecanoic acid (MePPA) via Stille cross-coupling reaction

For experimental studies by animal PET [¹¹C]-labeled 15-(4-methylphenyl)pentadecanoic acid (MePPA) is an attractive alternative to the radioiodinated 15-(4-iodophenyl)pentadecanoic acid (IPPA) which has widely been used for imaging of fatty acid metabolism. The important physiological aspect is that the iodine atom and the methyl substituent have similar steric and lipophilic properties. For preparation of [¹¹C]MePPA, Stille cross-coupling reaction was applied since the same tin precursor as for the radiosynthesis of IPPA and readily available [¹¹C]CH₃I can be used. Unsaturated tris(dibenzylideneacetone)dipalladium(0)/tri(o-tolyl)phosphine [Pd₂(dba)₃/P(o-tolyl)₃] was taken as the catalytic system. The reaction conditions were optimized with respect to temperature, time, solvent and amount of precursor. The best radiochemical yields of 73 ± 2.8% (decay corr.) were obtained using 0.525 mg tin precursor in DMF at 80 °C already after a reaction time of 10 min. The labeled methyl ester was hydrolyzed by 1 M NaOH/EtOH at 80 °C within 3 min to give [¹¹C]IPPA in a RCY of 62 ± 3.0%. The radiochemical purity of the product assured by HPLC was >99% and the overall preparation time including HPLC purification and formulation was 40 min.     

N-[11C]methyl-3,4-methylenedioxyamphetamine (Ecstasy) and 2-methyl-N-[11C]methyl-4,5-methylenedioxyamphetamine: Synthesis and biodistribution studies

In order to evaluate the neurobiological mechanism causing the psychogenic effects of methylenedioxy-derivatives of amphetamine, the carbon-11 labeled analogues of 3,4-methylenedioxymethamphetamine (MDMA),2 and 2,N-dimethyl-4,5-methylenedioxyamphetamine (MADAM-6)4 were prepared for application in in-vivo PET studies by methylation of 3,4-methylenedioxyamphetamine (MDA)1 and 2-methyl-4,5-methylenedioxyamphetamine3 with [¹¹C]CH₃I. The radiochemical yield was determined in dependence on time, temperature and amount of precursor. The best conditions for a fast labeling reaction with carbon-11 on a preparative scale were found to be a reaction time of 10 min using 1 mg of the corresponding dimethyl-precursors1 or3, thus obtaining radiochemical yields of 60% (based on produced [¹¹C]CH₃I). Biodistribution studies were performed in rats, a high brain to blood ratio of 7.5 was observed for [¹¹C]MDMA in contrast to a ratio of 3.7 for [¹¹C]MADAM-6.     

The synthesis of a new cardiac sympathetic nerve imaging agent N-[11C]CH3-dopamine and biodistribution study

In this study, we synthesized and characterized N-[¹¹C]methyl-dopamine ([¹¹C]MDA) for cardiac sympathetic nerve imaging. [¹¹C]MDA was synthesized by direct N-methylation of dopamine with [¹¹C]methyl iodide and purified by semi-preparation reverse high pressure liquid chromatography (HPLC). The total synthesis time was 45 min including HPLC purification. The radiochemical yields of [¹¹C]MDA was 20 ± 3 %, without decay correction. The radiochemical purity was >98 % and the specific activity was about 50 GBq/mmol. The biological properties of [¹¹C]MDA were evaluated by biodistribution study in normal mice. PET imaging was performed in healthy Chinese mini-swines. Biodistribution study showed that [¹¹C]MDA had high myocardium uptake. PET/CT imaging showed [¹¹C]MDA had clear and symmetrical myocardium uptake, which was blocked obviously by injecting imipramine hydrochloride. [¹¹C]MDA would be a promising candidate of radiotracer for cardiac sympathetic nervous system imaging.     

Preparation of N-[11C]methyl-2,5-dimethoxy-4-methylamphetamine

In order to evaluate the neurobiological mechanism causing the psychogenic effects of N-methyl-2,5-dimethoxy-4-methylamphetamine (MDOM), the¹¹C labelled analogue was prepared for application in in vivo PET studies by the reaction of 2,5-dimethoxy-4-methylamphetamine (DOM) with [¹¹C]CH₃I. The radiochemical yield was determined in dependence on time, temperature, solvent and amount of substrate. The best conditions for fast labelling reactions with¹¹C on a preparative scale were found to be a reaction time of 10 miutes at 110°C using 1 mg DOM in acetonitrile thus obtaining radiochemical yields of 80% (based on produced [¹¹C]CH₃I).     

A simplified [11C]phosgene synthesis

A new flow-through system for the production of [¹¹C]phosgene, a versatile labelling agent in radiochemistry for PET, is described. Cyclotron-produced [¹¹C]CH₄ is mixed with Cl₂ and converted into [¹¹C]CCl₄ by passing the mixture through an empty quartz tube at 510 °C. The outflow is directed through a Sb-filled guard that takes out Cl₂ and then, without intentional O₂ addition, through a second empty quartz tube at 750 °C, giving rise to [¹¹C]phosgene in 30–35% radiochemical yield.     

N-[11C]methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB): synthesis, quality control and biodistribution

N-[¹¹C]methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine ([¹¹C]MBDB) 3 was prepared by methylation of the demethyl precursor BDB with [¹¹C]CHI. The radiosynthesis was optimized with regard to temperature, reaction time and amount of precursor, best results (i.e., 84% radiochemical yield, based on [¹¹C]CH₃I activity) were obtained using 3 mg BDB at a reaction temperature of 130 °C in 8 minutes. With respect to a facilitated workup routine, productions were performed with 0.6 mg BDB at 110 °C for 10 minutes, yielding more than 50% of 3. The radiochemical purity of the final tracer solution was >98%, the specific activity was determined to be 300 GBq/mol (8000 Ci/mmol). Biodistribution, studies in rats showed two major metabolic pathways as indicated by an increasing liver uptake (9.1% ID/organ at 5 minutes to 21% ID/organ at 30 minutes) and a high urine activity (up to 16% ID/g). In brain tracer uptake was more than 1%, with a brain to blood ratio of almost 12 resulting from a very rapid blood clearance of 3.     

One-Pot Synthesis of 11C-Labelled Primary Benzamides via Intermediate [11C]Aroyl Dimethylaminopyridinium Salts

Electrophilic ¹¹C-labelled aroyl dimethylaminopyridinium salts, obtained by carbonylative cross-coupling of aryl halides with [¹¹C]carbon monoxide, were prepared for the first time and shown to be valuable intermediates in the synthesis of primary [¹¹C]benzamides. The methodology furnished a set of benzamide model compounds, including the two poly (ADP-ribose) polymerase (PARP) inhibitors niraparib and veliparib, in moderate to excellent radiochemical yields. In addition to providing a convenient and practical route to primary [¹¹C]benzamides, the current method paves the way for future application of [¹¹C]aroyl dimethylaminopyridinium halide salts in positron emission tomography (PET) tracer synthesis.     

Enantioselective syntheses of no-carrier-added (n.c.a.) (s)-4-chloro-2-[f] fluorophenylalanine and (s)-(α-methyl) -4-chloro-2-[f]fluorophenylalanine

(S)-4-Chloro-2-fluorophenylalanine and (S)-(α-methy)-4-chloro-2-fluorophenylalanine were synthesized and labeled with no carrier added (n.c.a.) fluorine-18 through a radiochemical synthesis relying on the highly enantioselective reaction between 4-chloro-2-[¹⁸F]fluorobenzyl iodide and the lithium enolate of (2S)-1-(tert-butyloxycarbonyl)-2-(tert-butyl)-3-methyl-1,3-imidazolidine-4-one for (S)-4-chloro-2-[¹⁸F]fluorophenylalanine and (2S,5S)-1-(tert-butyloxycarbonyl)-2-(tert-butyl)-3,5-dimethyl-1,3-imidazolidine-4-one for (S)-(α-methyl) -4-chloro-2-[¹⁸F] fluorophenylalanine. Quantities of about 20–25 mCi were obtained at the end of sy nthesi s, ready for injection after hydrolysis and high performance liquid chromatography (HPLC) purification, with a radiochemical yield of 17%–20% corrected to the end of bombardment after a total synthesis time of 90–105 min from [¹⁸F] fluoride. The enantiomeric excesses were shown to be 97% or more for both molecules without chiral separation and the radiochemical and chemical purities were 98% or better.     

Broad Scope and High-Yield Access to Unsymmetrical Acyclic [11C]Ureas for Biomedical Imaging from [11C]Carbonyl Difluoride

Effective methods are needed for labelling acyclic ureas with carbon-11 (t_1/2=20.4 min) as potential radiotracers for biomedical imaging with positron emission tomography (PET). Herein, we describe the rapid and high-yield syntheses of unsymmetrical acyclic [¹¹C]ureas under mild conditions (room temperature and within 7 min) using no-carrier-added [¹¹C]carbonyl difluoride with aliphatic and aryl amines. This methodology is compatible with diverse functionality (e. g., hydroxy, carboxyl, amino, amido, or pyridyl) in the substrate amines. The labelling process proceeds through putative [¹¹C]carbamoyl fluorides and for primary amines through isolable [¹¹C]isocyanate intermediates. Unsymmetrical [¹¹C]ureas are produced with negligible amounts of unwanted symmetrical [¹¹C]urea byproducts. Moreover, the overall labelling method tolerates trace water and the generally moderate to excellent yields show good reproducibility. [¹¹C]Carbonyl difluoride shows exceptional promise for application to the synthesis of acyclic [¹¹C]ureas as new radiotracers for biomedical imaging with PET.     

Asymmetric synthesis of L-2-amino[3-11C]butyric acid, L-[3-11C]norvaline and L-[3-11C]valine

The short-lived radionuclide 11C (t1/2 = 20.4 min) has been used in the asymmetric synthesis of L-2-amino[3-11C]butyric acid, L-[3-11C]-norvaline and L-[3-11C]valine. The syntheses were performed by alkylation of [(+)-2-hydroxypinanyl-3-idene]-glycine tert-butyl ester under anhydrous conditions in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone with lithiated 2,2,6,6-tetramethylpiperidine as base, using the appropriate 11C-alkyl iodides prepared in a one-pot reactor from [11C]carbon dioxide. Following removal of the protecting groups, the -[3-11C]amino acids were obtained in 80-82% enantiomeric excess and in 9-25% radiochemical yields, decay corrected and calculated on the basis of the amount of [11C]carbon dioxide at the start of the syntheses within 50-55 min.     

Enantioselective synthesis of no-carrier added (NCA) 6-[18F]Fluoro-L-Dopa

6-[¹⁸F]Fluoro-L-Dopa (6-FDOPA) is the analogue of L-Dopa, the biosynthesis precursor for dopamine. As a PET tracer, it was widely applied for the presynaptic dopamine function studies in human brain. The application of a chiral phase-transfer-catalyst (PTC) in enantioselective synthesis of N.C.A. 6-[¹⁸F]Fluoro-L-Dopa has been developed recently. An improved procedure was described in this study. The labeling precursor (6-Trimethylammoniumveratraldehyde Triflate) and PTC (O-Allyl-N-(9)-anthracenylcinchonidinium Bromide) were synthesized. A successful synthesis route was developed for the preparation of 6-[¹⁸F]Fluoro-L-Dopa with high radiochemical yields (4-9%, decay uncorrected) and short synthesis time(80min). The radiochemical purity was over 99% and no D-isomer was detected by HPLC analysis using a chiral mobile phase.     

[11C]-labeling of some caffeine derivatives for mapping adenosine A2a receptors by PET technique

[¹¹C]-labeled form of ten A_2a adenosine receptor specific 8-styryl-7-methyl-xanthine derivatives ([¹¹C]-caffeines) were synthesised by N-methylation of the corresponding 8-styryl-xanthine derivatives using [¹¹C]-methyl iodide in optimized reaction conditions. The results show that the [¹¹C]-methylations take place with excellent radiochemical yields (35–93%), and can be utilised easily in online preparations. These labeled ligands may facilitate the positron emission tomographic (PET) investigation of adenosine A_2a receptors.     

[11C]Carbonyl Difluoride—a New and Highly Efficient [11C]Carbonyl Group Transfer Agent

Herein, the synthesis and use of [¹¹C]carbonyl difluoride for labeling heterocycles with [¹¹C]carbonyl groups in high molar activity is described. A very mild single-pass gas-phase conversion of [¹¹C]carbon monoxide into [¹¹C]carbonyl difluoride over silver(II) fluoride provides easy access to this new synthon in robust quantitative yield for labeling a broad range of cyclic substrates, for example, imidazolidin-2-ones, thiazolidin-2-ones, and oxazolidin-2-ones. Labeling reactions may utilize close-to-stoichiometric precursor quantities and short reaction times at room temperature in a wide range of solvents while also showing high water tolerability. The overall radiosynthesis protocol is both simple and reproducible. The required apparatus can be constructed from widely available parts and is therefore well suited to be automated for PET radiotracer production. We foresee that this straightforward method will gain wide acceptance for PET radiotracer syntheses across the radiochemistry community.     

[11C]Carbonyl Difluoride—a New and Highly Efficient [11C]Carbonyl Group Transfer Agent

Herein, the synthesis and use of [¹¹C]carbonyl difluoride for labeling heterocycles with [¹¹C]carbonyl groups in high molar activity is described. A very mild single‐pass gas‐phase conversion of [¹¹C]carbon monoxide into [¹¹C]carbonyl difluoride over silver(II) fluoride provides easy access to this new synthon in robust quantitative yield for labeling a broad range of cyclic substrates, for example, imidazolidin‐2‐ones, thiazolidin‐2‐ones, and oxazolidin‐2‐ones. Labeling reactions may utilize close‐to‐stoichiometric precursor quantities and short reaction times at room temperature in a wide range of solvents while also showing high water tolerability. The overall radiosynthesis protocol is both simple and reproducible. The required apparatus can be constructed from widely available parts and is therefore well suited to be automated for PET radiotracer production. We foresee that this straightforward method will gain wide acceptance for PET radiotracer syntheses across the radiochemistry community.     

Rapid ‘on-column’ preparation of hydrogen [11C]cyanide from [11C]methyl iodide via [11C]formaldehyde

Hydrogen [¹¹C]cyanide ([¹¹C]HCN) is a versatile ¹¹C-labelling agent for the production of ¹¹C-labelled compounds used for positron emission tomography (PET). However, the traditional method for [¹¹C]HCN production requires a dedicated infrastructure, limiting accessibility to [¹¹C]HCN. Herein, we report a simple and efficient [¹¹C]HCN production method that can be easily implemented in ¹¹C production facilities. The immediate production of [¹¹C]HCN was achieved by passing gaseous [¹¹C]methyl iodide ([¹¹C]CH₃I) through a small two-layered reaction column. The first layer contained an N-oxide and a sulfoxide for conversion of [¹¹C]CH₃I to [¹¹C]formaldehyde ([¹¹C]CH₂O). The [¹¹C]CH₂O produced was subsequently converted to [¹¹C]HCN in a second layer containing hydroxylamine-O-sulfonic acid. The yield of [¹¹C]HCN produced by the current method was comparable to that of [¹¹C]HCN produced by the traditional method. The use of oxymatrine and diphenyl sulfoxide for [¹¹C]CH₂O production prevented deterioration of the molar activity of [¹¹C]HCN. Using this method, compounds labelled with [¹¹C]HCN are now made easily accessible for PET synthesis applications using readily available labware, without the need for the ‘traditional’ dedicated cyanide synthesis infrastructure.

In a reaction column, gaseous [¹¹C]methyl iodide was converted to [¹¹C]formaldehyde in a first layer containing N-oxide and then transformed into hydrogen [¹¹C]cyanide in a second layer containing hydroxylamine-O-sulfonic acid within 2 minutes.     

Module-assisted one-pot synthesis of [18F]SFB for radiolabeling proteins

The need of reliable production of N-succinimidyl 4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB), a versatile ¹⁸F-labeled prosthetic group for protein labeling, has increased dramatically due to the easy availability of proteins or their engineered derivatives for targeted molecular imaging. A module-assisted radiosynthesis of [¹⁸F]SFB was developed using a three-step, one-pot procedure and ethyl 4-(trimethylammonium)benzoate triflate (1) as the starting material. The radiochemical transformations were carried out in a general-purpose, custom-made module and streamlined by an anhydrous deprotection strategy using t-BuOK/DMSO. After HPLC-purification, [¹⁸F]SFB was synthesized in radiochemical yields of 20–30% (n > 10, not decay-corrected) and excellent radiochemical and chemical purities (>98%). The total synthesis and purification time required is ~90 min. Using the purified [¹⁸F]SFB, three ¹⁸F-labeled proteins, bovine serum albumin (BSA), chicken egg albumin (CEA) and transferrin, were synthesized in yields of 61.0–79.5%. The ¹⁸F-Annexin V for apoptosis imaging was also produced in 5% radiolabeling yield and >95% radiochemical purity.     

(S)-2-((S)-2-(4-(3-[18F]fluoropropyl)benzamido)-3-phenylpropanamido)pentanedioic acid labeled with 18F

As degradation product of Antineoplaston A10 in vivo, phenylacetyl glutamine showed antitumor activities. According to literatures, we designed and radiosynthesized a phenylacetyl glutamine derivative, which was achieved under a mild reaction condition. Evaluations in vitro and in vivo were performed on tumor bearing mice. Excitingly, the radiochemical purity of (S)-2-((S)-2-(4-(3-fluoropropyl)benzamido)-3-phenylpropanamido)pentanedioic acid ([¹⁸F]FBPPA) was 98%, and besides the best radiochemical yield was up to 46%. T/Bl (Tumor/Blood) and T/M (Tumor/Muscle) ratios of [¹⁸F]FBPPA at 60 min post injection were 2.33 and 3.51. Meanwhile, it showed satisfied stability in vitro and in vivo, compared with 2-[¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG). Although [¹⁸F]FBPPA deserved further studies to make optimizations on its structure, the results revealed it might become a potential PET imaging agent for detecting tumors.     

Enzymatic Synthesis of [3-14C]Cinnamic Acid

Convenient and efficient route of the synthesis of [3-¹⁴C] cinnamic acid is reported. [1-¹⁴C]Benzoic acid, prepared by carbonation of Grignard reagent with [¹⁴C]carbon dioxide, was reduced to [1-¹⁴C]benzyl alcohol. In the enzymatic step this alcohol was selectively oxidised to [1-¹⁴C]benzaldehyde using enzyme YADH (Ec. 1.1.1.1) and immediately condensed with malonic acid. This combined chemical and enzymatic approach allows to obtain [3-¹⁴C]cinnamic acid with radiochemical yield higher than 50% in respect to the starting alcohol.     

Optimization of the production of [61Cu]Diacetyl-bis(N 4-methylthiosemicarbazone) for PET studies

Summary Copper-61 produced via the ^natZn(p,x)⁶¹Cu nuclear reaction was used for the preparation of [⁶¹Cu]diacetyl-bis(N⁴-methylthiosemicarbazone) ([⁶¹Cu]ATSM) (4) using a house-made ATSM ligand. After a proton irradiation of an electroplated zinc layer by 22 MeV protons at 180 mA for 3.2 hours, ⁶¹Cu was recovered by two-step chromatography using a cation and an anion exchange column. About 222 GBq (6.00 Ci) of ⁶¹Cu²⁺ was obtained with a radiochemical separation yield of more than 95% and a radionuclidic purity of better than 99%. Colorimetric methods showed that traces of chemical impurities in the product were below the accepted limits. The [⁶¹Cu]ATSM production was optimized for reaction conditions (buffer concentration and temperature) with a radiochemical yield of higher than 80%, radiochemical purity of better than 98% and a specific activity of about 246 Ci/mmol. The produced [⁶¹Cu]ATSM is a PET radiotracer for hypoxia imaging with an intermediate half life and a satisfactory quality, suitable for future PET studies.