Yield ratio of [11C]-CO2, [11C]-CO and [11C]-CH4 from the irradiation of N2/H2-mixtures in a gas target

The¹⁴N/p, /¹¹C-reaction was studied in different N₂/H₂-mixtures. The products are [¹¹C]-CO₂, [¹¹C]-CO and [¹¹C]-CH₄. The yield ratio may be controlled by varying the bombardment conditions. High pressure, high H₂-content, high beam current and high proton energy shift the ratio towards [¹¹C]-CH₄. Lower beam current and lower proton energy increase the yield of [¹¹C]-CO₂. The production of [¹¹C]-CO is constant over a wide range of conditions /about 10%/. For the production of [¹¹C]-CH₄ in good yield a target gas holder for high pressures has been developed. Details are given in Fig. 7. This target gas holder was filled with 5% H₂ in N₂ at 3×10⁶ Pa. Proton irradiation of the mixture gives a typical yield of [¹¹C]-CH₄ of 400–500 mCi at a beam current of 15–20 A within 20 min. Only traces of other¹¹C-labelled compounds could be detected under these conditions.     

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.     

Site-selective amination and/or nitrilation via metal-free C(sp2)–C(sp3) cleavage of benzylic and allylic alcohols

Benzylic/allylic alcohols are converted via site-selective C(sp²)–C(sp³) cleavage to value-added nitrogenous motifs, viz., anilines and/or nitriles as well as N-heterocycles, utilizing commercial hydroxylamine-O-sulfonic acid (HOSA) and Et₃N in an operationally simple, one-pot process. Notably, cyclic benzylic/allylic alcohols undergo bis-functionalization with attendant increases in architectural complexity and step-economy.

Benzylic/allylic alcohols are converted via site-selective C(sp²)–C(sp³) cleavage to value-added nitrogenous motifs, viz., anilines and/or nitriles as well as N-heterocycles, utilizing commercial hydroxylamine-O-sulfonic acid (HOSA) and Et₃N in an operationally simple, one-pot process.     

Rapid in situ synthesis of [C]methyl azide and its application in C click-chemistry

We synthesized [¹¹C]methyl azide ([¹¹C]MeA) by reacting [¹¹C]methyl iodide ([¹¹C]MeI) in situ with an azide-donor and used it in the synthesis of ¹¹C-labeled 1,2,3-triazoles. A one-pot click approach comprised the infusion of gaseous [¹¹C]MeI into a mixture of NaN₃, ethynylbenzene, and CuI in water at a temperature of 100 °C yielding the ¹¹C-triazole in radiochemical yields (RCY) of 25%. In a two-step labeling protocol, we synthesized the [¹¹C]MeA in acetonitrile in advance to the click step. Using the more soluble complex as source of , a much higher trapping efficiency of [¹¹C]MeI in this solvent ensured an almost quantitative conversion of [¹¹C]MeI to [¹¹C]MeA within 5-10 min at room temperature. The [¹¹C]MeA was thereafter reacted with ethynylbenzene at 100 °C yielding 1-[¹¹C]methyl-4-phenyl-1H-1,2,3-triazole in preparative RCY of 60%. As a final proof of applicability, we used ¹¹C-click-chemistry for the labeling of N-terminal 4-ethynylbenzene derivatized d-Glu-d-Tyr-[Cys-Tyr-Trp-Lys-Thr-Cys]-Thr, a cyclic water-soluble Tyr³-octreotate derivative.     

Remote controlled unit for the production of [2-11C] isopropyl iodide

A remote controlled system is described for the production of [2-¹¹C] isopropyl iodide. The synthesis involves carbonation of methyl lithium with¹¹CO₂ followed by reduction with lithium aluminum hydride, hydrolysis and iodination with hydroiodic acid. The purification is performed by preparative gaschromatography on a Chromosorb 102-Porapak Q column. For a 30 min irradiation at 15 A beam intensity the method yields about 300 mCi /11 GBq/ of radiochemically and chemically pure [2-¹¹C] isopropyl iodide with a specific activity of 210 to 250 mCi. mol^–1 at the end of synthesis /EOB+25 min/. The remote controlled unit is also useful for the production of other alkyl iodides, acetone and acetic acid, labelled with¹¹C.     

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.     

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

For in vivo receptor studies N-[¹¹C]methyl-2,5-dimethoxy-4-bromo-amphetamine, [¹¹C]MDOB, was synthesized by the reaction of [¹¹C]CH₃I with DOB in acetonitrile. The labelling yield was determined in dependence on amount of precursor, time and temperature of the methylation reaction. During 10 to 15 minutes 60% to 70% of [¹¹C]MDOB has been obtained at 110°C.     

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.     

Structures and stabilities of [C3H3O]+ ions in the gas phase: A molecular orbital study

The relative energies of 11 [C₃H₃O]⁺ ions are calculated by different molecular orbital methods (MINDO/3, MNDO, ab initio with 3-21G and 4-31G* basis set and configuration interaction). The four most stable structures are: a ([CH₂?CH? CO]⁺), b c ([CH?C? CHOH]⁺) and d ([CH₂?C?COH]⁺); their relative energies at the CI/4-31G*//3-21G level are 0, 117, 171 and 218 kJ mol^?1, respectively. The isomerizations c→[CH?CH? CHO]⁺→[CH₂?C? CHO]⁺→ a and dissociations into [C₂H₃]⁺+CO and [HCO]⁺+C₂H₂ are explored. The calculated potential energy profile reveals that the energy-determining step is the 1,3-H migration c→[CH?CH? CHO]⁺. This explains the value of unity of the branching ratio and the spread of kinetic energy released for the two dissociation channels.     

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).     

Salts of HCN‐Cyanide Aggregates: [CN(HCN)2]− and [CN(HCN)3]−

Although pure hydrogen cyanide can spontaneously polymerize or even explode, when initiated by small amounts of bases (e.g. CN^?), the reaction of liquid HCN with [WCC]CN (WCC=weakly coordinating cation=Ph₄P, Ph₃PNPPh₃=PNP) was investigated. Depending on the cation, it was possible to extract salts containing the formal dihydrogen tricyanide [CN(HCN)₂]^? and trihydrogen tetracyanide ions [CN(HCN)₃]^? from liquid HCN when a fast crystallization was carried out at low temperatures. X‐ray structure elucidation revealed hydrogen‐bridged linear [CN(HCN)₂]^? and Y‐shaped [CN(HCN)₃]^? molecular ions in the crystal. Both anions can be considered members of highly labile cyanide‐HCN solvates of the type [CN(HCN)_n]^? (n=1, 2, 3 …) as well as formal polypseudohalide ions.     

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.     

[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.     

Production of 6-l-[18F]Fluoro-m-tyrosine in an Automated Synthesis Module for 11C-Labeling

6-l-[¹⁸F]Fluoro-m-tyrosine (6-l-[¹⁸F]FMT) represents a valuable alternative to 6-l-[¹⁸F]FDOPA which is conventionally used for the diagnosis and staging of Parkinson’s disease. However, clinical applications of 6-l-[¹⁸F]FMT have been limited by the paucity of practical production methods for its automated production. Herein we describe the practical preparation of 6-l-[¹⁸F]FMT using alcohol-enhanced Cu-mediated radiofluorination of Bpin-substituted chiral Ni(II) complex in the presence of non-basic Bu₄ONTf using a volatile iPrOH/MeCN mixture as reaction solvent. A simple and fast radiolabeling procedure afforded the tracer in 20.0 ± 3.0% activity yield within 70 min. The developed method was directly implemented onto a modified TracerLab FX C Pro platform originally designed for ¹¹C-labeling. This method enables an uncomplicated switch between ¹¹C- and ¹⁸F-labeling. The simplicity of the developed procedure enables its easy adaptation to other commercially available remote-controlled synthesis units and paves the way for a widespread application of 6-l-[¹⁸F]FMT in the clinic.     

Azodicarbonsäureester und Diazoessigester als Reaktionspartner des Ferriophosphaalkens [Cp*(CO)2FeP=C(Ph)NMe2]

Azodicarboxylates and Diazoacetates as Reactants of the Ferriophosphaalkene [Cp*(CO)₂FeP=C(Ph)NMe₂] Reaction of equimolar amounts of the ferriophosphaalkene [Cp*(CO)₂FeP=C(Ph)NMe₂] ( 1 ) and diethyl azodicarboxylate afforded the complex (C₅Me₄CH₂)(CO)₂Fe ( 3 ) as the result of a cheletropic [1+4] cycloaddition with subsequent transprotonation. The diazoacetates N₂=CHCO₂R ( 8a :=tBu; 8b :Et) and 1 gave rise to the formation of the N‐metallated 1, 2, 3‐diazaphospholes [Cp*(CO)₂Fe‐ ] ( 11a, b ). Compounds 3, 11a and 11b were characterized by means of elemental analyses and spectroscopy (IR, ¹H, ¹³C{¹H}, ³¹P{¹H}‐NMR). The molecular structure of 11a was determined by X‐ray diffraction analysis.     

[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.     

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.     

Gaseous [C2H3O]+ ions

[C₂H₃O]⁺ ions with the initial structures [CH₃CO]⁺, and [CH₂CHO]⁺ cannot be distinguished on the basis of their collisional activation spectra, demonstrating that these isomers interconvert at energies below their threshold for decomposition. Self-protonation of ketene leads to the [CH₃CO]⁺ ion, while the [C₂H₃O]⁺ ion generated from glycerol most probably has the structure of an oxygen protonated ketene [CH₂?C?OH]⁺.     

[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.     

Synthesis of [carbonyl-C]acetophenone via the Stille cross-coupling reaction of [1-C]acetyl chloride with tributylphenylstannane mediated by Pd2(dba)3/P(MeNCH2CH2)3N·HCl

The Stille cross-coupling reaction of [1-¹¹C]acetyl chloride with tributylphenylstannane leading to [carbonyl-¹¹C]acetophenone was studied with the goal of developing a new ¹¹C-labeling method for positron emission tomography tracer synthesis. The coupled product [carbonyl-¹¹C]acetophenone was synthesized using the Pd₂(dba)₃/P(MeNCH₂CH₂)₃N·HCl system with a 60-61% radiochemical conversion from [1-¹¹C]acetyl chloride (decay-corrected, n = 3).