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.     

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.     

A new technique for labeling of [11C]-choline, a positron-emitting tracer for tumor imaging

Summary [¹¹C]-choline has been reported as a potential tracer for imaging a variety of human tumors with positron emission tomography (PET). A new labeling technique for [¹¹C]-choline was established depending on parameters optimized, such as reaction time, volume, temperature, and the quantity of DMAE.The synthesis yield was improved from 82.0% to 96.5% (EOB), while the consumption of DMAE precursor decreased from 60 to 2 mg. Absolute yield of [¹¹C]-choline was 2500 MBq for a 10-minute irradiation at15mA, and a total synthesis time of less than 8 minutes from [¹¹C]-CH₃I to [¹¹C]-choline.     

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.     

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.     

Study of the reactivity of palladacycles containing [C(sp, ferrocene),N,S] or [C(sp),N,S] terdentate ligands with symmetric alkynes

The study of the reactivity of the cyclopalladated complex [Pd{[(η⁵-C₅H₃)-CHN-(C₆H₄-2-SMe)]Fe(η⁵-C₅H₅)}Cl] (1c) with the alkynes R¹-CC-R¹ (with R¹ = CO₂Me, Ph or Et) is reported.Compound 1c reacts with the equimolar amount of MeO₂C-CC-CO₂Me in refluxing CH₂Cl₂ to give [Pd{[(MeO₂C-CC-CO₂Me)(η⁵-C₅H₃)-CHN-(C₆H₄-2-SMe)]Fe(η⁵-C₅H₅)}Cl] (2c), which arises from the monoinsertion of the alkyne into the σ[Pd-C(sp², ferrocene)] bond.However, when the reaction was performed using Ph-CC-Ph or Et-CC-Et no evidence of the insertion of these alkynes into the σ[Pd-C(sp², ferrocene)] bond was detected.In contrast with these results, when 1c was treated with the Tl[BF₄] followed by the removal of the TlCl formed and the subsequent addition of MeO₂C-CC-CO₂Me the reaction gave 2c and [Pd{[(MeO₂C-CC-CO₂Me)₂(η⁵-C₅H₃)-CHN-(C₆H₄-2-SMe)]Fe(η⁵-C₅H₅)}][BF₄] (3c); but when the alkyne was R¹-CC-R¹ (with R¹ = Ph or Et), the ionic palladacycles [Pd{[(R¹-CC-R¹)₂(η⁵-C₅H₃)-CHN-(C₆H₄-2-SMe)]Fe(η⁵-C₅H₅)}][BF₄] · CH₂Cl₂ [with R¹ = Ph (5c) or Et (6c)] were isolated. In compounds 3c, 5c and 6c, the mode of binding of the butadienyl unit is η³. The reactions of 2c, 3c, 5c and 6c with PPh₃ are also reported. The results obtained from these studies reveal that the σ(Pd-S) bond in 2c is more prone to cleave than in 4c-6c. X-ray crystal structures of 2c, 5c and [Pd{[(MeO₂C-CC-CO₂Me)(η⁵-C₅H₃)-CHN-(C₆H₄-2-SMe)]Fe(η⁵-C₅H₅)}Cl(PPh₃)] (7c), are also described. Compound 7c arises from 2c by cleavage of the Pd-S bond and the incorporation of a PPh₃ in the coordination sphere of the palladium. A parallel study focused on the reactions of [Pd{[2-CH₂-4,6-Me₂-C₆H₂]-CHN-(C₆H₄-2-SMe)}Cl] (1d) (with a [Csp³,N,S]⁻ terdentate group) with the three alkynes reveals that the σPd-C(sp², ferrocene)] bond of 1c is more reactive than the σ[Pd-C(sp³)] bond of 1d.     

Structures and stabilities of [C3H2]+ ˙ and [C3H2]2+ ions

Ab initio molecular orbital theory using basis sets up to 6-311G^{* *}, with electron correlation incorporated via configuration interaction calculations with single and double substitutions, has been used to study the structures and energies of the C₃H₂ monocation and dication. In agreement with recent experimental observations, we find evidence for stable cyclic and linear isomers of [C₃H₂]^{+ ˙}. The cyclic structure (, a) represents the global minimum on the [C₃H₂]^{+ ˙} potential energy surface. The linear isomer (, b) lies somewhat higher in energy, 53 kJ mol^?1 above a. The calculated heat of formation for [HCCCH]^{+ ˙} (1369 kJ mol^?1) is in good agreement with a recent experimental value (1377 kJ mol^?1). For the [C₃H₂]²⁺ dication, the lowest energy isomer corresponds to the linear [HCCCH]²⁺ singlet (h). Other singlet and triplet isomers are found not to be competitive in energy. The [HCCCH]²⁺ dication (h) is calculated to be thermodynamically stable with respect to deprotonation and with respect to C? C cleavage into CCH⁺ + CH⁺. The predicted stability is consistent with the frequent observation of [C₃H₂]²⁺ in mass spectrometric experiments. Comparison of our calculated ionization energies for the process [C₃H₂]^{+ ˙} → [C₃H₂]²⁺ with the Q_min values derived from charge-stripping experiments suggests that the ionization is accompanied by a significant change in structure.     

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.     

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]⁺.     

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.     

The Protonation of [Pt3(m̈-CO)3(PCy3)3]

The cluster [Pt₃(m?-CO)₃(PCy₃)₃] can be protonated with HBF₄ · OEt₂ to form the cluster [Pt₃(m?-CO)₃(PCy₃)₃](m?₃-H) ⁺BF ( 2 ). This unstable compound was isolated and characterised by NMR and IR spectroscopy.     

Molecular Structure of Tetrahydroxycalix[4]arene [-(C<Subscript>6</Subscript>H<Subscript>3</Subscript>OH)-CH<Subscript>2</Subscript>-]<Subscript>4</Subscript> in the Gas Phase

Gas-phase electron diffraction and HF/6-31G*, HF/6-31G**, and B3LYP/6-31G* ab initio calculations were used to find that in the gas phase at 242°C the calix[4]arene [-(C₆H₃OH)-CH₂-]₄ molecule possesses a C₄ conformation. Geometric parameters of the molecule were determined, and the energies of C-H?O hydrogen bonds (7.3 kcal mol^?1) were estimated by the AM1 method.     

Stereoselective addition of allylmagnesium chloride to the CN bond of [4.3.0] boron heterobicycles

An efficient, simple protocol for the addition of allylmagnesium chloride to the CN bond of [4.3.0] boron heterobicycles afforded five new dioxaboracyclononenes 4a-e in moderate yields (51-61%). The boronates were characterized by ¹H, ¹³C, ¹¹B and 2D NMR experiments, and confirmed by X-ray analogues. The stereochemistry of the N-H, -CH₂CHCH₂ and B-Ph fusion is always cis, as established through NMR, and confirmed by X-ray structure of 4d. The structure of one of the addition products was established by X-ray analysis showing that, in the solid state, it exists as a polymeric structure formed by hydrogen bonds between the amine proton and the ester oxygen of the five-membered ring.     

One‐Pot,Direct Incorporation of [11C]CO2 into Carbamates

Why beat about the bush? An operationally simple and mild reaction based on the direct fixation of ¹¹CO₂ with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) has been developed for the synthesis of ¹¹C‐labeled carbamates at 75 °C within 10 minutes in radiochemical yields above 70 % (see scheme). This strategy should be immediately useful for the construction of new radiotracers for positron emission tomography and other applications.

     

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.     

A new convenient method for the synthesis of [2-C]thymine utilizing [C]phosgene

β-(N-Benzoylamino)methacrylamide, a key intermediate for the preparation of [2-¹¹C]thymine, was synthesized in three steps from ethyl α-formylpropionate and NH₃. Reaction of the alkali metal salts of β-(N-benzoylamino)methacrylamide with [¹¹C]phosgene gave [2-¹¹C]thymine. The yield of [2-¹¹C]thymine was 362 ± 53 MBq at EOS (n = 3) (18 MeV proton beam; 10 μA, 10 min). The total synthesis was accomplished in just 16 min from the end of bombardment.     

Hydrolysis of [Pt(dien)H2O]2+ and [Pd(dien)H2O]2+ complexes in water

The hydrolysis of the [Pt(dien)H₂O]²⁺ and [Pd(dien)H₂O]²⁺ complexes has been investigated by potentiometry at 298 K, in 0.1 mol dm^–3 aqueous NaClO₄. Least-squares treatment of the data obtained indicates the formation of mononuclear and -hydroxo-bridged dinuclear complexes with stability constants: log ₁₁ = –6.94 for [Pt(dien)OH]⁺, log ₁₁ = –7.16 for [Pd(dien)OH]⁺, and also log ₂₂ = –9.37 for [Pt₂(dien)₂(OH)₂]²⁺ and log ₂₂ = –10.56 for [Pd₂(dien)₂(OH)₂]²⁺. At pH values > 5.5, formation of the dimer becomes significant for the Pt^II complex, and at pH > 6.5 for the Pd^II complex. These results have been analyzed in relation to the antitumor activity of Pt^II complexes.     

Heterogeneous catalytic synthesis and structure of 5,5a,10a,11-tetrahydro-10H-indeno[1,2-b]quinoline

Hydrogenation of 10H-indeno[1,2-b]quinoline in benzene in the presence of R₂S₇ gave 5,5a,10a,11-tetrahydro-10H-indeno[1,2-b]quinoline, the structure of which was established by mass-, IR, UV,¹³C, and¹H NMR spectra. Thecis fusion of the indan and tetrahydroquinoline fragments, the axial orientation of the proton at C(5a), and the equatorial orientation of the proton at C(10a) were confirmed by molecular mechanics calculations using the PC MODEL program.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1098–1101, June, 1994.     

[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.