[C]Formaldehyde revisited: considerable concurrent [C]formic acid formation in the low-temperature conversion of [C]carbon dioxide into [C]formaldehyde

The reduction of [¹¹C]carbon dioxide with lithium aluminium hydride in diethyl ether at temperatures ranging from −56°C to 19°C was studied. In contrast to what others have reported, considerable amounts of [¹¹C]formic acid were found at all studied temperatures.     

Two routes to [C-carbonyl]organo-isocyanates utilizing [C]phosgene ([C]organo-isocyanates from [C]phosgene)

Two generic radiosynthetic routes for the preparation of [¹¹C-carbonyl]isocyanates have been developed. Reaction of N-organo-sulfinylamines; RNSO, (R = Me, Et, allyl, cyclohexyl and phenyl) with [¹¹C]phosgene gave the corresponding [¹¹C-carbonyl]isocyanates in good radiochemical yield (53–68%) from [¹¹C]phosgene (decay corrected) in ca 16 min from EOB. Alternatively, the reaction of [¹¹C]phosgene with N,N′-organo-ureas; (RNH)₂CO, (R = Me, Et, Pr and phenyl) also gave the corresponding [¹¹C-carbonyl]isocyanates in moderate radiochemical yield (9–37%) from [¹¹C]phosgene (decay corrected) in ca 16 min from EOB. For identification, the [¹¹C-carbonyl]organo-isocyanates were derivatized with 1-(2-methoxyphenyl)piperazine in situ to [¹¹C-carbonyl]carboxamides and the position of radiolabelling in the carbonyl group confirmed by [^11/13C]co-labeling and subsequent carbon-13 NMR spectroscopy.     

Preparation of [11C]carbon dioxide from [11C]cyanide

[¹¹C]carbon dioxide was prepared from [¹¹C]cyanide. First, [¹¹C]CH₄ was produced by the (p, α) reaction on a N₂/H₂ mixture and was converted to [¹¹C]CN⁻ by reaction with ammonia over platinum at 1273 K. The [¹¹C]CN⁻ was adsorbed on a cobalt(II, III) oxide/ceramic furnace material at room temperature and was subsequently converted to [¹¹C]CO₂ by heating the cobalt(II, III) oxide to 948 K over a 10 min period and collecting the [¹¹C]CO₂ in a trap at 77 K. Specific activities as high as 600 mCi/μmol at end of bombardment (EOB) were obtained in a 15 μA irradiation for 10 min.     

Two routes to [11C-carbonyl]organo-isocyanates utilizing [11C]phosgene ([11C]organo-isocyanates from [11C]phosgene).

Two generic radiosynthetic routes for the preparation of [¹¹C-carbonyl]isocyanates have been developed. Reaction of N-organo-sulfinylamines; RNSO, (R = Me, Et, allyl, cyclohexyl and phenyl) with [¹¹C]phosgene gave the corresponding [¹¹C-carbonyl]isocyanates in good radiochemical yield (53–68%) from [¹¹C]phosgene (decay corrected) in ca 16 min from EOB. Alternatively, the reaction of [¹¹C]phosgene with N,N′-organo-ureas; (RNH)₂CO, (R = Me, Et, Pr and phenyl) also gave the corresponding [¹¹C-carbonyl]isocyanates in moderate radiochemical yield (9–37%) from [¹¹C]phosgene (decay corrected) in ca 16 min from EOB. For identification, the [¹¹C-carbonyl]organo-isocyanates were derivatized with 1-(2-methoxyphenyl)piperazine in situ to [¹¹C-carbonyl]carboxamides and the position of radiolabelling in the carbonyl group confirmed by [^11/13C]co-labeling and subsequent carbon-13 NMR spectroscopy.     

A simple,versatile, low-cost and remotely operated apparatus for [11C]acetate, [11C]choline, [11C]methionine and [11C]PIB synthesis

A simple, efficient and remotely operated synthesis apparatus for carrying out routine [¹¹C]carboxylation, on-column and bubbling [¹¹C]methylation was essential for reliable, day-to-day production of [¹¹C]-labelled PET radiopharmaceuticals. We developed an in-house apparatus specifically applied to the synthesis of [¹¹C]acetate, [¹¹C]choline, [¹¹C]methionine and 2-(4′-N-[¹¹C]methylaminophenyl)-6-hydroxybenzothiazole ([¹¹C]PIB), where high radiochemical purity (⩾97%) and moderate radiochemical yields (18% for [¹¹C]PIB, 41–55% for the others) could be achieved. These findings provided evidence that this was a fast, versatile and reliable apparatus suitable for a PET/CT centre with limited financial budget and hot cell space for synthesis of [¹¹C]-labelled radiopharmaceuticals.     

On-line preparation of [11C]carbon dioxide from [11C]methane

[¹¹C]Methane, produced from the (p, α) nuclear reaction on a nitrogen-5.6% hydrogen target, has been oxidized in an “on-line” synthetic train to yield [¹¹C]carbon dioxide. [¹¹C]methane is quantitatively adsorbed from the target gas on a Porapak Q column cooled to liquid nitrogen temperature. Following absorptive concentration, the [¹¹C]methane is oxidized by passage over cobalt(II–III) oxide powder heated to 500°C in a stream of nitrogen-2.0% oxygen. The isotopic dilution occurring during this conversion was determined to be 60%.     

[11C]octopamine synthesis using [11C]cyanide: Chemical and enzymatic approaches for the [11C]cyanohydrin synthesis

[¹¹C]-p- and m-octopamine hydrochloride were synthesized from [¹¹C]HCN in a two-step sequence. Chemical and enzymatic approaches were used for the formation of the [¹¹C]cyanohydrin intermediates as the key step. Isolated radiochemical yields of 0.7–2.3% at the end-of-synthesis were obtained with an overall preparation time of 40–60 min. The enantiomeric purity of the [¹¹C]-p-octopamine obtained through the enzymatic process was 92% e.e. in the (S)-enantiomer, whereas that of the [¹¹C]-m-octopamine was 42% e.e. in the (R)-enantiomer, as determined by HPLC without any derivatization.     

Production of [C]chloroform by direct chlorination of [C]methane without catalyst support for the synthesis of [C]diazomethane

The preparation of [¹¹C]chloroform by direct chlorination of [¹¹C]methane using gaseous chlorine by variation of temperature and reaction time (inert gas flow) without catalyst support for the online production of [¹¹C]diazomethane in a flow-through synthesis apparatus is described in this work. At an oven temperature of 400 °C and a He flow of 50 mL/min, [¹¹C]chloroform was synthesized inside a quartz glass column in a radiochemical yield of 31±2% with respect to [¹¹C]methane. The online preparation of [¹¹C]diazomethane by reaction of [¹¹C]chloroform with hydrazine in an ethanolic KOH solution with small amounts of 18-crown-6-crownether succeeded with a radiochemical yield of 20±3% with respect to [¹¹C]methane. The product [¹¹C]diazomethane was measured indirectly in the form of 4-nitrobenzoic acid[¹¹C]methylester using the esterification of 4-nitrobenzoic acid as a monitor reaction.     

An automated radiosynthesis of 2-[11C]thymidine using anhydrous [11C]urea derived from [11C]phosgene.

2-[11C]Thymidine has been produced from [11C]methane via [11C]phosgene and [11C]urea. Anhydrous [11C]urea was prepared from [11C]phosgene by reaction with liquid ammonia. This novel approach avoids the problems associated with the synthesis of anhydrous [11C]urea from [11C]cyanide. A fully automated system based on a modular approach and under PLC control has been developed. The system provides 2-[11C]thymidine reliably and reproducibly for clinical PET studies. The radiosynthesis takes 45-50 min from [11C]methane and the average yield was 1.5-3.3 GBq (40-90 mCi). The specific radioactivity was typically in the range 29.6-51.8 GBq mumol-1 (0.8-1.4 Ci mumol-1) at EOS corresponding to 6-12 micrograms of stable thymidine. The radiochemical yield of 2-[11C]thymidine was ca. 14% from [11C]methane.     

Radiochromatographic resolution of [14C]DL-tryptophan, [14C]DL-phenylalanine and [35S]DL-methionine on a cellulose column

[¹⁴C]DL-Tryptophan, [¹⁴C]DL-phenylalanine and [³⁵S]DL-methionine were resolved using cellulose column chromatography. The assignment for the resolved enantiomers was carried out by means of co-chromatography with non-labeled DL-amino acids after modification with fluorodinitrobenzene. The optical purity of the enantiomers was estimated to be greater than 99%. The resolved enantiomers were provided for bioassay, showing that the enantiomer was biochemically active.     

Enzymatic synthesis of [1-11C]pyruvic acid, L-[1-11C]lactic acid and L-[1-11C]alanine via DL-[1-11C]alanine

L-[1-11C]Lactic acid was prepared enzymatically from [1-11C]pyruvic acid by way of DL-[1-11C]alanine, using remote, semiautomated procedures. The DL isomers of alanine were prepared by a modification of the Bucherer-Strecker reaction from no-carrier-added (NCA) hydrogen [11C]cyanide. The enantiomer mixture was transformed to [1-11C]pyruvic acid by successive elution through columns of (a) immobilized D-amino acid oxidase (D-AAO)/catalase and (b) immobilized L-alanine dehydrogenase (L-AID) or L-amino acid oxidase (L-AAO/catalase). [1-11C]-Pyruvic acid was subsequently converted to L-[1-11C]lactic acid by passage through a L-lactic dehydrogenase (L-LDH) column. L-[1-11C]Alanine and [1-11C]-pyruvic acid were separated chromatographically by way of a cation-exchange column (AG50W-X2, H+ form). Typically the synthesis time was 35-40 min after cyclotron production of hydrogen [11C]cyanide (400 mCi), with radiochemical yields of 25 mCi (25%) for L-[1-11C]lactic acid, 35 mCi (29%) for [1-11C]pyruvic acid, and 20 mCi (20%) for L-[1-11C]alanine. The use of immobilized enzymes eliminates the possibility of protein contamination and assures the production of sterile, pyrogen-free products, allowing for rapid and effective regio- and stereo-specific transformations.     

An alternative synthesis of DL-[1-11C]Alanine from [11C]HCN

The synthesis of dl-[1-¹¹C]alanine from [1-¹¹C]HCN via dl-[1-¹¹C]2-aminopropanenitrile and its use in an enzymatic synthesis of [1-¹¹C]pyruvic acid is reported. The purified dl-[1-¹¹C]alanine was obtained in a radiochemical yield of 75% with a radiochemical purity higher than 98% within 40 min after end of bombardment (EOB). [1-¹¹C]Pyruvic acid was prepared by enzymatic synthesis from crude dl-[1-¹¹C]alanine using a previously reported procedure for the synthesis of [3-¹¹C]pyruvic acid. dl-[1-¹¹C]Alanine and [1-¹¹C]pyruvic acid prepared by these methods have been found to be sterile and free of pyrogens, and can thus be used in studies of the distribution of these radiopharmaceuticals in man using positron emission tomography (PET).     

A semi-automated synthesis system for routine preparation of [11C]YM-09151-2 and [11C]pyrilamine from [11C]methyl iodide

A synthesis system has been developed for routine preparation of the ¹¹C-labeled receptor ligands, [¹¹C]YM-09151-2 and [¹¹C]pyrilamine, from [¹¹C]methyl iodide produced automatically. The system features semi-automated operation, from the reaction of the desmethyl derivative with [¹¹C]methyl iodide to filtration with a specifically developed syringe pump of the final product in saline into a sterile vial. The preparations were completed within 45 min after irradiation and approx. 1 GBq (27 mCi) of [¹¹C]YM-09151-2 or [¹¹C]pyrilamine was obtained with a radiochemical and chemical purity of >99% and an average specific activity of 44 GBq/μmol (1.2 Ci/μmol) at the end of synthesis. Sterile and pyrogen-free ¹¹C-labeled receptor ligands suitable for human injection are routinely prepared using the present synthesis system.     

Enhanced radiosyntheses of [11C]raclopride and [11C]DASB using ethanolic loop chemistry

IntroductionTo improve the synthesis and quality control of carbon-11 labeled radiopharmaceuticals, we report the fully automated loop syntheses of [¹¹C]raclopride and [¹¹C]DASB using ethanol as the only organic solvent for synthesis module cleaning, carbon-11 methylation, HPLC purification, and reformulation.MethodsEthanolic loop chemistry is fully automated using a GE TRACERLab FX_C-Pro synthesis module, and is readily adaptable to any other carbon-11 synthesis apparatus. Precursors (1 mg) were dissolved in ethanol (100 μL) and loaded into the HPLC loop. [¹¹C]MeOTf was passed through the HPLC loop and then the labeled products were purified by semi-preparative HPLC and reformulated into ethanolic saline.ResultsBoth [¹¹C]raclopride (3.7% RCY; > 95% RCP; SA = 20831 Ci/mmol; n = 64) and [¹¹C]DASB, both with (3.0% RCY; > 95% RCP; SA = 15152 Ci/mmol; n = 9) and without (3.0% RCY; > 95% RCP; SA = 10931 Ci/mmol; n = 3) sodium ascorbate, have been successfully prepared using the described methodology. Doses are suitable for human use and the described methods are now employed for routine clinical production of both radiopharmaceuticals at the University of Michigan.ConclusionsEthanolic loop chemistry is a powerful technique for preparing [¹¹C]raclopride and [¹¹C]DASB, and we are in the process of adapting it for other carbon-11 radiopharmaceuticals prepared in our laboratories ([¹¹C]PMP, [¹¹C]PBR28 etc.).     

Preparation of 1-[125I]iodo-[114C]dodecane

1-[¹²⁵I]Iodo-[1¹⁴C]dodecane was prepared using the phosphorus halide/alcohol-reaction. Since the conventional synthesis of iodoalkanes requires apparatus and procedures which do not conform to radioprotection standards, a new apparatus was also constructed. Apparatus and method can also be used for the synthesis of other halogen-alkanes.     

High molar activity of [11C]TCH346 via [11C]methyl triflate using the "wet" [11C]CO2 reduction method.

[(11)C]TCH346, a compound acting on the glycolytic enzyme, glycerol-aldehyde-3-phosphate dehydrogenase, was produced under optimised conditions by methylation of the desmethyl compound with no-carrier added (n.c.a.) [(11)C]methyl triflate. An i.v. injectable solution of n.c.a. [(11)C]TCH346 containing 4040+/-1550 MBq (n=6) containing a molar activity between 40 and 5700 GBq/micromol and a radiochemical purity of >99% was obtained within 30 min (after EOB) by irradiation of nitrogen gas containing 0.5% oxygen with 16.5 MeV protons at 45 microA for 30 min. The alkylation reagent [(11)C]methyl triflate was prepared via on-line conversion of [(11)C]methyl iodide. For the formation of [(11)C]methyl iodide, [(11)C]carbon dioxide from the target chamber was reduced by a lithium aluminium hydride solution, and the methanol obtained on-line was converted using triphenylphosphine diiodide. The molar activity of [(11)C]TCH346 could be improved from 40 up to nearly 5700GB q/micromol during the optimisation of the synthesis using the same stock solution of lithium aluminium hydride solution in tetrahydrofuran.     

Comparison of three PET dopamine D2-like receptor ligands, [11C]raclopride, [11C]nemonapride and [11C]N-methylspiperone, in rats

We studied the tracer kinetics of three dopamine D2-like receptor ligands, [11C]raclopride ([11C]RAC), [11C]nemonapride ([11C]NEM) and [11C]N-methylspiperone ([11C]MSP), in anesthetized rats by tissue dissection, ex vivo ARG and PET in order to clarify their characteristics for PET imaging. The in vivo affinity of the three ligands for the striatum ([11C]MSP > [11C]NEM > [11C]RAC) obeyed the in vitro affinity for dopamine D2 receptors. The affinity of [11C]RAC and [11C]MSP for the cerebellum was very low, but the affinity of [11C]NEM for the cerebellum was compatible to that for the cortex and was not to be ignored. Also the affinity of [11C]MSP for the cortex was relatively high. [11C]RAC showed the highest selectivity. The striatal PET image with [11C]RAC was clearer than that with [11C]NEM or [11C]MSP, but the activity decreased much faster than that measured by tissue dissection because of the partial volume effect. The striatal activity with [11C]NEM remained high and that with [11C]MSP gradually increased. [11C]RAC and [11C]MSP, but not [11C]NEM, showed a high accumulation in the periorbital region.