A simple Tracerlab module modification for automated on-column [11C]methylation and [11C]carboxylation.

A modification of commercial [11C]methylation module which can be implemented for both on-column [11C]methylation and [11C]carboxylation in the same automated system is described. This module configuration was applied to the solid-phase synthesis of N-[11C]methyl-choline ([11C]choline) and L-(S-methyl-[11C])methionine ([11C]methionine), using [11C]CH(3)I as methylating agent, as well as to the synthesis of [11C]acetate by [11C]carboxylation with [11C]CO2 of methylmagnesium chloride with high and reproducible radiochemical yields in short reaction time, demonstrating to be a fast and reliable tool for the production of these [11C]radiopharmaceuticals for clinical use.     

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.     

Development of a modular system for the synthesis of PET [C]labelled radiopharmaceuticals

[¹¹C]labelled radiopharmaceuticals as N-[¹¹C]methyl-choline ([¹¹C]choline), l-(S-methyl-[¹¹C])methionine ([¹¹C]methionine) and [¹¹C]acetate have gained increasing importance in clinical PET and for the routine production of these radiopharmaceuticals, simple and reliable modules are needed to produce clinically relevant radioactivity. On the other hand, flexible devices are needed not only for the routine synthesis but also for more complex applications as the development of new tracers. The aim of this work was the adaptation of an Eckert Ziegler modular system for easy routine synthesis of [¹¹C]choline, [¹¹C]methionine and [¹¹C]acetate using components that account for straightforward scaling up and upgrades.     

Synthesis of oncological [11C]radiopharmaceuticals for clinical PET

Positron emission tomography (PET) is a nuclear medicine modality which provides quantitative images of biological processes in vivo at the molecular level. Several PET radiopharmaceuticals labeled with short-lived isotopes such as (18)F and (11)C were developed in order to trace specific cellular and molecular pathways with the aim of enhancing clinical applications. Among these [(11)C]radiopharmaceuticals are N-[(11)C]methyl-choline ([(11)C]choline), l-(S-methyl-[(11)C])methionine ([(11)C]methionine) and 1-[(11)C]acetate ([(11)C]acetate), which have gained an important role in oncology where the application of 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) is suboptimal. Nevertheless, the production of these radiopharmaceuticals did not reach the same level of standardization as for [(18)F]FDG synthesis. This review describes the most recent developments in the synthesis of the above-mentioned [(11)C]radiopharmaceuticals aiming to increase the availability and hence the use of [(11)C]choline, [(11)C]methionine and [(11)C]acetate in clinical practice.     

Automated synthesis of [11C]choline, a positron-emitting tracer for tumor imaging.

(beta-Hydroxyethyl)tri([11C]methyl)ammonium ([11C]choline) is a tracer very effective in imaging various human tumors using positron emission tomography (PET). We have constructed a computer-controlled [11C]choline synthetic apparatus which carries out the whole process of synthesis and product purification automatically. The setup is simple and the process quick. In 20 min, 11 GBq of [11C]choline (chloride) is obtainable from 26 GBq of [11C]CO2. The final product is a sterile and pyrogen-free [11C]choline "injection".     

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.).     

Simple automated system for simultaneous production of 11C-labeled tracers by solid supported methylation.

We herein describe a simple setup for the automated simultaneous synthesis of L-[methyl-11C]methionine and N-[methyl-11C]choline by solid-supported methylation. The setup is extremely simple and easy to adapt to other automated systems and due to its versatility, the method can be utilized for the production of other radiopharmaceuticals requiring a simple [11C]methylation step. Furthermore, it can be used for multiple simultaneous synthesis.     

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 simplified and improved synthesis of [11C]phosgene with iron and iron (III) oxide

[11C]Phosgene ([11C]COCl2), a useful precursor for labeling several radiopharmaceuticals, is generally produced by catalytic oxidation of [11C]carbon tetrachloride over Fe granules, although in low yields or with poor reproducibility. In order to develop am improved synthesis of [11C]phosgene, two oxidizing agents, Fe2O3 and CuO, were examined. The yield of [11C]phosgene was significantly increased using Fe2O3 powder mixed with Fe granules, while the use of CuO alone, or CuO powder mixed with Fe granules resulted in an insignificant yield. The yield and specific activity of S- (-) [11C]CGP-12177 synthesized using Fe2O3 powder mixed with Fe granules were markedly higher than those synthesized by the previous methods using Fe granules alone or Fe granules mixed with Fe powder. Thus, in the present study, we developed a simple and practical method for the synthesis of [11C]phosgene, which provided an improved yield of S- (-) [11C]CGP-12177.     

Amino acid distribution and metabolism in pituitary adenomas using positron emission tomography with D-[11C]methionine and L-[11C]methionine

Four patients with hormonally inactive pituitary adenomas were examined with positron emission tomography (PET) after injection, during different examinations, of L-[methyl-11C]methionine and D-[methyl-11C]methionine, respectively. After the rapid distribution phase, the enantiomer L-[11C]methionine, which is metabolically active, showed a considerable continuous irreversible trapping attributed to amino acid metabolism. The stereoisomer D-[11C]methionine, which does not participate in protein synthesis, showed a rapid distribution within the whole adenoma tissue, with a distribution space on the order of 100%. A minimal irreversible trapping was observed which could be explained by technical factors. It is concluded that PET using the two enantiomers allows a separation of passive distribution and metabolism, and that L-[11C]methionine can be used for in vivo quantitative studies of amino acid metabolism of pituitary adenomas.     

PET studies with L-[1-11C]tyrosine, L-[methyl-11C]methionine and 18F-fluorodeoxyglucose in prolactinomas in relation to bromocryptine treatment

Aspects of metabolism in prolactinomas were investigated by positron emission tomography using L-[1-11C]tyrosine, L-[methyl-11C]methionine and 18F-fluorodeoxyglucose (18FDG). Using L-[1-11C]tyrosine, four patients were monitored prior to and 18 h after an injection of 50 mg bromocriptine. At 18 h after bromocriptine intervention, L-[1-11C]tyrosine uptake into tumour was reduced with 28% (P less than 0.07). A correlation analysis of the bromocriptine-induced decrease in L-[1-11C]tyrosine uptake and the reduction of serum prolactin levels indicated that the action of bromocriptine on prolactin synthesis and prolactin release is not coupled. In the untreated situation, the four patients were investigated with 18FDG as well, but the prolactinomas could not be visualized. Three untreated patients were studied with L-[methyl-11C]methionine. The tumour-imaging potential of L-[methyl-11C]methionine and L-[1-11C]tyrosine appeared to be nearly equivalent for prolactinomas. Unlike prolactinoma tissue, the salivary glands showed a pronounced preference for L-[1-11C]tyrosine as compared to L-[methyl-11C]methionine. L-[1-11C]tyrosine is a valuable tool to obtain information on the metabolism and treatment of prolactinomas.     

Synthesis of L- and D-[methyl-11C]methionine

This report describes the synthesis of L- and D-[methyl-11C]methionine in pure enantiomeric forms. The compounds were prepared routinely approximately 1,000 times with less than 20 failures. Starting with carbon-11 (11C) methyl iodide, a simple one-carbon precursor produced from a one-pot or a two-pot apparatus, L- and D-[methyl-11C]methionine were prepared, respectively, with an optical purity higher than 99% in 40%-90% radiochemical yields. The total time for synthesis, starting from [11C]carbon dioxide, was 12-15 min. The crude product usually had a radiochemical purity greater than 95%. The total time for synthesis, including LC purification, was 20-30 min. The radiochemical purity of the product in each case was greater than 98%.     

Discrepancies in brain tumor extent as shown by computed tomography and positron emission tomography using [68Ga]EDTA, [11C]glucose, and [11C]methionine

A patient with an anaplastic (malignant) astrocytoma was examined with computed tomography (CT) and with positron emission tomography (PET), in the latter case using [68Ga]EDTA, [11C]glucose, and [11C]methionine. The CT examination as well as the [68Ga]EDTA study showed a small tumor located in the region of the head of the left caudate nucleus. The [11C]glucose examination showed increased uptake on the same region, as did the [11C]methionine examination, but the latter also showed a considerable uptake in the entire left thalamic region. The patient died 15 days after the [11C]methionine study and a histologic evaluation of thin sections obtained at autopsy showed excellent agreement between tumor extent and activity distribution after [11C]methionine administration. The tumor tissue seen only with [11C]methionine was histologically different from that part of the tumor observed with the other tracers. Although cytologically similar, the latter showed large necrotic areas and an ability to induce marked endothelial proliferation, whereas in the former neither necroses nor notable endothelial proliferation was seen. In this case more than 50% of the tumor would have remained radiologically imperceptible without the [11C]methionine PET examination.     

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.     

Biodistribution and radiation dosimetry of [11C]choline: a comparison between rat and human data

Purpose  

Methyl-¹¹C-choline ([¹¹C]choline) is a radiopharmaceutical used for oncological PET studies. We investigated the biodistribution and biokinetics of [¹¹C]choline and provide estimates of radiation doses in humans.     

A simple modification of GE tracerlab FX C Pro for rapid sequential preparation of [11C]carfentanil and [11C]raclopride

A simple modification of the GE Tracerlab FX C Pro system which enabled performance of both solvent capture (loop method) and conventional solution phase [¹¹C]methylation in the same module is described. By the quick setup and automated method, [¹¹C]carfentanil and [¹¹C]raclopride could be prepared in rapid succession without opening the hot cell. The radiochemical yields were over 40% and 30% (decay-corrected and based on [¹¹C]methyl iodide) for [¹¹C]carfentanil and [¹¹C]raclopride, respectively. The radiochemical purities were greater than 95% and specific activities over 5 Ci/mmol for both tracers. The modification is extremely easy and can be utilized for multiple syntheses of other ¹¹C-labeled radiopharmaceuticals in a fast and reliable manner.     

Comparison of L-[1-11C]methionine and L-methyl-[11C]methionine for measuring in vivo protein synthesis rates with PET

To evaluate the feasibility of using either L-[1-11C]-methionine or L-[methyl-11C]methionine for measuring protein synthesis rates by positron emission tomography (PET) in normal and neoplastic tissues, distribution and metabolic studies with 14C- and 11C-labeled methionines were carried out in rats bearing Walker 256 carcinosarcoma. The tissue distributions of the two 14C-labeled methionines were similar except for liver tissue. Similar distribution patterns were observed in vivo by PET using 11C-labeled methionines. The highest 14C incorporation rate into the protein-bound fraction was found in the liver followed by tumor, brain, and pancreas. The incorporation rates in liver and pancreas were different for the two methionines. By chloroform-methanol fractionation of these four tissues, in liver significantly different amounts of 14C were observed in macromolecules. Also in brain tissue slight differences were found. By HPLC analyses of the protein-free fractions of plasma, tumor, and brain tissue at 60 min after injection, for both methionines several 14C-labeled metabolites in different amounts, were detected. About half of the 14C-labeled material in the protein-free fraction was found to be methionine. In these three tissues the amount of nonprotein metabolites and [14C]bicarbonate amount ranged from 10% to 17% and 12% to 15% for L-[1-14C]methionine and L-[methyl-14C]methionine, respectively. From these results it can be concluded that the minor metabolic pathways have to be investigated in order to quantitatively model the protein synthesis by PET.     

Comparison of three different purification methods for the routine preparation of [11C] Metomidate.

PET with (R)-[O-methyl-11C] metomidate ([11C] MTO) is an attractive method for the characterisation of adrenal masses discriminating lesions of adrenal cortical origin from noncortical lesions. [11C] MTO was prepared by the reaction of [11C] methyliodide with the corresponding free acid. Three purification methods have been compared. The method of choice uses preparative HPLC with a ready-to-use weak acidic solvent.     

Synthesis of [11C] coenzyme Q-related compounds for in vivo estimation of mitochondrial electron transduction and redox state in brain

We have studied the synthesis of [11C]2,3-dimethoxy-5-methyl-6-(10-hydroxy)-decyl-1,4-benzoquinone (idebenone) and [11C]2,3-dimethoxy-5-methyl-1,4-benzoquinone (CoQo) by methylation of their respective desmethyl precursors using [11C]CH3I for in vivo measurement of mitochondrial electron transfer and redox state. The [11C]idebenone was more lipophilic than [11C]CoQo; the latter became hydrophilic by reduction. Clearance of [11C]idebenone from mouse brain was more rapid than that of [11C]CoQo. The results indicated that modification of the isoprenoid side chain in [11C]CoQ is necessary to develop more suitable radiopharmaceuticals.     

Improved synthesis of the peripheral benzodiazepine receptor ligand [11C]DPA-713 using [11C]methyl triflate.

Recently, the pyrazolopyrimidine, [11C] N,N-Diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl]acetamide (DPA-713) has been reported as a new promising marker for the study of peripheral benzodiazepine receptors with positron emission tomography. In the present study, DPA-713 has been labelled from the corresponding nor-analogue using [11C]methyl triflate (CH3OTf). Conditions for HPLC were also modified to include physiological saline (aq. 0.9% NaCl)/ethanol:60/40 as mobile phase making it suitable for injection. The total time of radiosynthesis, including HPLC purification, was 18-20 min. This reported synthesis of [11C]DPA-713, using [11C]CH3OTf, resulted in an improved radiochemical yield (30-38%) compared to [11C]methyl iodide (CH3I) (9) with a simpler purification method. This ultimately enhances the potential of [11C]DPA-713 for further pharmacological and clinical evaluation. These improvements make this radioligand more suitable for automated synthesis which is of benefit where multi-dose preparations and repeated syntheses of radioligand are required.