11C-clomipramine: Synthesis and analysis

A method is described for the labelling of the antidepressant clomipramine with¹¹C. A product of 10–20 mCi is obtained in 40 min after the irradiation. The chemical and radiochemical purity of¹¹C-clomipramine is investigated.     

Development of [<Superscript>64</Superscript>Cu]-DOTA-anti-CD20 for targeted therapy

Copper-64 was produced as a by-product of ⁵⁵Co via ⁶⁴Ni(p,n)⁶⁴Cu by 15 MeV proton bombardment of ^natNi resulting in a thick target yield of 5.31 MBq/μAh (143.5 μCi/μAh) and a radiochemical separation yield of 95% (radionuclide purity >97% after 25 hours of bombardment). Rituximab was successively labeled with [⁶⁴Cu]-CuCl₂. N-succinimidyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA-NHS) was prepared at 25 °C using DOTA and N-hydroxy succinimide (NHS) in CH₂Cl₂ followed by the addition of 1 ml of a Rituximab pharmaceutical solution. Radiolabeling was performed at 37 °C in 3 hours. Radio thin-layer chromatography showed an overall radiochemical purity of 90–95% at optimized conditions (specific activity=30 GBq/mg, labeling efficacy; 82%) using various chromatography systems. The final isotonic ⁶⁴Cu-DOTA-Rituximab complex was passed through a 0.22 μm filter and checked by gel electrophoresis for radiolysis control. Stability of the final product was checked in the formulation and in presence of human serum at 37 °C.     

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).     

Preparation of high purity labelled Rose-Bengal with radioiodine

The exchange of Rose-Bengal in the mono-sodium salt with elementary¹³¹I in an organic medium allows for the preparation of a labelled product substantially higher in radiochemical purity than that produced by other methods. Purification of the starting material before the labelling process has been done by adsorption chromatography. Under the conditions described a radiochemical yield more than 97% can be obtained within 30–60 minutes. The product was stable during sterilization and storage for 10 days and was found to be free of¹³¹I.     

The modified cyrogenic adsorption method for the laboratory separation of85Kr from the atmosphere

This paper decribes syntheses for the¹¹C-labelled chemotherapeutic drug, CCNU,¹¹C-labelled BFNU and CFNU (analogs of BCNU) as well as an improved synthesis for¹¹C-BCNU. Also discussed are procedures for the separation of dual isomers in the case of¹¹C-labelled CCNU and CFNU. The specific activity of these no-carrier-added radiopharmaceuticals was approximately 10⁴ lower than expected for a carrier-free product. The syntheses were normally finished 20–25 min after the end of the collection of¹¹C-COCl₂. Chemical and radiochemical purity of the final product, as determined by HPLC and TLRC respectively, was at least 98%. The syntheses yielded 10–25 mCi of nitrosourea ready for use in PET studies.To whom correspondance should be addressed at Medical Cyclotron Unit.     

Automated production of carbon-11 labelled acetate to allow detection of transient myocardial ischemia in man,using positron emission tomography

The synthesis of¹¹C-acetate has been achieved via carbonation of methyl magnesium bromide with¹¹C-labelled carbon dioxide. Using this procedure, 7.4 GBq /200 mCi/ of¹¹CO₂ produced by the¹⁴ _N/P,/¹¹C nuclear reaction, was converted, within 20 min into¹¹C-acetate with an activity higher than 2.22 GBq /60 mCi/. Chemical and biologic quality control shows that the product is pure, sterile, and pyrogen-free and therefore suitable for human use. Handling considerable amounts of activity has led us to automate the¹¹C-acetate synthesis. The different parts of the system-programmable controller, sensors, automatic neutralization system-are described in detail.     

A rapid and high-yield aqueous phase preparation procedure for123I-labelled meta-iodobenzylguanidine

A new, aqueous phase preparation procedure for¹²³I-mIBG /meta-iodobenzylguanidine/ is described. It comprises a copper-catalyzed exchange reaction between aqueous¹²³I-iodide and mIBG at 150 °C for 45 min, a purification via anion-exchange chromatography, and a sterilization via micropore filtration. Overall preparative yield, radiochemical purity and specific activity amount to >90%, >99.7% and >10¹⁵ Bq.mol^–1 mIBG, respectively. Other features are simplicity /no evaporation of water or other solvents/, reproducibility of labelling yield and radiochemical purity, and speed /total time required 1.5 h/.     

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.     

Carbon-14 labelling of biomolecules induced by14CO ionized gas

Ionized¹⁴CO gas provides a rapid method for producing¹⁴C-labelled biomolecules. The apparatus consists of a high vacuum system in which a small amount of¹⁴CO is ionized by electron impact. The resulting species drift towards a target where they interact with the molecule of interest to produce¹⁴C-labelled compounds. Since the reaction time is only 2 minutes, the method is particularly promising for producing tracer biomolecules with short-lived¹¹C at high specific activities. We have studied the applicability of the method to various classes of compounds of biological importance, including sterids, alkaloids, prostaglandins, nucleosides, amino acids and proteins. All compounds treated gave rise to¹⁴C addition and degradation products. Furthermore, for some compounds, chromatographic analysis in multiple systems followed by derivatization and crystallization to constant specific activity, indicated that carbon exchange may occur to produce the labelled, but otherwise unaltered substrate in yields of the order of 10–100 mCi/mol. More conclusive proof of radiochemical identity must await production of larger quantities of material and rigorous purification including at least two different chromatographic techniques. Supported by the Medical Research Council of Canada Grant MA-6137, and by the Banting Research Foundation.     

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.     

Preparation of 1-Phenyl 3-Methyl 4-Nitro 5-125I- Pyrazole (5-125I-MNPP) as a Possible Cannabinoid Receptor Imaging Agent

A rapid method for labelling of 1-phenyl 3-methyl 4-nitro 5-chloro pyrazole (5-Cl-MNPP) with radioactive iodide Na¹²⁵I via ¹²⁵I -for- Cl exchange has been reported. This method has been done in dry state (without catalyst and in presence of acetamide), in dimethyl formamide (DMF) as a solvent (without catalyst and in presence of tetrabutyl ammonium bromide (TBAB) as phase transfer catalyst (PTC)). In dry state, a trial to reduce the reaction temperature from 170 to 120 °C for the reaction between 5-Cl-MNPP and Na¹²⁵I in presence of acetamide as a molten medium was tested. Using some organic solvents such as ethanol, dimethyl sulfoxide (DMSO), acetonitrile, and DMF, it was found that DMF gave low radiochemical yield of 5-¹²⁵I-MNPP (25%) within 30 min. However, the addition of 1 mg of TBAB to DMF increased the radiochemical yield of 5-¹²⁵I-MNPP from 25 to 95 within 30 minutes. The product 5-¹²⁵I-MNPP was purified by reverse phase, high performance liquid chromatography (HPLC), with radiochemical purity of greater than 98.0%. The biodistribution of 5-¹²⁵I-MNPP was demonstrated in normal mice through intravenous injection in the tail vein. The data show high uptake in the target organs equal to 2.5±0.22, 10.5±0.21, 4.3±0.27, 3.2±0.18 and 48.5±0.26 for brain, intestines, heart, kidneys and liver respectively. This indicates that, 5-¹²⁵I-MNPP can be freely penetrate the blood brain barrier (B.B.B.) and can be expected its usefulness in the quantitative determination of cannabinoid receptor in the brain.     

Automated preparation of carbon-11 ethanol and carbon-11 butanol for human studies using positron emission tomography

An automated continuous flow process has been developed for the synthesis of¹¹C-ethanol and¹¹C-butanol. These alcohols were synthesized via the same route. The reaction of¹¹CO₂ with methylmagnesium bromide or with n-propylmagnesium chloride, followed by a lithium aluminum hydride reduction and hydrolysis produced respectively¹¹C-ethanol and¹¹C-butanol. Preparation can be completed in 25 min. In each case the radiochemical purity, as determined by high pressure liquid chromatography /HPLC/ was greater than 98%. Biological quality control shows that the products are suitable for human use. The process has been completely automated to limit radiation exposure to personnel, reduce preparation time, and increase reproducibility.     

Radiofluorination of 2-fluoropyridines by isotopic exchange with [<Superscript>18</Superscript>F]fluoride

In homoaromatic systems, isotopic exchange (¹⁸F/¹⁹F) was previously (J Label Compd Radiopharm 18(12):1721–1730 [2], J Chem Soc Perkin Trans 1(3):295–298 [3]) proven to be advantageous, yet in general specific activity is thought to be low. For heteroaromatic systems, in particular, very few examples are published regarding the ¹⁸F-labelling of 2-substituted pyridines (J Label Compd Radiopharm 42:975–985 [9]). Therefore, in 2-fluoropyridines, we decided to study the ¹⁸F labelling by isotopic exchange (¹⁸F/¹⁹F). The radiochemical yield for 2-fluoropyridine was 90 ± 2%. Even if 2-fluoropyridine was substituted by an electron-donating group such as a methyl or a methoxy group, radiochemical yields were 80 ± 1 and 78 ± 1%, respectively. Although in benzenes, these substituents are known to decrease nucleophilic substitutions by ¹⁸F-Fluoride significantly. Moreover, by choosing appropriate concentrations of 2-fluoropyridines, reasonably high specific activities up to 10 GBq/μmol were obtained.     

11C-labelled etorphine for “in vivo” studies of opiate receptors in brain

In order to study “in vivo” opiate receptors, a method for¹¹C labelling of etorphine is described. 80 mCi (max. 120 mCi) of injectable labelled product radiochemically and chemically pure, are obtained in 25 minutes with a specific activity of 800 mCi/μmol.     

Synthesis of [11C]/(13C)amines via carbonylation followed by reductive amination

Twelve 11C-labelled amines were prepared via 11C-carbonylation followed by reductive amination. The 11C-carbonylation was performed in the presence of tetrakis(triphenylphosphine)palladium using aryl iodides or aryl triflates, [11C]carbon monoxide and phenyl-/methylboronic acid. The [11C]ketones formed in this step were then transformed directly into amines by reductive amination using different amines in the presence of TiCl4 and NaBH3CN. The 11C-labelled amines were obtained with decay-corrected radiochemical yields in the range 2-78%. The radiochemical purity of the isolated products exceeded 98%. (13C)Benzhydryl-phenyl-amine was synthesised and analysed by NMR spectroscopy for confirmation of the labelling position. Specific radioactivity was determined for the same compound. The reference compounds were prepared by reductive amination of ketones using conventional reaction conditions and three of the compounds were novel. The presented approach is a new method for the synthesis of [11C]/(13C)amines.     

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.     

Preparation and biodistribution of [67Ga]-DTPA-rituximab in normal rats

Rituximab was successively labeled with [⁶⁷Ga]-gallium chloride after residulation with freshly prepared cyclic DTPA-dianhydride. The best results of the conjugation were obtained by the addition of 1 ml of a rituximab pharmaceutical solution (5 mg/ml, in phosphate buffer, pH 8) to a glass tube pre-coated with DTPA-dianhydride (0.01 mg) at 25 °C with continuous mild stirring for 30 minutes. Radio thin-layer chromatography showed an overall radiochemical purity of 96–99% at optimized conditions (specific activity = 300–500 MBq/mg, labeling efficiency 77%). The final isotonic ⁶⁷Ga-DTPA-rituximab complex was checked by gel electrophoresis for radiolysis control. Radio-TLC was performed to ensure the formation of only one species, followed by filtration through a 0.22 μm filter. Preliminary in vivo studies in normal rat model was performed to determine the biodistribution of the radioimmunoconjugate up to 6 hours.     

A facile preparation of ammonium [<Superscript>14</Superscript>C]thiocyanate

Summary An attractive and simple method has been developed for the preparation of ammonium [¹⁴C]thiocyanate from [¹⁴C]thiourea which eliminates the necessity of handling highly hazardous potassium [¹⁴C] cyanide. [¹⁴C]thiourea was isomerized to ammonium [¹⁴C]thiocyanate by heating the aqueous solution of thiourea (12%) in a sealed tube at 160 °C for 24 hours. The product formed was purified by silica-gel column chromatography. A radiochemical yield of 92.7% was obtained based on [¹⁴C]thiourea. The specific activity of the product obtained was 53.3 mCi/mmol (1.97 GBq/mmol) and the radiochemical purity was greater than 99%. This method has not been reported so far for the production of this labeled compound.     

Quality control of99mTc-DTPA-octreotide by reverse high performance liquid chromatography

DTPA-Octreotide(Pentetreotide), a somatostatin analogue which can bind specifically and with high affinity to somatostatin receptor in vitro and vivo, labeled with^99mTc by tin reduction in acetate buffer, has been characterized by Reverse-phase High performance Liquid Chromatography. The effect of different solvents, mobile phase pH, linear gradient and the injected volume on the separation efficiency was evaluated. The results show that the separation efficiency is best using μBondapak-C₁₈ (300×3.9 mm²), linear gradient of 40% to 80% methanol (1.0 ml/min) in 0.05M acetate buffer (pH 5.5) over a 30 min period and maintaining for another 10 min. The labeled product is a mixture which mainly consists of five components (a, b, c, d, e) successfully proved by HPLC. Paper chromatography is also evaluated in this paper. It may be used to determine the radiochemical purity of the labeling product, but is not a good choice for the verification each components.     

Synthesis of radioiodinated 4-[*I]iodoantipyrine via isotopic exchange

Radioiodinated 4-[*I]iodoantipyrine labeled with radioiodine (i.e., ¹²³I or ¹²⁵I or ¹³¹I) has been used for modeling radiation damage on cell nuclei of tumor cells where the characteristic high linear energy transfer (high-LET) of the Auger electron could be demonstrated. Also, the compound is currently used for the measurement of regional cerebral blood flow (rCBF) in autoradiography. 4-[¹³¹I]iodoantipyrine was synthesized by two methods via a nucleophilic isotopic exchange reaction between ¹³¹I as iodide ion [¹³¹I^–] and inactive 4-[¹²⁷I]iodoantipyrine: either in absolute ethyl alcohol catalyzed by ammonium acetate or in dry state molten ammonium acetate (m.p. 114 °C) as an isotopic exchange medium without carrier addition. The first one is called wet method: where a solution of 4-iodoantipyrine and ammonium acetate in absolute ethyl alcohol and lyophilized Na¹³¹I was heated briefly up to boiling (80 to 90 °C) for 30 minutes under reflux. The second one is called dry state-molten method: where the alcoholic solution containing 4-iodoantipyrine and ammonium acetate and the lyophilized Na¹³¹I were heated briefly in a nitrogen stream to dryness at 120 to 125 °C for 5 minutes or melted by gradual heating at 150 to 160 °C for 5 minutes. A radiochemical yield ranged between 90%–95% in each method has been obtained for 4-[¹³¹I]iodoantipyrine. In both methods, the reaction proceeds properly without carrier addition by an addition – elimination mechanism. The physico-chemical parameters affecting the radiochemical yield of the isotopic exchange reaction [i.e., reaction time, temperature, exchange medium, concentration of the reactants, carrier (KI) addition and pH] were investigated. Chromatographic analysis i.e., TLC and HPLC were used to determine the radiochemical yield as well as the purity of the final product, which was as pure as 99.9%.