Production of Cu using natural cobalt target and its separation using ascorbic acid and common anion exchange resin

⁶¹Cu was produced by ^natCo(α, xn)⁶¹Cu reaction. ⁶¹Cu production yield was 89.5 MBq/μAh (2.42 mCi/μAh) at the end of irradiation (EOI). A simple radiochemical separation method using anion exchange resin and ascorbic acid has been employed to separate the product radionuclide from inactive target material and co-produced non-isotopic impurities. The radiochemical separation yield was about 90%. Radiochemical purity of ⁶¹Cu was >99% 1 h after EOI. Final product was suitable for making complex with N₂S₂ type of ligands.     

A new, simple, high-yield synthesis of "no-carrier-added" 11C-labelled DMO

This paper describes a fast (20 min), convenient, and high yield synthesis of "no-carrier-added" 11C-labelled 5,5-dimethyloxazoladine-2,4-dione (DMO). During the synthesis [11C]phosgene is reacted in situ with 2-hydroxy-2-methylpropionamide in the presence of KOH for 20 min in a -5 degrees C bath and then for 5 min at room temperature. Filtration through a reverse-phase (C18) Sep-Pack column purifies the final product. This synthesis yields about 40 mCi of 11C-labelled DMO (radiochemical yield 40-60%) with a chemical purity exceeding 98% and a radiochemical purity exceeding 99%. The specific activity at the end of the synthesis is 80 Ci/mmol.     

Synthesis of 1-[c]methylpiperidin-4-yl propionate ([c]pmp) for in vivo measurements of acetylcholinesterase activity

Synthesis of 1-[¹¹C]methylpiperidin-4-yl propionate ([¹¹C]PMP), an in vivo substrate for acetylcholinesterase, is reported. An improved preparation of 4-piperidinyl propionate (PHP), the immediate precursor for radiolabeling, was accomplished in three steps from 4-hydroxypiperidine by (a) protection of the amine as the benzyl carbamate, (b) acylation with propionyl chloride, and (c) deprotection of the carbamate by catalytic hydrogenation. The final product was obtained in an overall 82% yield. Reaction of the free base form of PHP with [¹¹C]methyl trifluoromethanesulfonate at room temperature in N,N-dimethylformamide, followed by high performance liquid chromatography (HPLC) purification, provided [¹¹C]PMP in 57% radiochemical yield, >99% radiochemical purity, and >1500 Ci/mmol at the end of synthesis. The total synthesis time from end-of-bombardment was 35 min. [¹¹C]PMP can thus be reliably prepared for routine clinical studies of acetylcholinesterase in human brain using positron emission tomography.     

Direct electrophilic iodination of 2-thiouracil using iodo-gen™

5-Iodo-2-thiouracil (ITU) is of interest due to its ability to bind specifically to the pigment melanin during melanogenesis and is of potential value in the diagnosis and treatment of malignant melanoma. Radioiodinated ITU was prepared directly from 2-thiouracil in a two-phase reaction using Iodo-Gen™ in 0.05 M phosphate buffer pH 7.0. The identity radiochemical purity and stability of the product were checked by reversed-phase high pressure liquid chromatography (HPLC). ITU labeled with ¹²³I, ¹²⁵I or ¹³¹I has been produced in millicurie amounts and isolated on a semi-preparative reversed-phase HPLC column. Production time was 2–3 h, overall radiochemical yields averaged 80%; the radiochemical purity was greater than 98%. Specific activities on the order of 20 Ci/mmol have been obtained.     

NCA 16α-[18F]fluoroestradiol-17β: The effect of reaction vessel on fluorine-18 resolubilization,product yield,and effective specific activity

Although the reported synthesis of the title compound resulted in a high radiochemical yield (43% based on resolubilized ¹⁸F), the effective specific activity at EOS was low (166 Ci/mmol). Reduction in the amount of carrier fluoride in the target water improved the effective specific activity of the product, but with a concommitant decrease in the resolubilized yield of the fluoroestradiol (12.7%). A re-examination of the labeling parameters was performed to determine the conditions that would increase the yield of the fluoroestrogen and maintain a high effective activity for the product. Since the amount of resolubilized ¹⁸F in THF is important in obtaining high specific activity compounds in this type of synthesis, several types of vessels were investigated to determine their effect on the evaporation of the [¹⁸O]H₂O target water and subsequent resolubilization of ¹⁸F into THF. Of these vessels (Pt crucible, borosilicate glass, siliconized borosilicate glass, Vacutainer^R), the Vacutainer afforded the highest resolubilization of ¹⁸F into THF (90%), resulting in an improved resolubilized yield for the fluoroestradiol (28%) and an increased effective specific activity at EOS for the product (1600–3939 Ci/mmol).     

Carbon-11 choline: synthesis, purification, and brain uptake inhibition by 2-dimethylaminoethanol

We report an improved method for the synthesis and purification of [11C]methylcholine from the precursors [11C]methyliodide and 2-dimethylaminoethanol (deanol). Preparation time, including purification, is 35 min postbombardment. Forty millicuries of purified injectable [11C]choline were produced with a measured specific activity of greater than 300 Ci/mmol and a radiochemical purity greater than 98%. The decay corrected radiochemical yield for the synthesis and purification was approximately 50%. Residual precursor deanol, which inhibits brain uptake of choline, is removed by a rapid preparative high performance liquid chromatography (HPLC) method using a reverse phase cyano column with a biologically compatible 100% water eluent. Evaporation alone did not completely remove the deanol precursor. Brain uptake of the [11C]choline product was six times greater after HPLC removal of deanol because doses of less than 1 microgram/kg significantly inhibit [14C]choline brain uptake.     

Synthesis procedure for routine production of [carbonyl-11C]desmethyl-WAY-100635.

An improved one-pot synthesis procedure for routine production of [carbonyl-(11)C]desmethyl-WAY-100635 ([(11)C]DWAY) is described. An efficient purification of the crude product has also been developed and was accomplished by C-18 reversed-phase semi-preparative HPLC using 55/45 EtOH-NaH(2)PO(4) buffer (20 mM, pH=6.5) as the eluent. The desired product fraction was collected in a 2.0-2.5 mL volume and formulated with 11 mL of 0.9% saline. The radioligand was ready for human use in 45 min (EOB). The product was obtained with a radiochemical yield of 11.1+/-1.8% (EOB, n=15) with a radiochemical purity of >99%. Specific activity was 133.2-185.0 GBq/micromol (3.6-5.0 Ci/micromol, EOS, n=2) when ca. 37.0 GBq (ca. 1.0 Ci) of starting [(11)C]CO(2) was used. Unlabeled mass of [(11)C]DWAY was found to be 0.15-0.24 microg/mL and the precursor was present in less than 50 ng/mL in final production solution.     

Excitation functions of proton induced reactions on cobalt: Production of no-carrier added nickel-57, a positron emitting label for doxorubicin

Excitation functions were measured, by the stacked-foil technique, for the ⁵⁹Co(p, 3n)⁵⁷Ni and ⁵⁹Co(p, 4n)⁵⁶Ni nuclear reactions from threshold up to 60 MeV. The excitation function for the ⁵⁹Co(p, 3n)⁵⁷Ni reaction shows a maximum cross section of 13.8±1.5 mb at 38 MeV. The optimum energy range for production of ⁵⁷Ni was found to be 41 → 26 MeV resulting in an experimental thick target yield of 19.3 MBq/μAh) (522 μCi/μAh). The level of the ⁵⁶Ni impurity is only 0.21% at EOB giving a ⁵⁷Ni product of 99.7% radionuclide purity at the time of use (24 h post EOB). Cross section data for the production of ⁵⁶Ni, ⁵⁶Co, ⁵⁷Co, ⁵⁸Co, ⁵²Mn, ⁵⁴Mn and ⁵¹Cr are also presented. A radiochemical procedure, based on cation-exchange chromatography, for the separation of radionickel from an activated cobalt target and other radiochemical and chemical impurities, has been developed. The ⁵⁷Ni activity was eluted, using 2 M HCl from a Dowex-50W × 8(H⁺) column, in a 95% radiochemical yield (15 mL). The ⁵⁷Ni has been used to label the anti-cancer drug, doxorubicin, thereby providing the means for pharmacokinetic and pharmacodynamic studies of this compound using positron emission tomography. The labelling has been optimized to give a radiochemical yield of >94%.     

Syntheses and specific activity determinations of no-carrier-added (NCA) F-18-labeled butyrophenone neuroleptics--benperidol, haloperidol, spiroperidol, and pipamperone

A general method for the syntheses of no-carrier-added (NCA) 18F-labeled butyrophenone neuroleptics--benperidol, haloperidol, spiroperidol, and pipamperone is described. These 18F-labeled neuroleptic drugs are synthesized by a multistep synthesis in an overall radiochemical yield of 10-20% at end of bombardment (EOB) in a synthesis time of 90 min from EOB. The sequence involves the synthesis of NCA p-[18F]fluorobenzonitrile from NCA [18F]-fluoride and p-nitrobenzonitrile using the rapidly converted to gamma-chloro-p-[18F]fluorobutyrophenone which is alkylated with appropriate amines to give NCA 18F-labeled benperidol, haloperidol, spiroperidol, and pipamperone. The final product is purified by preparative high performance liquid chromatography (HPLC). The 18F solution used in the synthesis as determined by ion chromatography contains 15.3 +/- 9.0 nmol of stable fluoride. The specific activities of the resulting butyrophenone neuroleptics were determined to be 3 Ci/mumol (at EOB) (range 1-6 Ci/mumol) as determined by radioreceptor assay and HPLC assay.     

Evaluation of radioiodination of meta-iodobenzylguanidine (MIBG) catalysed by in situ generated Cu(I) and directly added Cu(II)

A reliable method of labelling MIBG with ¹³¹I is reported. Radioiodination involved nucleophilic exchange reaction (160°C, 30 min) catalysed by directly added Cu(II) or by Cu(I) generated in situ by addition of Na₂S₂O₅ to CuSO₄. An additional step of purification of the radiolabelled MIBG by anion exchange chromatography is recommended. The radiochemical (RC) yield was over 90%, while the typical RC purity of ¹³¹I-MIBG was not less than 98%. Higher labelling yield was achieved with Cu(I) than when using Cu(II), and with ¹²⁵I (commercial product) than with ¹³¹I obtained by wet radiochemical processing method in-house. The purity and stability of MIBG-¹³¹I was confirmed by biodistribution studies in monkeys with 0.03% and 0.8% uptake in adrenals and myocardium, respectively. It is concluded that Cu(I) or Cu(II) catalysed radioiodination method is well suited for production of MIBG-¹³¹I.     

High purity production and potential applications of copper-60 and copper-61.

Previously we described the high yield production of 64Cu using a target system designed specifically for low energy, biomedical cyclotrons. In this study, the use of this target system for the production of 60Cu and 61Cu is described and the utility of these isotopes in the labeling of biomolecules for tumor and hypoxia imaging is demonstrated. 60Cu and 61Cu were produced by the 60Ni(p,n)60Cu, 61Ni(p,n)61Cu, and 60Ni(d,n)61Cu nuclear reactions. The nickel target (>99% enriched or natural nickel) was plated onto a gold disk as described previously (54-225 microm thickness) and irradiated (14.7 MeV proton beam and 8.1 MeV deuteron beam). The copper isotopes were separated from the nickel via ion exchange chromatography and the radioisotopic purity was assessed by gamma spectroscopy. Yields of up to 865 mCi of 60Cu have been achieved using enriched 60Ni. 61Cu has been produced with a maximum yield of 144 mCi using enriched 61Ni and 72 mCi using enriched 60Ni. Specific activities (using enriched material) ranged from 80 to 300 mCi/microg Cu for 60Cu and from 20 to 81 mCi/microg Cu for 61Cu. Bombardments of natural Ni targets were performed using both protons and deuterons. Yields and radioisotopic impurities were determined and compared with that for enriched materials. 60Cu was used to radiolabel diacetyl-bis(N4-methylthiosemicarbazone), ATSM. 60Cu-ATSM was injected into rats that had an occluded left anterior descending coronary artery. Uptake of 60Cu-ATSM in the hypoxic region of the heart was visualized clearly using autoradiography. In addition, 60Cu-ATSM was injected into dogs and excellent images of the heart and heart walls were obtained using positron emission tomography (PET). 61Cu was labeled to 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid-octreotide (TETA-octreotide) and the PET images of tumor-bearing rats were obtained up to 2 h postinjection. After decay of the 61Cu, the same rat was injected with 64Cu-TETA-octreotide and the images were compared. The tumor images obtained using 61Cu were found to be superior to those using 64Cu as predicted based on the larger abundance of positrons emitted by 61Cu vs. 64Cu.     

Computer-controlled large scale production of high specific activity [11C]RO 15-1788 for PET studies of benzodiazepine receptors

Ethyl 8-fluoro-5,6-dihydro-5-[11C]methyl-6-oxo-4H-imidazo [1,5-a] [1,4]benzodiazepine-3-carboxylate ([11C]RO 15-1788) has been prepared automatically with high specific activity for in vivo visualization or quantitative analysis of brain benzodiazepine receptors. The yield, radiochemical yield, radiochemical purity and specific activity of the product ready for an i.v. injection were 276 +/- 76 mCi, 50.8 +/- 7.8%, 99.3 +/- 0.3% and 2.9 +/- 0.5 Ci/mumol, respectively, taking an average of the latest 3 runs. The time required was about 25 min. Each product was sufficient to carry out three successive clinical studies by positron emission tomography (PET). All the procedures other than evaporation and filtration at the final stage were carried out with specially designed equipment connected to a central control system for radioisotope production.     

Synthesis of a [C]Methoxy derivative of α-Dihydrotetrabenazine: a radioligand for studying the vesicular monoamine transporter

The synthesis of [¹¹C]TBZOMe, a [¹¹C]methoxy derivative at the 2-hydroxy position of α-dihydrotetrabenazine, was carried out by an O-[¹¹C]methylation reaction. The product [¹¹C]TBZOMe (100–200 mCi) was obtained in 15–40% radiochemical yield (corrected for decay) within 37 min, and in high specific activity (2000–2500 Ci/mmol) and radiochemical purity (>97%). [¹¹C]TBZOMe is a potential new radioligand for studying the vesicular monoamine transporter using positron emission tomography.     

Synthesis of "no-carrier-added" alpha-[11C]methyl-L-tryptophan

Described here is a synthesis of "no-carrier-added" alpha-[11C]methyl-L-tryptophan based on alkylation with 11CH3I of an anion generated by reacting the Schiff base of L-tryptophan methyl ester with di-isopropylamine. The synthesis requires approximately 30 min after the end of 11CO2 collection and gives alpha-[11C]methyl-L-tryptophan in a 20-25% radiochemical yield calculated at the end of the synthesis and without correction for radioactive decay. The specific activity of the final radiopharmaceutical, measured at the end of the synthesis, was around 2,000 Ci/mmol. Data confirming the stereospecificity of the synthesis are also presented.     

Radioiodination via isotope exchange in pivalic acid

A variety of benzoic and aryl aliphatic mono and polyiodinated acids and esters (sterol, triglyceride) were radioiodinated in 55–99% radiochemical yield by isotope exchange with Na ¹²⁵I in a melt of pivalic acid. In general, the reaction was complete in 1 h at 155°C with little or no substrate decompostion. High specific activity studies afforded ¹²⁵I-labeled iopanoic acid with a specific activity of over 700 Ci/mmol.     

An improved one-pot procedure for the preparation of [11C-carbonyl]-WAY100635

A simple one-pot procedure for the preparation of [11C-carbonyl]-WAY100635, a potent 5HT1A receptor antagonist, was developed. The procedure involves the trapping of 11CO2 in a tetrahydrofuran (THF) solution of cyclohexylmagnesium chloride, elimination of excess Grignard reagents with anhydrous HCl, reaction with SOCl2, and the reaction of the resulting acid chloride with WAY100634 (2 mg) and triethylamine (20 microL) in THF. The total synthesis time is 45 min. Starting from 1326 +/- 173 mCi of 11CO2, the average amount of [11C-carbonyl]-WAY100635 (n = 40) at end-of-synthesis (EOS) was 30 +/- 13 mCi (2.3% radiochemical yield), or 148 +/- 61 mCi (11%) at end-of-bombardment (EOB). The radiochemical purity was >99%, and the specific activity was 3.6 +/- 1.9 Ci/micromol (EOS, n = 40), or 21.3 +/- 9.8 Ci/micromol at EOB. This method is reliable and flexible for routine clinical studies.     

Recovery of 131I from alkaline solution of n-irradiated tellurium target using a tiny Dowex-1 column

A simple and inexpensive ion-exchange chromatography method for the separation of medically useful no-carrier-added (nca) iodine radionuclides from bulk amounts of irradiated tellurium dioxide (TeO₂) target was developed and tested using ¹³¹I. The radiochemical separation was performed using a very small Dowex-1×8 ion-exchange column. The overall radiochemical yield for the complete separation of ¹³¹I was 92±1.8 (standard deviation) % (n=8). The separated nca ¹³¹I was of high, ～99%, radionuclidic and radiochemical purity and did not contain detectable amounts of the target material. This method may be adopted for the radiochemical separation of other different iodine radionuclides produced from tellurium matrices through cyclotron as well as reactor irradiation.     

Simultaneous production of high specific activity 64Cu and 61Co with 11.4 MeV protons on enriched 64Ni nuclei

The ⁶⁴Cu and ⁶¹Co radionuclides were produced simultaneously by irradiation of enriched ⁶⁴Ni on a low energy proton-only cyclotron. Nickel targets were prepared by electrodeposition of enriched ⁶⁴Ni (>95%) on Au backing at thicknesses of 25–225 mg/cm² with efficiencies >99%. Irradiations up to 30 μA for 8 h were performed with 11.4 MeV protons using a water-cooled target mounting. Radiochemical separation of ⁶⁴Cu and ⁶¹Co from ⁶⁴Ni was performed by chromatography of the chlorocomplexes in a single step using an anion exchange resin column with a yield >95%. Using this method, the Ni target material was recovered and re-plated for subsequent production runs with an overall efficiency >96%. The excitation function for the ⁶⁴Ni(p,n)⁶⁴Cu reaction was measured and compared with published values. Experimental thick target saturation yields of 159 mCi/μA for ⁶⁴Cu and 715 μCi/μA for ⁶¹Co were achieved. Typical specific activities of ⁶⁴Cu were found to be 18.8±3.3 Ci/μmol.     

Automated synthesis of 11beta-methoxy-4,16alpha-[16alpha-(18)F]difluoroestradiol (4F-M[(18)F]FES) for estrogen receptor imaging by positron emission tomography

Addition of both a 4-fluoro and 11beta-methoxy group onto 16alpha-[(18)F]fluoroestradiol ([(18)F]FES) yields 11beta-methoxy-4,16alpha-[16alpha-(18)F]difluoroestradiol (4F-M[(18)F]FES) with potential improved properties for positron emission tomography (PET) imaging of estrogen receptor densities in breast cancer patients. In order to provide 4F-M[(18)F]FES as a radiopharmaceutical for clinical trials, we developed an automated synthesis procedure using 3-O-methoxymethyl-11beta-methoxy-4-fluoro-16,17-O-sulfuryl-16-epiestriol as precursor. The radio synthesis involves stereoselective opening of the protected cyclic sulfone precursor via nucleophilic fluorination with [(18)F]fluoride in acetonitrile. After removal of the protecting ether and 17beta-sulphate groups by rapid hydrolysis in acidic ethanol and subsequent reversed-phase HPLC purification, the pure 4F-M[(18)F]FES was obtained as a sterile physiological saline solution in 45-50% radiochemical yield (decay corrected). The radiochemical purity of the final product was >98% and the effective specific activity (ESA) of 4F-M[(18)F]FES prepared under optimized conditions was >15,000 Ci/mmol. The total preparation time was 110+/-5 min and the product was shown to be stable for at least 6 h.     

Automatic synthesis of 16 alpha-[(18)F]fluoro-17beta-estradiol using a cassette-type [(18)F]fluorodeoxyglucose synthesizer

16 alpha-[(18)F]fluoro-17beta-estradiol ([(18)F]FES) is a radiotracer for imaging estrogen receptors by positron emission tomography. We developed a clinically applicable automatic preparation system for [(18)F]FES by modifying a cassette-type [(18)F]fluorodeoxyglucose synthesizer. Two milligrams of 3-O-methoxymethyl-16,17-O-sulfuryl-16-epiestriol in acetonitrile was heated at 105 degrees C for 10 min with dried [(18)F]fluoride. The resultant solution was evaporated and hydrolyzed with 0.2 N HCl in 90% acetonitrile/water at 95 degrees C for 10 min under pressurized condition. The neutralization was carried out with 2.8% NaHCO(3), and then the high-performance liquid chromatography (HPLC) purification was performed. The desired radioactive fraction was collected and the solvent was replaced by 10 ml of saline, and then passed through a 0.22-microm filter into a pyrogen-free vial as the final product. The HPLC purification data demonstrated that [(18)F]FES was synthesized with a yield of 76.4+/-1.9% (n=5). The yield as the final product for clinical use was 42.4+/-3.2% (n=5, decay corrected). The total preparation time was 88.2+/-6.4 min, including the HPLC purification and the solvent replacement process. The radiochemical purity of the final product was >99%, and the specific activity was more than 111 GBq/micromol. The final product was stable for more than 6 h in saline containing sodium ascorbate. This new preparation system enables us to produce [(18)F]FES safe for clinical use with high and reproducible yield.