Production of123I and28Mg by high-energy nuclear reactions for applications in life sciences

The advantages of high energy cyclotrons as compared to small compact cyclotrons for the production of special radionuclides are outlined. The routine production of¹²³I (T=13.3 h) and²⁸Mg (T=21.1 h) by means of high energy nuclear reactions at the Jülich Isochronous Cyclotron is described. The reaction¹²⁷I(d,6n)^{123 123}I at 78 to 64 MeV is used for the production of¹²³I with thick target yields of 8 mCi/μAh and high radionuclidic purity. The practical experience in the application of this process, which is well suited for the production of Na¹²³I and for¹²³Xe-exposure labelling techniques, is reported.²⁸Mg is produced by the²⁷Al(α, 3p)²⁸Mg reaction at E_α=140 to 30 MeV with thick target yields of 40 μCi/μAh. The carrier-free²⁸Mg is separated from the matrix activities by coprecipitation and anion exchange with chemical yields of 80%.     

Preparation of isotopic antimony targets

Thin self-supporting ¹²³Sb targets were needed for studies using GAMMASPHERE investigating transverse wobbling in the highly-deformed triaxial nucleus ¹³⁵Pr. The experiment was carried out using the ¹²³Sb(¹⁶O,4n)¹³⁵Pr reaction with the 80 MeV ¹⁶O beam provided by the ATLAS accelerator facility. In particle–particle coincidence measurements ¹²¹Sb targets were irradiated with a 332 MeV ²⁸Si beam from ATLAS to measure evaporation residues and fission. The antimony targets were prepared self-supporting by the method of physical vapor deposition onto polished glass substrates or on various backing materials. Target thicknesses on the order of 500–1,000 μg/cm² were obtained and used for the experiments. Details of the target production and performance in beam will be discussed.     

Experiences in the routine production of123I via the124Te(p, 2n)123I reaction with a low energy cyclotron

This paper deals with the results and experimental observations obtained in routine production of¹²³I via¹²⁴Te(p, 2n)¹²³I reaction, using the low energy cyclotron (protons, E_max=22 MeV) at the German Cancer Research Center in Heidelberg. The reaction was studied during the past 4 years using¹²⁴TeO₂ targets with various levels of enrichment. The purpose of the study was to determine which target material provided the highest quality and most economical production of¹²³I. A viable routine production was defined as one in which¹²³I could be conveniently and reproducably prepared in reasonable purity while maintaining a low cost for the entire process. Different methods of sublimation of¹²³I activity from the¹²⁴TeO₂ target were examined to determine the optimal conditions for recovery of radioactivity and recycling of target material. A rapid method is described which permits quantitative separation of¹²³I while allowing only a negligible loss of¹²⁴TeO₂.     

Development of a process for routine production of123I using the127I(p, 5n)123Xe→123I reaction

The object of this paper is to give details of a production method for¹²³I, now in routine use at Harwell. We employ the (p, 5n) reaction, irradiating a liquid target of di-iodomethane (CH₂I₂) spiked with additional iodine, with 58 MeV protons. A yield of ∼9 mCi/μAh is obtained; the only detectable radionuclidic impurity is¹²⁵I, present to the extent of ∼0.15% by activity at the time of separation of Xe from I.     

Hippuran-123I: Preparation and quality control

A kit-like procedure is described for the labelling of Hippuran by exchange in a melt with carrier-free iodide-123 directly formed from the decay of¹²³Xe. Decay and subsequent melting for 15 min at 180°C are performed in one and the same ampoule. This results in a transfer of 95% of the¹²³I-activity into Hippuran with a residual¹²³I-content of <1.0%. Quality control is based on thin-layer chromatography. Contaminants are discussed and a comparison is made with commercial preparations of Hippuran-¹³¹I.     

A modified method for no carrier added radioiodination of L-tyrosine via chloramine-T as an oxidizing agent

A modified method for the preparation of L-[^131/123I] iodotyrosine as a brain imaging agent is described. The method is based on direct electrophilic radioiodination of L-tyrosine with NaI [^131/123I] using chloramine-T (CAT) and 0.001 g KI as a carrier at pH 7.0. The product was purified by reverse phase high performance liquid chromatography (HPLC). A high radiochemical yield up to 85% of L-[^131/123I] iodotyrosine has been achieved with radiochemical purity of greater than 97%. The relation between the pKa of L-tyrosine and pH of the reaction medium was calculated in order to correlate the radiochemical yield of L-[^131/123I] iodotyrosine and the state of the three ionizable groups of L-tyrosine. Also, the influence of the reaction conditions on the radiochemical yield of L-[^131/123I] iodotyrosine was investigated.     

Automated production of 64Cu prepared by 18?MeV cyclotron

⁶⁴Cu (T_1/2?=?12,7?h, ??^? 37,1?%, ??⁺ 17,9?%, EC 41?%) is a useful radioisotopes for positron emission tomography radiopharmaceutical. We used the reaction route ⁶⁴Ni(p,n)⁶⁴Cu for the ⁶⁴Cu preparation. A basic disadvantage of this route, a high price of the enriched target material, was eliminated by using very simple recycling procedure. Compact solid target irradiation system was installed at the end of the external beam line of the IBA Cyclone 18/9 cyclotron. In this paper, the irradiation of ⁶⁴Ni target and separation of ⁶⁴Cu from a target material is described. The separation was achieved by anion exchange chromatography with HCl as a elution solution. The distribution ratio for different HCl concentrations on Bio-Rad AG1-X8 and elution profile of ⁶⁴Cu were investigated. ⁶⁴Cu production rate for 100?mg ⁶⁴Ni of 99.09?% purity (ISOFLEX) on gold target was 104?MBq/??Ah. The activity of the product was checked by ionisation chamber (Curiementor), gamma spectrometry using a HPGe detector and liquid scintillation counting using the triple-to-double coincidence ratio method. The separation process of ⁶⁴Cu was made in a home-made separation module.     

Production of123I using the CV-28 cyclotron at IPEN-CNEN/SP

These studies had the purpose of establishing the optimal conditions for the production of¹²³I through the¹²⁴Te (p, 2n)¹²³I reaction, using the CV-28 Cyclotron (E_max=24 MeV for protons) at IPEN-CNEN/SP. Two different targets (TeO₂ and TeO₂+2% Al₂O₃) were irradiated in order to check their physical resistance against beam current (up to 12 A) and length of irradiation (10 min — 2h), and to evaluate the recovery of the radioiodine produced, by a dry distillation process with a high frequency induction furnace. Later on, enriched¹²⁴TeO₂ (96.2%) targets were irradiated, and¹²³I was produced routinely with a production yield of (3. 31±0.07) mCi/Ah, 1.7% of¹²⁴I at EOB and radiochemically pure.     

Anion-exchange and solvent extraction studies on the separation of radioiodine with particular reference to the production of 123I via proton irradiation of 123Te metal target

The separation of radioiodine was investigated using two wet chemical procedures, namely anion-exchange and solvent extraction. Some factors affecting the separation, such as HCl, NaOH and tetrabutyl ammonium bromide (TBAB) concentrations, used solvents ethyl acetate, benzene and carbon tetrachloride and different quaternary ammonium salts were studied. For each procedure the optimum conditions were deduced. The separation of ¹²³I was effected from proton-irradiated ¹²³Te target under the optimized conditions of the two procedures. The yield of ¹²³I obtained using the Dowex 21k anion-exchanger and tetrabutyl ammonium bromide solution as eluting agent was 88±3%; the radionuclidic purity was high and the time needed was 60 minutes. In solvent extraction process using TBAB in ethyl acetate as the extracting agent, the yield of ¹²³I was low (47±3%), the radionuclidic purity was not as good as in the anion-exchange method, and the time needed was 150 minutes. Therefore, the anionexchange method is preferable. A comparison of this wet chemical method of separation of ¹²³I with the commonly used dry distillation method is given. The wet method appears to be more suitable when a ¹²³Te metal target is used.     

Development of an ion-exchange method for separation of radioiodine from tellurium and antimony and its application to the production of 124I via the 121Sb(α,n)-process

A novel anion-exchange chromatographic method for separation of radioiodine from an antimony target irradiated with ³He- or α-particles was developed, with separation yield of radioiodine amounting to 90 ± 5 % and its decontamination factor from the Te and Sb radionuclides to ~10⁴. The optimized separation method developed was then applied to the production of ¹²⁴I via the ¹²¹Sb(α,n)¹²⁴I process using a highly enriched ¹²¹Sb target. Quality control tests showed that the separated ¹²⁴I occurred >99 % as iodide and the longer lived impurities ¹²⁶I and ¹²⁵I amounted to 0.16 % and <0.05 %, respectively. The trace level of inactive Sb impurity was determined by ICP–OES.     

Ga2O for target, solvent extraction for radiochemical separation and SnO2for the preparation of a68Ge/68Ga generator

Summary The target for the production of⁶⁸Geconsists of a disc of gallium suboxide, Ga₂O, with a 19 mm diameter. The suboxide was primarily prepared by repeatedly mixing metallic Ga and Ga₂O₃at 700 °C. The target (2.4 g) was quite stable under a long-time irradiation with a 34 MeV proton beam at a current of ~80<span lang=EN-ZA style='font-size:12.0pt; font-family:Symbol;mso-bidi-font-family:Symbol;mso-ansi-language:EN-ZA'>mA. The dissolution of the target was performed using 12M sulphuric acid solution, assisted with the dropwise addition of 30% H₂O₂solution, and took less than 4 hours. A solvent extraction method, using a 9M H₂SO₄-0.3M HCl/CCl₄system, was employed for the radiochemical separation of⁶⁸Ge from Ga and Zn radionuclides, while 0.05M HCl was used for the back extraction of⁶⁸Ge from the organic phase. The⁶⁸Ge obtained in the dilute HCl was directly loaded onto a column containing either a hydrous tin dioxide or a crystalline tin dioxide, obtained by calcinations of the hydrous oxide at 450, 700, and 900 °C. The calcinated hydrous tin dioxide at 900 °C showed the highest crystallinity and highest⁶⁸Ga elution yield and was selected for use in the generator. The⁶⁸Ga elution from the column generator packed with 2 g of tin dioxide, using 3 ml of 1M HCl, and yielded an average of 65%. The breakthrough of⁶⁸Ge was 6.1^. 10^-4%.     

Studies on the234U and238U ratio in natural materials

With the use of an 80 MeV isochronous cyclotron, a preparation procedure for¹²³I is outlined. The nuclear reaction applied in the process is: $$^{127} I\left( {p,5n} \right)^{123} Xe\xrightarrow[{2.1h}]{{\beta ^ + CE}}^{123} I$$ A liquid target is irradiated and a continuous gas-liquid extraction of parent¹²³Xe is performed. After a short growth time the daughter¹²³I is dissolved and treated for various applications. The radionuclidic purity is very high, only¹²⁵I is detectable with a maximum of 0.2% to the end of the preparation process. In this production of carrier-free¹²³Xe and¹²³I, the major chemical problem consists of a separation into microquantities. Attempts to find a solution to various technical problems are also described.     

Experiences in routine production of123I in Manitoba for delivery to other Canadian centres

An experience at¹²³I production with a low beam current cyclotron used in combination with the¹²⁴Te(p, 2n)¹²³I reaction on 90.8% enrichment¹²⁴Te is described.     

Pure iodine-123 production by small cyclotron for medical use

For improvement of radionuclidic purity of¹²³I a method was elaborated to obtain highly enriched [¹²³Te] tellurium. Using this new TeO₂ target the optimum irradiation conditions have been investigated for the production of¹²³I via¹²³Te (p,n)¹²³I and the radionuclide impurity levels were also determined.     

Excitation functions of proton induced nuclear reactions on natural tellurium up to 18 MeV for validation of isotopic cross sections

Summary Excitation functions of proton induced nuclear reactions on natural Te were investigated up to 18 MeV. Cross sections for production of ^{121,123,124,126,128,130g}I and ^121gTe were measured. The new experimental data were compared with the results of ALICE-IPPE model calculations and with data found in the literature and measured on natural or enriched Te targets. The new data can be effectively used for validation of recommended cross sections of medically relevant ¹²³I and ¹²⁴I.     

Radiochemistry,Production Processes,Labeling Methods,and ImmunoPET Imaging Pharmaceuticals of Iodine-124

Target-specific biomolecules, monoclonal antibodies (mAb), proteins, and protein fragments are known to have high specificity and affinity for receptors associated with tumors and other pathological conditions. However, the large biomolecules have relatively intermediate to long circulation half-lives (>day) and tumor localization times. Combining superior target specificity of mAbs and high sensitivity and resolution of the PET (Positron Emission Tomography) imaging technique has created a paradigm-shifting imaging modality, ImmunoPET. In addition to metallic PET radionuclides, ¹²⁴I is an attractive radionuclide for radiolabeling of mAbs as potential immunoPET imaging pharmaceuticals due to its physical properties (decay characteristics and half-life), easy and routine production by cyclotrons, and well-established methodologies for radioiodination. The objective of this report is to provide a comprehensive review of the physical properties of iodine and iodine radionuclides, production processes of ¹²⁴I, various ¹²⁴I-labeling methodologies for large biomolecules, mAbs, and the development of ¹²⁴I-labeled immunoPET imaging pharmaceuticals for various cancer targets in preclinical and clinical environments. A summary of several production processes, including ¹²³Te(d,n)¹²⁴I, ¹²⁴Te(d,2n)¹²⁴I, ¹²¹Sb(α,n)¹²⁴I, ¹²³Sb(α,3n)¹²⁴I, ¹²³Sb(³He,2n)¹²⁴I, ^natSb(α, xn)¹²⁴I, ^natSb(³He,n)¹²⁴I reactions, a detailed overview of the ¹²⁴Te(p,n)¹²⁴I reaction (including target selection, preparation, processing, and recovery of ¹²⁴I), and a fully automated process that can be scaled up for GMP (Good Manufacturing Practices) production of large quantities of ¹²⁴I is provided. Direct, using inorganic and organic oxidizing agents and enzyme catalysis, and indirect, using prosthetic groups, ¹²⁴I-labeling techniques have been discussed. Significant research has been conducted, in more than the last two decades, in the development of ¹²⁴I-labeled immunoPET imaging pharmaceuticals for target-specific cancer detection. Details of preclinical and clinical evaluations of the potential ¹²⁴I-labeled immunoPET imaging pharmaceuticals are described here.     

Development of [103Pd]-2-acetylpyridine 4 N-methyl thiosemicarbazone complex for targeted therapy

Summary Due to interesting biological properties of palladium-thiosemicarbazono complexes, production of a ¹⁰³Pd-labeled anti-cancer complex, i.e., [¹⁰³Pd]-2-acetylpyridine ⁴N-methylthiosemicarbazone ([¹⁰³Pd]-APMTS) was developed. Palladium-103 (T_1/2 = 16.96 d) produced via the ¹⁰³Rh(p,n)¹⁰³Pd nuclear reaction using natural rhodium target, was separated from the irradiated target material. Proton energy was 18 MeV with 200 mA irradiation for 15 hours (final activity 700 mCi of ¹⁰³Pd²⁺, RCY>95%, radionuclidic purity>99%). The final activity was eluted in form of Pd(NH₃)₂Cl₂ in order to react with 2-acetylpyridine-⁴N-methylthiosemicarbazone to yield [¹⁰³Pd]-APMTS. Chemical purity of the final product was confirmed to be within the accepted limits by polarography. [¹⁰³Pd]-APMTS was prepared with a radiochemical yield of more than 80% at room temperature after 3 hours. The labeling reaction was optimized for time, temperature and radioactivity and ligand ratio. A mixture of APMTS and Pd activity in ethanol was heated at 90 °C for 3 hours followed by reverse phase SPE purification using C₁₈ plus Sep-Pak. Radiochemical purity of more than 99% using RTLC and specific activity of about 12500 Ci/mol was obtained. The stability of the tracer was checked in the final product and the presence of human serum at 37 °C up to 3 hours. The partition coefficient of the final complex was determined by octanol : saline buffer distribution.     

A new81Rb−81mKr generator from enriched82Kr gas for medical use

Present work describes the construction and results of a new⁸¹Rb production target system using highly enriched⁸²Kr (99.95%) gas target material. The method yields a carrier-free product of highest activity and highest possible purity. It allows complete recovery of the expensive target material by freezing and avoids tedious chemical separation procedures. The remote-controlled target system has been constructed and functions extremely well.⁸¹Rb is used for the preparation of a new type of⁸¹Rb–^81mKr generator with a capacity of approximately 60 mCi for use in nuclear medical diagnostic (lung ventillation studies and angioscintigraphy).     

Iodine-123 production at a small cyclotron for medical use

An improved method has been developed to obtain highly enriched [¹²³Te] tellurium for the production of medically important¹²³I. Excitation function of the¹²³Te(p,n)¹²³I reaction, production yields and radionuclidic impurity levels were determined as a function of bombarding energy and target thickness.     

Production of high yield [13N] ammonia by proton irradiation from pressurized aqueous solutions

The method of direct production of large quantities of [¹³N]ammonia in the cyclotron water target for clinical cardiac studies by PET or synthetic uses was considered. Two main approaches based on the proton irradiation either of dilute aqueous ethanol solution under helium pressure or pure water pressurized by hydrogen were evaluated. Using ethanol as a target additive at the relatively low helium pressure of 400 KPa up to 22.2 GBq (600 mCi, EOB) of final product can be produced with radiochemical purity of more than 98%. Under comparable conditions the water target pressurized by hydrogen was about two times less effective for production of [¹³N]NH₃ because of the formation of considerable amounts of [¹³N]N₂. A possible mechanism of labelled nitrogen production was discussed.