Innovative Target for Production of Technetium-99m by Biomedical Cyclotron.

Technetium-99m (99mTc) is the most used radionuclide worldwide in nuclear medicine for diagnostic imaging procedures. 99mTc is typically extracted from portable generators containing 99Mo, which is produced normally in nuclear reactors as a fission product of highly enriched Uranium material. Due to unexpected outages or planned and unplanned reactor shutdown, significant 99mTc shortages appeared as a problem since 2008 The alternative cyclotron-based approach through the 100Mo(p,2n)99mTc reaction is considered one of the most promising routes for direct 99mTc production in order to mitigate potential 99Mo shortages. The design and manufacturing of appropriate cyclotron targets for the production of significant amounts of a radiopharmaceutical for medical use is a technological challenge. In this work, a novel solid target preparation method was developed, including sputter deposition of a dense, adherent, and non-oxidized Mo target material onto a complex backing plate. The latter included either chemically resistant sapphire or synthetic diamond brazed in vacuum conditions to copper. The target thermo-mechanical stability tests were performed under 15.6 MeV proton energy and different beam intensities, up to the maximum provided by the available GE Healthcare (Chicago, IL, USA) PET trace medical cyclotron. The targets resisted proton beam currents up to 60 µA (corresponding to a heat power density of about 1 kW/cm²) without damage or Mo deposited layer delamination. The chemical stability of the proposed backing materials was proven by gamma-spectroscopy analysis of the solution obtained after the standard dissolution procedure of irradiated targets in H2O2.

14 MeV Neutrons for 99Mo/99mTc Production: Experiments, Simulations and Perspectives.

BACKGROUND: the gamma-emitting radionuclide Technetium-99m (99mTc) is still the workhorse of Single Photon Emission Computed Tomography (SPECT) as it is used worldwide for the diagnosis of a variety of phatological conditions. 99mTc is obtained from 99Mo/99mTc generators as pertechnetate ion, which is the ubiquitous starting material for the preparation of 99mTc radiopharmaceuticals. 99Mo in such generators is currently produced in nuclear fission reactors as a by-product of 235U fission. Here we investigated an alternative route for the production of 99Mo by irradiating a natural metallic molybdenum powder using a 14-MeV accelerator-driven neutron source. METHODS: after irradiation, an efficient isolation and purification of the final 99mTc-pertechnetate was carried out by means of solvent extraction. Monte Carlo simulations allowed reliable predictions of 99Mo production rates for a newly designed 14-MeV neutron source (New Sorgentina Fusion Source). RESULTS: in traceable metrological conditions, a level of radionuclidic purity consistent with accepted pharmaceutical quality standards, was achieved. CONCLUSIONS: we showed that this source, featuring a nominal neutron emission rate of about 1015 s-1, may potentially supply an appreciable fraction of the current 99Mo global demand. This study highlights that a robust and viable solution, alternative to nuclear fission reactors, can be accomplished to secure the long-term supply of 99Mo.

Identification and Characterization of Human Proteoforms by Top-Down LC-21 Tesla FT-ICR Mass Spectrometry.

Successful high-throughput characterization of intact proteins from complex biological samples by mass spectrometry requires instrumentation capable of high mass resolving power, mass accuracy, sensitivity, and spectral acquisition rate. These limitations often necessitate the performance of hundreds of LC-MS/MS experiments to obtain reasonable coverage of the targeted proteome, which is still typically limited to molecular weights below 30 kDa. The National High Magnetic Field Laboratory (NHMFL) recently installed a 21 T FT-ICR mass spectrometer, which is part of the NHMFL FT-ICR User Facility and available to all qualified users. Here we demonstrate top-down LC-21 T FT-ICR MS/MS of intact proteins derived from human colorectal cancer cell lysate. We identified a combined total of 684 unique protein entries observed as 3238 unique proteoforms at a 1% false discovery rate, based on rapid, data-dependent acquisition of collision-induced and electron-transfer dissociation tandem mass spectra from just 40 LC-MS/MS experiments. Our identifications included 372 proteoforms with molecular weights over 30 kDa detected at isotopic resolution, which substantially extends the accessible mass range for high-throughput top-down LC-MS/MS.

Recent achievements in Tc-99m radiopharmaceutical direct production by medical cyclotrons.

99mTc is the most commonly used radionuclide in the field of diagnostic imaging, a noninvasive method intended to diagnose a disease, assess the disease state and monitor the effects of treatments. Annually, the use of 99mTc, covers about 85% of nuclear medicine applications. This isotope releases gamma rays at about the same wavelength as conventional X-ray diagnostic equipment, and owing to its short half-life (t½ = 6 h) is ideal for diagnostic nuclear imaging. A patient can be injected with a small amount of 99mTc and within 24 h almost 94% of the injected radionuclide would have decayed and left the body, limiting the patient's radiation exposure. 99mTc is usually supplied to hospitals through a 99Mo/99mTc radionuclide generator system where it is produced from the ß decay of the parent nuclide 99Mo (t½ = 66 h), which is produced in nuclear reactors via neutron fission. Recently, the interruption of the global supply chain of reactor-produced 99Mo, has forced the scientific community to investigate alternative production routes for 99mTc. One solution was to consider cyclotron-based methods as potential replacement of reactor-based technology and the nuclear reaction 100Mo(p,2n)99mTc emerged as the most worthwhile approach. This review reports some achievements about 99mTc produced by medical cyclotrons. In particular, the available technologies for target design, the most efficient extraction and separation procedure developed for the purification of 99mTc from the irradiated targets, the preparation of high purity 99mTc radiopharmaceuticals and the first clinical studies carried out with cyclotron produced 99mTc are described.

Photonic-band-gap traveling-wave gyrotron amplifier.

We report the experimental demonstration of a gyrotron traveling-wave-tube amplifier at 250 GHz that uses a photonic band gap (PBG) interaction circuit. The gyrotron amplifier achieved a peak small signal gain of 38 dB and 45 W output power at 247.7 GHz with an instantaneous -3 dB bandwidth of 0.4 GHz. The amplifier can be tuned for operation from 245-256 GHz. The widest instantaneous -3 dB bandwidth of 4.5 GHz centered at 253.25 GHz was observed with a gain of 24 dB. The PBG circuit provides stability from oscillations by supporting the propagation of transverse electric (TE) modes in a narrow range of frequencies, allowing for the confinement of the operating TE03-like mode while rejecting the excitation of oscillations at nearby frequencies. This experiment achieved the highest frequency of operation for a gyrotron amplifier; at present, there are no other amplifiers in this frequency range that are capable of producing either high gain or high output power. This result represents the highest gain observed above 94 GHz and the highest output power achieved above 140 GHz by any conventional-voltage vacuum electron device based amplifier.

Application of LiMgPO4 crystal for proton beam quality control in radiotherapy.

The radioluminescence (RL) emitted by LiMgPO4 detector under proton beam irradiation was investigated in real time at the radiotherapy facility in the Institute of Nuclear Physics Polish Academy of Sciences in Krakow. The facility uses protons accelerated by the AIC-144 isochronous cyclotron up to the energy of 60 MeV. The measurements of RL were carried out using a remote optical fiber device with a luminophore detector and photomultiplier located at opposite ends of the optical fiber. A thin slice of LiMgPO4 doped with Tm (1.2 mol%) crystal was exposed to the proton beam. The tested detector allowed for the measurement of proton beam current, flux fluence and determination of proton beam time structure parameters. The investigation of LiMgPO4 crystal showed its high sensitivity, fast reaction time to irradiation and possibility of application as the detector for control of proton beam parameters.

The production of [124I]iodine and [86Y]yttrium.

The use of paired tracers such as (124)I/(131)I and (86)Y/(90)Y allows pretherapy PET imaging with positron emitting radioisotopes of the same element as used for therapy. Whereas nowadays most therapy nuclides are produced by reactors or generators, the production of the corresponding PET isotopes requires the irradiation of adequate targets using particle accelerators such as cyclotrons. This paper describes the production routes for (124)I and (86)Y.

High-speed terahertz time-domain spectroscopy of cyclotron resonance in pulsed magnetic field.

We present time-resolved cyclotron resonance spectra of holes in p-Ge measured during single magnetic field pulses by using a rapid-scanning, fiber-coupled terahertz time-domain spectroscopy system. The key component of the system is a rotating monolithic delay line featuring four helicoid mirror surfaces. It allows measurements of THz spectra at up to 250 Hz repetition rate. Here we show results taken at 150 Hz. In a single 900 ms measurement 135 cyclotron resonance spectra were recorded that fully agree with what is expected from literature.

Mass spectral fragmentation analysis of triterpene saponins from Ardisia crenata Sims by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry.

We used the electrospray ionization (ESI) Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) technique to study the characteristic mass fragmentation patterns of eight triterpene saponins from Ardisia crenata Sims. Eight triterpene saponins were analyzed using parent mass list-triggered data-dependent multiple-stage accurate mass analysis at a resolving power of 100,000 in the external calibration mode. The chemical formula with unsaturation numbers was calculated from accurate m/z values of precursor, and product ions were obtained and used to assign the structures of eight triterpene saponins and two trace unknown compounds. The mass accuracies obtained for all full-scan MS and MS(n) spectra were within 7 ppm (< 5 ppm in most cases) in the ESI negative-ion mode. On FTICR-MS and FTICR-MS/MS, the eight triterpene saponins showed characteristic mass fragmentation patterns that facilitated the identification of their structural types, including the individual monosaccharide types, the monosaccharide numbers, and the sequences of the substituted saccharide groups. We proposed their fragmentation mechanisms. Based on their characteristic mass fragmentation patterns and fragmentation mechanisms, two unknown trace triterpene saponins were identified in the mixture.

Parallel Detection of Fundamental and Sixth Harmonic Signals Using an ICR Cell with Dipole and Sixth Harmonic Detectors.

Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) is a powerful instrument for high-resolution analysis of biomolecules. However, relatively long signal acquisition periods are needed to achieve mass spectra with high resolution. The use of multiple detector electrodes for detection of harmonic frequencies has been introduced as one approach to increase scan rate for a given resolving power or to obtain increased resolving power for a given detection period. The achieved resolving power and scan rate increase linearly with the order of detected harmonic signals. In recent years, ICR cell geometries have been investigated to increase the order of the harmonic frequencies and enhance harmonic signal intensities. In this study, we demonstrated PCB-based ICR cell designs with dipole and sixth harmonic detectors for parallel detection of fundamental and harmonic (6f) signals. The sixth harmonic signals from the sixth harmonic detector showed an expected 6 times higher resolving power with (M + 3H)3+ charge state insulin ions as compared with that from fundamental signals from the dipole detector. Moreover, the insulin isotopic peaks with sixth harmonic frequency signals acquired with the sixth harmonic detector were resolved for a 40 ms data acquisition period but unresolved with the same duration dipole detector signals, corresponding to a 6-fold improvement in achievable spectral acquisition rates for a given resolving power.

DNA DSB Repair Dynamics following Irradiation with Laser-Driven Protons at Ultra-High Dose Rates.

Protontherapy has emerged as more effective in the treatment of certain tumors than photon based therapies. However, significant capital and operational costs make protontherapy less accessible. This has stimulated interest in alternative proton delivery approaches, and in this context the use of laser-based technologies for the generation of ultra-high dose rate ion beams has been proposed as a prospective route. A better understanding of the radiobiological effects at ultra-high dose-rates is important for any future clinical adoption of this technology. In this study, we irradiated human skin fibroblasts-AG01522B cells with laser-accelerated protons at a dose rate of 109 Gy/s, generated using the Gemini laser system at the Rutherford Appleton Laboratory, UK. We studied DNA double strand break (DSB) repair kinetics using the p53 binding protein-1(53BP1) foci formation assay and observed a close similarity in the 53BP1 foci repair kinetics in the cells irradiated with 225 kVp X-rays and ultra- high dose rate protons for the initial time points. At the microdosimetric scale, foci per cell per track values showed a good correlation between the laser and cyclotron-accelerated protons indicating similarity in the DNA DSB induction and repair, independent of the time duration over which the dose was delivered.

Internal radiation dose assessment of radiopharmaceuticals prepared with cyclotron-produced 99m Tc.

PURPOSE: Technetium-99m (99m Tc) is the radioisotope most widely used in diagnostic nuclear medicine. It is readily available from 99 Mo/99m Tc generators as the ß- decay product of the 99 Mo (T½  = 66 h) parent nuclide. This latter is obtained as a fission product in nuclear reactors by neutron-induced reactions on highly enriched uranium. Alternative production routes, such as direct reactions using proton beams on specific target materials [100 Mo(p,2n)99m Tc], have the potential to be both reliable and relatively cost-effective. However, results showed that the 99m Tc extracted from proton-bombarded 100 Mo-enriched targets contains small quantities of several Tc radioisotopes (93m Tc, 93 Tc, 94 Tc, 94m Tc, 95 Tc, 95m Tc, 96 Tc, and 97m Tc). The aim of this work was to estimate the dose increase (DI) due to the contribution of Tc radioisotopes generated as impurities, after the intravenous injection of four radiopharmaceuticals prepared with cyclotron-produced 99m Tc (CP-99m Tc) using 99.05% 100 Mo-enriched metallic targets. METHODS: Four 99m Tc radiopharmaceuticals (pertechnetate, sestamibi (MIBI), hexamethylpropylene-amine oxime (HMPAO) and disodium etidronate (HEDP)) were considered in this study. The biokinetic models reported by the International Commission on Radiological Protection (ICRP) for each radiopharmaceutical were used to define the main source organs and to calculate the number of disintegrations per MBq that occurred in each source organ (Nsource ) for each Tc radioisotope present in the CP-99m Tc solution. Then, target organ equivalent doses and effective dose were calculated for each Tc radioisotope with the OLINDA/EXM software versions 1.1 and 2.0, using the calculated Nsource values and the adult male phantom as program inputs. Total effective dose produced by all Tc isotopes impurities present in the CP-99m Tc solution was calculated using the fraction of total activity corresponding to each radioisotope and compared with the effective dose delivered by the generator-produced 99m Tc. RESULTS: In all cases, the total effective DI of CP-99m Tc radiopharmaceuticals calculated with either versions of the OLINDA software was less than 10% from 6 up to 12 h after EOB. 94m Tc and 93m Tc are the Tc radioisotopes with the highest concentration in the CP-99m Tc solution at EOB. However, their contribution to DI 6 h after EOB is minimal, due to their short half-lives. The radioisotopes with the largest contribution to the effective DI are 96 Tc, followed by 95 Tc and 94 Tc. This is due to the types of their emissions and relatively long half-lives, although their concentration in the CP-99m Tc solution is five times lower than that of 94m Tc and 93m Tc at the EOB. CONCLUSIONS: The increase in the radiation dose caused by other Tc radioisotopes contained in CP-99m Tc produced as described here is quite low. Even though the concentrations of the 94 Tc and 95 Tc radioisotopes in the CP-99m Tc solution exceed the limits established by the European Pharmacopoeia, CP-99m Tc radiopharmaceuticals could be used in routine nuclear medicine diagnostic studies if administered from 6 to 12 h after the EOB, thus maintaining the effective DI within the 10% limit.

NEUTRON FLUX DISTRIBUTION IN THE RADIOISOTOPES TARGET ROOMS AND MAZE IN SYRIAN CYCLOTRON.

Gold activation foils were used in this work to measure thermal, epithermal and fast neutron fluxes in the 18F, 123I, (201Tl, 67Ga) production units in Syrian cyclotron. The neutron flux distribution around the targets were determined. It shows that, the maze thermalizes the fast neutrons and reduces the flux about four orders of magnitudes. The results can be adopted by medical centers to identify radioactive hot spots and develop radiation protection.

Rapid and automated production of [68Ga]gallium chloride and [68Ga]Ga-DOTA-TATE on a medical cyclotron.

INTRODUCTION: The demand for Gallium-68 (68Ga) for labelling PET radiopharmaceuticals has increased over the past few years. 68Ga is obtained through the decayed parent radionuclide 68Ge using commercial 68Ge/68Ga generators. The principal limitation of commercial 68Ge/68Ga generators is that only a limited and finite quantity of 68Ga (<1.85 GBq at start of synthesis) may be accessed. The focus of this study was to investigate the use of a low energy medical cyclotron for the production of greater quantities of 68Ga and to develop an automated and rapid procedure for processing the product. METHODS: Enriched ZnCl2 was electrodeposited on a platinum backing using a NH4Cl (pH 2-4) buffer. The Zn target was irradiated with GE PETtrace 880 at 35 µA and 14.5 and 12.0 MeV beam energy. The irradiated Zn target was purified using octanol resin on an automated system. RESULTS: Following the described procedure, 68Ga was obtained in 6.30 ±â€¯0.42 GBq after 8.5 min bombardment and with low radionuclidic impurities (66Ga (<0.005%) and 67Ga (<0.09%)). Purification on a single octanol resin gave 82% recovery with resulting [68Ga]GaCl3 obtained in 3.5 mL of 0.2 M HCl. [68Ga]GaCl3 production from irradiation to final product was <45 min. To highlight the utility of the automated procedure, [68Ga]Ga-DOTA-TATE labelling was incorporated to give 1.56 GBq at EOS of the labelled peptide with RCY of >70%. CONCLUSIONS: A straightforward procedure for producing 68Ga on a low energy medical cyclotron was described. Current efforts are focus on high activity production and radiolabelling using solid target produced 68Ga.

Cyclotron production of 68Ga in a liquid target: Effects of solution composition and irradiation parameters.

OBJECTIVES: To optimize 68Ga production using a liquid cyclotron target, investigations were performed to compare production yields using different concentrations of [68Zn]Zn(NO3)2, nitric acid, and irradiation parameters. METHODS: Different concentrations of [68Zn]Zn(NO3)2 (0.6 M, 1.2 M and 1.42 M) in varying normality of nitric acid (0.8-1.5 N) were prepared and irradiated with protons (incident energy ~14 MeV) using a BMLT-2 liquid target at different beam currents (30-50 µA) and irradiation times (30-60 min). The 68Ga production and saturation yields were calculated and compared. [68Ga]GaCl3 was isolated using in-house developed hydroxamate resin and optimized for routine application. Recycling of [68Zn]Zn(NO3)2 from the recovered target solution was also investigated. RESULTS: On increasing concentration of [68Zn]Zn(NO3)2 from 0.6 M to 1.2 M in 0.8 N nitric acid, decay corrected yield of 68Ga at EOB was found to be 1.64 GBq (44.4 mCi) and 3.37 GBq (91.0 mCi), respectively at 30 µA beam current, indicating production yield was proportional to zinc nitrate concentration for a 30 min irradiation. However, when beam current was increased to 40 µA while maintaining nitric acid concentration at 0.8 N, the proportional relationship of 68Zn-concentration with 68Ga production yield was lost [0.6 M, 2.29 GBq (61.9 mCi); 1.2 M, 3.6 GBq (97.3 mCi)] for a 30 min irradiation. In fact, the effect was more profound for 60 min irradiations [0.6 M, 2.96 GBq (80.0 mCi); 1.2 M, 4.25 GBq (115 mCi)]. Increasing nitric acid concentration to 1.25-1.5 N improved 68Ga production yield for 40 µA, 60-min irradiations (1.2 M; 5.17 GBq (140 mCi)). MP-AES analysis showed metal impurities as <0.20 µg Ga (n = 3), <0.93 µg Zn (n = 3) and < 2.7 µg Fe (n = 3). Based on above finding, 1.42 M [68Zn]Zn(NO3)2 in 1.2 N-HNO3 solutions were also studied to achieve highest production yields of 9.85 ±â€¯2.09 GBq (266 ±â€¯57 mCi) for 60 min irradiation at 40 µA beam current. After recycling,> 99% pure recycled [68Zn]zinc nitrate was obtained in 82.6 ±â€¯13.6% yield. CONCLUSIONS: 68Ga production yields were dependent on all four variables: concentrations of [68Zn]Zn(NO3)2 and nitric acid, beam current and duration of irradiation. Of note, increasing beam current and irradiation time may require increased concentrations of nitric acid to achieve expected increments in 68Ga production yield.

A nanocarbon film electrode as a platform for exploring DNA methylation.

We describe the quantitative nonlabel electrochemical detection of both cytosine (C) and methylcytosine (mC) in oligonucleotides using newly developed nanocarbon film electrodes. The film consists of nanocrystalline sp2 and sp3 mixed bonds formed by employing the electron cyclotron resonance (ECR) sputtering method. We successfully used this film to develop a simple electrochemical DNA methylation analysis technique based on the measurement of the differences between the oxidation currents of C and mC since our ECR nanocarbon film electrode can directly measure all DNA bases more quantitatively than conventional glassy carbon or boron-doped diamond electrodes. The excellent properties of ECR nanocarbon film electrodes result from the fact that they have a wide potential window while maintaining the high electrode activity needed to oxidize oligonucleotides electrochemically. Proof-of-concept experiments were performed with synthetic oligonucleotides including different numbers of C and mC. This film allowed us to perform both C- and mC-positive assays solely by using the electrochemical oxidation of oligonucleotides without bisulfite or labeling processes.

Radiobiological characterization of proton beam at the National Cancer Center in Korea.

Estimation of the relative biological effectiveness (RBE) of the proton beam at the National Cancer Center Proton Therapy Center in Korea (NCCPTC) is required clinically for the treatment of cancer. The proton beam was fixed at 190 MeV with 6 cm a spread out Bragg peaks (SOBP) for which corresponds to most frequent clinical condition. The RBE was estimated from the survival of human salivary gland (HSG) cells using the traditional colonogenic and MTT assays. The HSG cells were also irradiated in a cell-stack chamber and monitored for survival to identify whether the characteristic depth-dependent survival pattern was observed. The RBE of the NCCPTC was estimated to be 1.024 +/- 0.007 and 1.049 +/- 0.028 at the middle of SOBP using colonogenic and MTT assays, respectively. Further analysis of the biological response of proton exposure revealed no difference compared to conventional X-ray treatment in western blot, and FACS analysis. The proton beam of the NCCPTC also exhibited the characteristic depth-dependent survival pattern. The estimated RBE value of NCCPTC was slightly smaller than generic RBE value of 1.1 for protons of the majority of centers. Due to the recommendation of a generic RBE of 1.1 for protons, a representative RBE value of 1.1 was assigned for clinical application for proton beams at the NCCPTC.

Heavy-ion microbeam system at JAEA-Takasaki for microbeam biology.

Research concerning cellular responses to low dose irradiation, radiation-induced bystander effects, and the biological track structure of charged particles has recently received particular attention in the field of radiation biology. Target irradiation employing a microbeam represents a useful means of advancing this research by obviating some of the disadvantages associated with the conventional irradiation strategies. The heavy-ion microbeam system at JAEA-Takasaki, which was planned in 1987 and started in the early 1990's, can provide target irradiation of heavy charged particles to biological material at atmospheric pressure using a minimum beam size 5 mum in diameter. A variety of biological material has been irradiated using this microbeam system including cultured mammalian and higher plant cells, isolated fibers of mouse skeletal muscle, silkworm (Bombyx mori) embryos and larvae, Arabidopsis thaliana roots, and the nematode Caenorhabditis elegans. The system can be applied to the investigation of mechanisms within biological organisms not only in the context of radiation biology, but also in the fields of general biology such as physiology, developmental biology and neurobiology, and should help to establish and contribute to the field of "microbeam biology".

Electron cyclotron resonance ion source experience at the Heidelberg Ion Beam Therapy Center.

Radiotherapy with heavy ions is an upcoming cancer treatment method with to date unparalleled precision. It associates higher control rates particularly for radiation resistant tumor species with reduced adverse effects compared to conventional photon therapy. The accelerator beam lines and structures of the Heidelberg Ion Beam Therapy Center (HIT) have been designed under the leadership of GSI, Darmstadt with contributions of the IAP Frankfurt. Currently, the accelerator is under commissioning, while the injector linac has been completed. When the patient treatment begins in 2008, HIT will be the first medical heavy ion accelerator in Europe. This presentation will provide an overview about the project, with special attention given to the 14.5 GHz electron cyclotron resonance (ECR) ion sources in operation with carbon, hydrogen, helium, and oxygen, and the experience of one year of continuous operation. It also displays examples for beam emittances, measured in the low energy beam transport. In addition to the outlook of further developments at the ECR ion sources for a continuously stable operation, this paper focuses on some of the technical processings of the past year.