Promises of cyclotron-produced 44Sc as a diagnostic match for trivalent β--emitters: in vitro and in vivo study of a 44Sc-DOTA-folate conjugate

In recent years, implementation of 68Ga-radiometalated peptides for PET imaging of cancer has attracted the attention of clinicians. Herein, we propose the use of 44Sc (half-life = 3.97 h, average β+ energy [Eβ+av] = 632 keV) as a valuable alternative to 68Ga (half-life = 68 min, Eβ+av = 830 keV) for imaging and dosimetry before 177Lu-based radionuclide therapy. The aim of the study was the preclinical evaluation of a folate conjugate labeled with cyclotron-produced 44Sc and its in vitro and in vivo comparison with the 177Lu-labeled pendant. Methods: 44Sc was produced via the 44Ca(p,n)44Sc nuclear reaction at a cyclotron (17.6 ± 1.8 MeV, 50 μA, 30 min) using an enriched 44Ca target (10 mg 44CaCO3, 97.00%). Separation from the target material was performed by a semiautomated process using extraction chromatography and cation exchange chromatography. Radiolabeling of a DOTA-folate conjugate (cm09) was performed at 95°C within 10 min. The stability of 44Sc-cm09 was tested in human plasma. 44Sc-cm09 was investigated in vitro using folate receptor–positive KB tumor cells and in vivo by PET/CT imaging of tumor-bearing mice Results: Under the given irradiation conditions, 44Sc was obtained in a maximum yield of 350 MBq at high radionuclide purity (>99%). Semiautomated isolation of 44Sc from 44Ca targets allowed formulation of up to 300 MBq of 44Sc in a volume of 200–400 μL of ammonium acetate/HCl solution (1 M, pH 3.5–4.0) within 10 min. Radiolabeling of cm09 was achieved with a radiochemical yield of greater than 96% at a specific activity of 5.2 MBq/nmol. In vitro, 44Sc-cm09 was stable in human plasma over the whole time of investigation and showed folate receptor–specific binding to KB tumor cells. PET/CT images of mice injected with 44Sc-cm09 allowed excellent visualization of tumor xenografts. Comparison of cm09 labeled with 44Sc and 177Lu revealed almost identical pharmacokinetics. Conclusion: This study presents a high-yield production and efficient separation method of 44Sc at a quality suitable for radiolabeling of DOTA-functionalized biomolecules. An in vivo proof-of-concept study using a DOTA-folate conjugate demonstrated the excellent features of 44Sc for PET imaging. Thus, 44Sc is a valid alternative to 68Ga for imaging and dosimetry before 177Lu-radionuclide tumor therapy.

The cyclotron production and nuclear imaging of bromine-77

In this investigation, bromine-77 was produced with a medical cyclotron and imaged with gamma cameras. Br-77 emits a 240 kev photon with a half life of 56 hours. The C-Br bond is stronger than the C-I bond and bromine is not collected in the thyroid. Bromine can be used to label many organic molecules by methods analogous to radioiodination. The only North American source of Br-77 in the 70's and 80's was Los Alamos National Laboratory, but it discontinued production in 1989. In this method, a p,3n reaction on Br-77 produces Kr-77 which decays with a 1.2 hour half life to Br-77. A cyclotron generated 40 MeV proton beam is incident on a nearly saturated NaBr or LiBr solution contained in a copper or titanium target. A cooling chamber through which helium gas is flowed separates the solution from the cyclotron beam line. Helium gas is also flowed through the solution to extract Kr-77 gas. The mixture flows through a nitrogen trap where Kr-77 freezes and is allowed to decay to Br-77. Eight production runs were performed, three with a copper target and five with a titanium target with yields of 40, 104, 180, 679, 1080, 685, 762 and 118 uCi respectively. Gamma ray spectroscopy has shown the product to be very pure, however corrosion has been a major obstacle, causing the premature retirement of the copper target. Phantom and in-vivo rat nuclear images, and an autoradiograph in a rat are presented. The quality of the nuclear scans is reasonable and the autoradiograph reveals high isotope uptake in the renal parenchyma, a more moderate but uniform uptake in pulmonary and hepatic tissue, and low soft tissue uptake. There is no isotope uptake in the brain or the gastric mucosa. ^

The new bern PET cyclotron, its research beam line, and the development of an innovative beam monitor detector

The new Bern cyclotron laboratory aims at industrial radioisotope production for PET diagnostics and multidisciplinary research by means of a specifically conceived beam transfer line, terminated in a separate bunker. In this framework, an innovative beam monitor detector based on doped silica and optical fibres has been designed, constructed, and tested. Scintillation light produced by Ce and Sb doped silica fibres moving across the beam is measured, giving information on beam position, shape, and intensity. The doped fibres are coupled to commercial optical fibres, allowing the read-out of the signal far away from the radiation source. This general-purpose device can be easily adapted for any accelerator used in medical applications and is suitable either for low currents used in hadrontherapy or for currents up to a few μA for radioisotope production, as well as for both pulsed and continuous beams.

The cyclotron laboratory and the RFQ accelerator in Bern

Two proton accelerators have been recently put in operation in Bern: an 18 MeV cyclotron and a 2 MeV RFQ linac. The commercial IBA 18/18 cyclotron, equipped with a specifically conceived 6 m long external beam line ending in a separate bunker, will provide beams for routine 18-F and other PET radioisotope production as well as for novel detector, radiation biophysics, radioprotection, radiochemistry and radiopharmacy developments. The accelerator is embedded into a complex building hosting two physics laboratories and four Good Manufacturing Practice (GMP) laboratories. This project is the result of a successful collaboration between the Inselspital, the University of Bern and private investors, aiming at the constitution of a combined medical and research centre able to provide the most cutting-edge technologies in medical imaging and cancer radiation therapy. The cyclotron is complemented by the RFQ with the primary goals of elemental analysis via Particle Induced Gamma Emission (PIGE), and the detection of potentially dangerous materials with high nitrogen content using the Gamma-Resonant Nuclear Absorption (GRNA) technique. In this context, beam instrumentation devices have been developed, in particular an innovative beam profile monitor based on doped silica fibres and a setup for emittance measurements using the pepper-pot technique. On this basis, the establishment of a proton therapy centre on the campus of the Inselspital is in the phase of advanced study.

Low current performance of the Bern medical cyclotron down to the pA range

A medical cyclotron accelerating H- ions to 18 MeV is in operation at the Bern University Hospital (Inselspital). It is the commercial IBA 18/18 cyclotron equipped with a specifically conceived 6 m long external beam line ending in a separate bunker. This feature is unique for a hospital-based facility and makes it possible to conduct routine radioisotope production for PET diagnostics in parallel with multidisciplinary research activities, among which are novel particle detectors, radiation biophysics, radioprotection, radiochemistry and radiopharmacy developments. Several of these activities, such as radiobiology experiments for example, require low current beams down to the pA range, while medical cyclotrons are designed for high current operation above 10 μA. In this paper, we present the first results on the low current performance of a PET medical cyclotron obtained by ion source, radio-frequency and main coil tuning. With this method, stable beam currents down to (1.5+/- 0.5 ) pA were obtained and measured with a high-sensitivity Faraday cup located at the end of the beam transport line.

No anticorrelation between cyclotron line energy and X-ray flux in 4U 0115+634

We report on an outburst of the high mass X-ray binary 4U 0115+634 with a pulse period of 3.6 s in 2008 March/April as observed with RXTE and INTEGRAL. During the outburst the neutron star’s luminosity varied by a factor of 10 in the 3–50 keV band. In agreement with earlier work we find evidence of five cyclotron resonance scattering features at ~10.7, 21.8, 35.5, 46.7, and 59.7 keV. Previous work had found an anticorrelation between the fundamental cyclotron line energy and the X-ray flux. We show that this apparent anticorrelation is probably due to the unphysical interplay of parameters of the cyclotron line with the continuum models used previously, e.g., the negative and positive exponent power law (NPEX). For this model, we show that cyclotron line modeling erroneously leads to describing part of the exponential cutoff and the continuum variability, and not the cyclotron lines. When the X-ray continuum is modeled with a simple exponentially cutoff power law modified by a Gaussian emission feature around 10 keV, the correlation between the line energy and the flux vanishes, and the line parameters remain virtually constant over the outburst. We therefore conclude that the previously reported anticorrelation is an artifact of the assumptions adopted in the modeling of the continuum.

The outburst decay of the low magnetic field magnetar SWIFT J1822.3−1606: phase-resolved analysis and evidence for a variable cyclotron feature

We study the timing and spectral properties of the low-magnetic field, transient magnetar SWIFT J1822.3−1606 as it approached quiescence. We coherently phase-connect the observations over a time-span of ∼500 d since the discovery of SWIFT J1822.3−1606 following the Swift-Burst Alert Telescope (BAT) trigger on 2011 July 14, and carried out a detailed pulse phase spectroscopy along the outburst decay. We follow the spectral evolution of different pulse phase intervals and find a phase and energy-variable spectral feature, which we interpret as proton cyclotron resonant scattering of soft photon from currents circulating in a strong (≳1014 G) small-scale component of the magnetic field near the neutron star surface, superimposed to the much weaker (∼3 × 1013 G) magnetic field. We discuss also the implications of the pulse-resolved spectral analysis for the emission regions on the surface of the cooling magnetar.

Accelerator and detector physics at the Bern medical cyclotron and its beam transport line.

The cyclotron laboratory for radioisotope production and multi-disciplinary research at the Bern University Hospital (Inselspital) is based on an 18-MeV proton accelerator, equipped with a specifically conceived 6-m long external beam line, ending in a separate bunker. This facility allows performing daily positron emission tomography (PET) radioisotope production and research activities running in parallel. Some of the latest developments on accelerator and detector physics are reported. They encompass novel detectors for beam monitoring and studies of low current beams.

A report on the three-dee, three-phase 20-inch cyclotron /

Unclassified Physics Distribution.

Magnetic deflector for mesons produced in the 184-inch cyclotron /

Work performed at the University of California Radiation Laboratory.

A proposal for the Mc2 Isochronous Cyclotron; a general purpose high-intensity 810-MeV proton accelerator.

Mode of access: Internet.

700 Mev negative hydrogen ion cyclotron facility.

"Contract AEC at (11-1) 34 Project 93, April 1963."