Cornelia Hoehr

44gSc production using a water target on a 13 MeV cyclotron

INTRODUCTION Access to promising radiometals as isotopes for novel molecular imaging agents requires that they are routinely available and inexpensive to obtain. Proximity to a cyclotron center outfitted with solid target hardware, or to an isotope generator for the metal of interest is necessary, both of which can introduce significant hurdles in development of less common isotopes. Herein, we describe the production of ⁴⁴Sc (t1/2=3.97 h, Eavg,β⁺=1.47MeV, branching ratio=94.27%) in a solution target and an automated loading system which allows a quick turn-around between different radiometallic isotopes and therefore greatly improves their availability for tracer development. Experimental yields are compared to theoretical calculations. METHODS Solutions containing a high concentration (1.44-1.55g/mL) of natural-abundance calcium nitrate tetrahydrate (Ca(NO₃)2·4 H₂O) were irradiated on a 13MeV proton-beam cyclotron using a standard liquid target. (44g)Sc was produced via the ⁴⁴Ca(p,n)(44g)Sc reaction. RESULTS (44g)Sc was produced for the first time in a solution target with yields sufficient for early radiochemical studies. Saturation yields of up to 4.6 ± 0.3 MBq/μA were achieved using 7.6 ± 0.3 μA proton beams for 60.0 ± 0.2 minutes (number of runs n=3). Experimental data and calculation results are in fair agreement. Scandium was isolated from the target mixture via solid-phase extraction with 88 ± 6% (n=5) efficiency and successfully used for radiolabelling experiments. The demonstration of the production of ⁴⁴Sc in a liquid target greatly improves its availability for tracer development.

Manganese-52 positron emission tomography tracer characterization and initial results in phantoms and in vivo

PURPOSE Manganese(II) is employed as a contrast agent with magnetic resonance imaging (MRI) for study of neuronal activation in rats and mice. However, at the concentrations required for MRI, Mn may induce pharmacological or toxic effects. Positron emission tomography (PET) imaging of (52)MnCl2 at tracer doses has the potential to allow similar Mn studies as manganese-enhanced MRI while providing quantitative results and avoiding toxic effects. In this work, (52)MnCl2 is produced and characterized as a PET tracer in phantoms and in rats. METHODS (52)MnCl2 was produced by proton irradiation of natural Cr foil and separated by column chromatography. Images were acquired on a Siemens Focus 120 small animal PET scanner. Phantom images were acquired to assess uniformity, resolution, cascade background correction, and count rate linearity. Images of rats were also acquired after systemic and intracerebroventricular (ICV) administration of (52)MnCl2 to investigate Mn(II) distribution in vivo. RESULTS Irradiation yield was 74.6 ± 8.5 kBq/μA min (52)Mn at end of bombardment with initial specific activity of at least 3.5 MBq/nmol. (52)Mn PET images show similar uniformity and resolution to (18)F. (18)F based detector efficiency normalization is adequate for (52)Mn imaging. Subtraction of a rescaled random events distribution from sinogram data is effective for cascade correction of (52)Mn PET data. After systemic injection, (52)Mn appears in structures throughout the body of rats, including bones, liver, intestines, and the pituitary gland, but does not appear detectably throughout the brain. After ICV injection, (52)Mn remains in the brain and spinal cord. CONCLUSIONS (52)Mn is a promising tracer for small animal PET imaging, yielding image quality comparable to (18)F. Potential applications include studies similar to Mn-enhanced neuronal MRI, and in other organ systems including bones, spinal cord, and the digestive tract.

Radiometals from liquid targets: 94mTc production using a standard water target on a 13 MeV cyclotron

Solutions containing a high concentration (0.325-0.995 g/ml) of natural-abundance ammonium heptamolybdate tetrahydrate ((NH(4))(6)Mo(7)O(24))·4H(2)O were irradiated at 13 MeV on a proton-beam cyclotron using a standard liquid target. (94m)Tc was produced via the (94)Mo(p,n)(94m)Tc reaction with measured yields of 110±20 MBq for the highest concentrated solution using 5 μA proton beams for 60 min. Saturation yields of up to 40±6 MBq/μA were achieved. Pertechnetate was isolated from the target mixture with 70.9±0.7% efficiency using a solid-phase extraction resin.

Production of Y-86 and other radiometals for research purposes using a solution target system.

INTRODUCTION Diagnostic radiometals are typically obtained from cyclotrons by irradiating solid targets or from radioisotope generators. These methods have the advantage of high production yields, but require additional solid target handling infrastructure that is not readily available to many cyclotron facilities. Herein, we provide an overview of our results regarding the production of various positron-emitting radiometals using a liquid target system installed on a 13 MeV cyclotron at TRIUMF. Details about the production, purification and quality control of (89)Zr, (68)Ga and for the first time (86)Y are discussed. METHODS Aqueous solutions containing 1.35-1.65 g/mL of natural-abundance zinc nitrate, yttrium nitrate, and strontium nitrate were irradiated on a 13 MeV cyclotron using a standard liquid target. Different target body and foil materials were investigated for corrosion. Production yields were calculated using theoretical cross-sections from the EMPIRE code and compared with experimental results. The radioisotopes were extracted from irradiated target material using solid phase extraction methods adapted from previously reported methods, and used for radiolabelling experiments. RESULTS We demonstrated production quantities that are sufficient for chemical and biological studies for three separate radiometals, (89)Zr (Asat = 360 MBq/μA and yield = 3.17 MBq/μA), (86)Y (Asat = 31 MBq/μA and yield = 1.44 MBq/μA), and (68)Ga (Asat = 141 MBq/μA and yield = 64 MBq/μA) from one hour long irradiations on a typical medical cyclotron. (68)Ga yields were sufficient for potential clinical applications. In order to avoid corrosion of the target body and target foil, nitrate solutions were chosen as well as niobium as target-body material. An automatic loading system enabled up to three production runs per day. The separation efficiency ranged from 82 to 99%. Subsequently, (68)Ga and (86)Y were successfully used to radiolabel DOTA-based chelators while deferoxamine was used to coordinate (89)Zr.

An analytical approach of thermodynamic behavior in a gas target system on a medical cyclotron

An analytical model has been developed to study the thermo-mechanical behavior of gas targets used to produce medical isotopes, assuming that the system reaches steady-state. It is based on an integral analysis of the mass and energy balance of the gas-target system, the ideal gas law, and the deformation of the foil. The heat transfer coefficients for different target bodies and gases have been calculated. Excellent agreement is observed between experiments performed at TRIUMFs 13 MeV cyclotron and the model.

A new transfer system for solid targets

As part of a collaborative research project funded by Natural Resources Canada, TRIUMF has designed and manufactured solid target and solid target processing systems for the production of technetium-99m using small medical cyclotrons. The system described herein is capable of transporting the target from a hotcell, where the target is loaded and processed, to the cyclotron and back again. The versatility of the transfer system was demonstrated through the successful installation and operation on the ACSI TR 19 at the BC Cancer Agency, the GE PETtrace cyclotrons at Lawson Health Research (LHRI) and the Centre for Probe Development and Commercialization (CDPC).

Manganese concentration mapping in the rat brain with MRI, PET, and autoradiography

Purpose: Mn2+ is used as a contrast agent and marker for neuronal activity with magnetic resonance imaging (MRI) in rats and mice, but its accumulation is generally not assessed quantitatively. In this work, nonradioactive Mn and 52Mn are injected simultaneously in rats, and imaged with MRI, positron emission tomography (PET) and autoradiography (AR). Mn distributions are compared between modalities, to assess the potential and limitations on quantification of Mn with MRI, and to investigate the potential of multimodal measurement of Mn accumulation. Methods: MRI (in vivo), PET (in vivo and post mortem), and AR (ex vivo) were acquired of rat brains, for which animals received simultaneous intraperitoneal (IP) or intracerebrovertricular (ICV)‐targeted injections containing the positron‐emitting radionuclide 52Mn and additional nonradioactive MnCl2, which acts as an MRI contrast agent. Pre and postinjection MR images were fit for the longitudinal relaxation rate (R1), coregistered, and subtracted to generate R1 difference maps, which are expected to be proportional to change in Mn concentration in tissue. AR and PET images were coregistered to smoothed R1 difference maps. Results: Similar spatial distributions were seen across modalities, with Mn accumulation in the colliculus, near the injection site, and in the 4th ventricle. There was no 52Mn accumulation measurable with PET in the brain after IP injection. In areas of very highly localized and concentrated 52Mn accumulation in PET or AR, consistent increases of R1 were not seen with MRI. Scatter plots of corresponding voxel R1 difference and PET or AR signal intensity were generated and fit with least squares linear models within anatomical regions. Linear correlations were observed, particularly in regions away from very highly localized and concentrated Mn accumulation at the injection site and the 4th ventricle. Accounting for radioactive decay of 52Mn, the MnCl2 longitudinal relaxivity was between 4.0 and 5.1 s−1/mM, which is within 22% of the in vitro relaxivity. Conclusions: This proof‐of‐concept study demonstrates that MR has strong potential for quantitative assessment of Mn accumulation in the brain, although local discrepancies from linear correlation suggest limitations to this use of MR in areas of inflammation or very high concentrations of Mn. These discrepancies also suggest that a combination of modalities may have additional utility for discriminating between different pools of Mn accumulation in tissue.

Modeling the pressure rise of a liquid target on a medical cyclotron: Steady-state analysis

The steady-state behaviour of a liquid target used to produce medical isotopes by low-energy cyclotrons is studied. A model based on the conservation of mass and energy is proposed to describe the pressure rise of the target assuming equilibrium between liquid and vapour phases during irradiation. The effects of water radiolysis are taken into account. Excellent agreement is achieved between the model, and both constant-temperature bath tests and experiments conducted on a 13MeV cyclotron at TRIUMF.

PET scanning of ocular melanomas after proton therapy

In an effort to understand the possibility of using PET as a tool for dose verification after proton therapy in ocular melanomas, a Lucite phantom was irradiated at the proton therapy facility at TRIUMF with a raw and spread-out Bragg peak of 74 MeV protons and scanned in two different PET scanners at UBC. A tantalum clip, used as a marker during patient treatment, was attached to the phantom. Irradiation with the raw Bragg peak results in a different activation profile than with the spread-out Bragg peak. The difference is easily observable in the PET scan. In addition, one patient treated for choroidal melanoma was scanned. In the patient scan the activity in the irradiated tumor is clearly visible. A FLUKA simulation of the facility is currently being validated against experimental measurements.

89Zr for antibody labeling and in vivo studies – a comparison between liquid and solid target production

INTRODUCTION Zirconium-89 (89Zr, t1/2=78.4h) liquid target (LT) production offers an approach to introduce this positron-emitting isotope to cyclotron centres without the need for a separate solid target (ST) production set up. We compared the production, purification, and antibody radiolabeling yields of 89Zr-(LT) and 89Zr-(ST), and assessed the feasibility of 89Zr-(LT) for preclinical PET/CT. METHODS 89Zr-(ST) production was performed with an 89Y foil on a TR 19 cyclotron at 13.8MeV. For LT production; an aqueous solution of yttrium nitrate (Y(NO3)3·6H2O) was irradiated on a TR 13 cyclotron at 12MeV. 89Zr was purified from the ST or LT material with hydroxamate resin, and used to radiolabel p-SCN-Bn-Deferoxamine (DFO)-conjugated Trastuzumab. MicroPET-CT imaging was performed at 1, 3 and 5days post-injection of 89Zr-DFO-Trastuzumab from ST or LT with biodistribution analysis on day 5. RESULTS Irradiation of the ST yielded 2.88±1.07GBq/μA with a beam current of 14.0±3.8μA and irradiation time of 137±48min at end of bombardment while LT yielded 0.27±0.05GBq/μA with a beam current of 9.9±2.2μA and irradiation time of 221±29min. Radiolabeling of DFO-Trastuzumab with 89Zr-(ST) or 89Zr-(LT) was successful with purity>97% and specific activity>0.12MBq/μg (of antibody). MicroPET-CT imaging and biodistribution profiles showed similar uptake of 89Zr-(ST)-DFO-Trastuzumab and 89Zr-(LT)-DFO-Trastuzumab in tumor and all organs of interest. CONCLUSION 89Zr-(LT) was effectively used to prepare antibody bioconjugates with specific activities suitable for small animal imaging. PET imaging and biodistribution revealed similar behaviours between bioconjugates labeled with 89Zr produced from the two target systems. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE These results have important implications for the production of PET isotopes such as 89Zr to cyclotron facilities with only LT capabilities - such as most clinical centres - expanding the availability of 89Zr-immunoPET.