Radiochemistry Development of 52Mn for Characterization of PET/MR Imaging Agents

Introduction: Manganese-52 (⁵²Mn) is a promising positron emitting radionuclide that can be used as dual modality signal enhancing contrast agent for PET/MRI in combination with natural Mn²⁺. ⁵²Mn has a 5.6-day half-life and emits a positron with a branching ratio of 29.4% and a low average positron energy of 242 keV. Mn²⁺ has already been investigated for its use as an MRI contrast agent because of its paramagnetic properties, with 5 unpaired electrons, natural Mn has the potential to replace or complement existing gadolinium compounds. Moreover, the use of tracer ⁵²Mn would enable quantification of the total Mn²⁺. The goal of this work is to produce, purify and apply ⁵²Mn to radiochemistry and imaging experiments with Mn²⁺ for use as a PET/MRI contrast agent.

Methods: ⁵²Mn was produced via the nuclear reaction ⁵²Cr(p,n)⁵²Mn using natural Cr targets on a TR24 cyclotron. The Cr targets were made with Cr metal powder by pressing ~200 mg at 5 tons for 5 mins to result in a 0.5 mm pellet. Targets were irradiated at 12.5 MeV incident on the Cr with a current of 15 µA. ⁵²Mn separation was carried out on AG1-X8 anion exchange resin utilizing a semi-automated system using acid washes followed by elution of the final ⁵²Mn product in 0.1 M HCl.

PET/MR phantoms were prepared with ⁵²Mn radioactivity ranging from 0-20 μCi and Mn²⁺ concentrations ranging from 0-1 mM. The ⁵²Mn/Mn²⁺ solution was used for PET/MRI scans where PET was acquired for 10-20 min and MRI was collected at various inversion times ranging from 200-1700 ms to create a T1 map.

Preliminary animal studies with ⁵²Mn/Mn²⁺ were also conducted where rats were injected using a syringe pump over 1.4 ± 0.1 h with ⁵²Mn radioactivity of 276.3 ± 20.0 μCi and Mn²⁺ concentrations ranging from 10 - 40 mg/kg. After PET/MR imaging, animals were sacrificed and ex vivo biodistributions were carried out.

Results: ⁵²Mn purified from natural Cr foils using 5 x 0.5 cm, gravity fed columns yielded non-decay corrected recoveries of 70.8 ± 3.3 % with a time of 8.2 ± 0.6 h whereas ⁵²Mn from the pressed powder Cr and electroplated Cr targets purified using pressurized 1 mL SPE tubes yielded non-decay corrected recoveries of 94.5 ± 2.4 % with a time of 4.2 ± 0.4 h. While enriched ⁵²Cr targets are under development, as natural Cr has 4 stable isotopes, impurities included Cr-51 (t_1/2 = 27.7 days) and Mn-54 (t_1/2 = 312 days).

Phantom images showed promising results with the ⁵²Mn/Mn²⁺ combination in which the varying amounts of radioactivity vs. Mn concentration could be clearly observed. The amounts of radioactivity added aligned well with the ROI drawn on each phantom which led us to move forward with in vivo studies. The [⁵²Mn]MnCl₂ phantoms contained 0 μCi, 6.07 ± 0.11 μCi, 11.86 ± 0.03 μCi, and 17.68 ± 0.32 μCi of ⁵²Mn as assessed with a high purity germanium detector and correlated well with ROIs which yields measurements of 0 μCi, 5.46 ± 0.60 μCi, 10.77 ± 1.95 μCi, and 16.74 ± 3.45 μCi, respectively. The T1 relaxivity of the phantoms was calculated to be 7.7 mM^-1s^-1 (R²=0.9999).

Animal images obtained with free [⁵²Mn]MnCl₂ in rat models showed primarily showed ⁵²Mn uptake in organs associated with hepatic excretion (small intestine, large intestine, and liver) in agreement with literature reports. Preliminary PET images showed high resolution and contrast and matched well with increased MRI contrast which showed a dose dependent signal enhancement.

Conclusions: ⁵²Mn can be produced using natural Cr targets and a semi-automated purification system that is continuing to be optimized. Preliminary phantom and animal studies show promising results for using the combination of ⁵²Mn/Mn²⁺ as a PET/MRI imaging agent.

Acknowledgments

This work was supported by the Department of Energy Isotope Program under grant DESC0015773 (PI: Lapi), the UAB cyclotron facility and the Department of Radiology.