Compton Imaging of Ac-225 In Pre-clinical Phantoms With a 3D-positioning CZT Camera

²²⁵Ac-based radiopharmaceuticals for targeted alpha therapy (TAT) have shown positive outcomes in recent clinical trials and pre-clinical studies, and it has emerged as a promising solution for future cancer treatments. Small-animal in-vivo imaging is critical to better understand ²²⁵Ac radiopharmaceuticals biokinetics and to accelerate evaluation and discovery of new ²²⁵Ac radiopharmaceuticals. However, gamma-ray imaging of ²²⁵Ac and its daughters is challenging due to the extremely low injected activities, the low branching ratios of the emitted $\gamma$ rays, and their broad range of energies. State-of-the-art scanners for single-photon emission computed tomography (SPECT) have sensitivity limitations when imaging such low activities, and imaging sessions of several hours are necessary, precluding in-vivo studies. We propose Compton imaging as an alternative to traditional SPECT imagers in order to enable a higher sensitivity and to decrease the minimum imageable activities of current systems. In this study, we explore a 3D-positioning cadmium zinc telluride (CZT) camera (M400, H3D) to achieve highly sensitive Compton imaging of ²²⁵Ac daughters at both high-energy (440 keV from ²¹³Bi) and low-energy gamma rays (218 keV from ²²¹Fr). The Compton sensitivity of the imaging system with a source as close as possible from the detector (7 mm) were 1014(33) cps/MBq and 467(23) cps/MBq for ²¹³Bi and ²²¹Fr, respectively. We studied the response of the camera using ²²⁵Ac point sources, including the demonstration of simultaneous imaging of ²¹³Bi and ²²¹Fr from multiple ²²⁵Ac sources at sub- $\mu \text{Ci}$ activity levels, ranging from 7.4 kBq to 25.9 kBq, in a 18-minute imaging session. Furthermore, we performed a mouse phantom experiment to demonstrate that we could form high-sensitive Compton images of ²¹³Bi and ²²¹Fr, concluding that we can image a mouse phantom with an activity of ~ 0.55 MBq in just 9 and 36 seconds for ²¹³Bi and ²²¹Fr, respectively, with a single detector head and in a single bed position. This is equivalent to imaging an activity of 3.7 kBq, a typical tumor uptake in mouse experiments with ²²⁵Ac, in 23 minutes for ²¹³Bi and 90 minutes for ²²¹Fr with a small 5.7 cm × 5.7 cm area prototype. Increasing angular coverage would further increase sensitivity. Finally, we also compared Compton imaging with collimated imaging.