Abstract Body:

Background: A Quantitative Particle IDentification digital autoradiography system (QPID) was developed using the TimePix3 sensor from the CERN Medipix collaboration[1] and a CeBr3 crystal gamma detector.

Methods: The TimePix3 sensor is a 256×256 pixelated solid state detector with 55 micron pixel pitch with each pixel being readout individually[2]. This allows one to tag single charge particle tracks with 12ns time resolution. By placing a CeBr3 gamma detector adjacent to the TimePix3 sensor, we can detect gamma emissions from the autoradiography sample. The TimePix3 sensor and CeBr3 crystal digitizer are driven by a common external clock time synchronizing the two and tagging charge particle tracks recorded by the TimePix3 sensor and gamma emissions recorded by the CeBr3 crystal in coincidence. Because of the different LET properties between alpha and beta emissions, the track footprints that are recorded on the TimePix3 sensors differ between the two particle species. These differences are used to distinguish between the two types of particles as well as calculating the total energy deposition. To distinguish between positive and negative beta tracks, positron plus gamma coincidence tagging can be applied using a 511keV energy threshold on the detected coincident gamma. The resulting particle identification features of the TimePix3 sensor in combination with a gamma detection crystal provides a unique autoradiography system capable of studying the bioequivalence between alpha and positron emitting radioligands, which is important for theranostics applications[3]. This is done through dual injection studies where both alpha and positron emitting radionuclide ligands are administered together into the mouse being studied. Thereafter, tissue samples where both radioisotopes have colocalized can be imaged on the QPID. The image processing of the data collected by the QPID generates two images, one formed from alpha tracks and the other formed from gamma coincidence tagged positron tracks. Because the QPID can measure emission rates in counts per second (cps), with the use of a suitable calibration factors one can convert alpha and positron cps into Bq resulting in fully quantitative measurements of both absorbed therapeutic and diagnostic ligands. The ability of the TimePix3 sensor to measure the energy deposited on a per particle track for both the alpha and beta particles allows one to additionally generate radiation dose images directly, facilitating microdosimetry of tissue.

Results: Early performance tests done on the TimePix3 sensor shows good count linearity up to 60kcps and an alpha spatial resolution of 87µm. The beta spatial resolution is dominated by the beta particle track range. Alpha and positron identification capabilities resulted in excellent separation between the two class of particles as demonstrated in a ²²³Ra and ¹⁸F image in which 100 Bq in a 0.5 µL drop of ²²³Ra and ¹⁸F are placed on a microscope slide a few millimeters apart and imaged on the QPID. The QPID successfully generated ²²³Ra and ¹⁸F only images. A mouse was injected with a mixed sample of ²²³RaCl2 and Na¹⁸F. One hour following injection, the mouse was sacrificed and a 50 µm thick microtome section of the spine was imaged on the QPID. The QPID generated separate ²²³RaCl and Na¹⁸F uptake images showing co-localization the two ligands. More detailed bio-equivalence studies are planned for ²²³RaCl and Na¹⁸F.

Conclusion: The QPID is a unique imaging system leveraging the latest technology from CERN bringing novel particle identification features to bear on digital autoradiography-based microdosimetry. Early tests show that the QPID can discern beta and alpha particles and quantify absorbed dose at micron resolution. Such work can help more accurately assess the predictive nature of dosimetry estimates of an imaging agent with those of its therapeutic partner.

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