AC-225 Imaging R01 Transfer

Project Summary (Abstract)
We propose to build a novel gamma imaging device based on the combination of Compton and proximity
reconstructions in order to achieve unprecedented sensitivities that will enable in vivo imaging of biodistributions
of 225Ac, a promising Targeted Alpha Therapy (TAT) isotope. TAT has demonstrated a remarkable efficacy and
specificity for cancer radiotherapy. This is due to the high linear energy transfer and the short free path of alpha
particles that result in a higher and more localized energy deposition than that of beta particles. 225Ac is a very
promising alpha-emitter that has successfully shown excellent results on the treatment of a number of
malignancies, namely, metastatic castration-resistant prostate cancer, pancreatic cancer and acute myeloid
leukemia. A key aspect of TAT is the targeting radiopharmaceutical that transports the 225Ac to the carcinogenic
cells, preventing free isotopes from delivering a highly toxic radioactive dose to healthy tissue. However,
development of novel radiopharmaceuticals is currently limited by the inability of commercial imaging systems
to detect 225Ac in vivo. As a result, their pharmacokinetics cannot be fully understood in clinical applications,
delaying their FDA approval and hindering the wide adoption of TAT. 225Ac and its daughters can be imaged
through the detection of the gamma rays emitted in their decay chain, but the main challenge of this technique
(and the reason why current gamma ray imaging systems are not suitable for this task) is that the gamma ray
emission activity is extremely low due to the very small doses injected in human patients (0.1MBq/kg) and in
preclinical studies (1MBq/kg in mice) to prevent a morbid toxicity. In this scenario, an apparatus with a high
gamma ray detection sensitivity is necessary in order to provide images with exposures no longer than a few
minutes. We plan to achieve this unprecedented sensitivity by designing a dedicated gamma camera that
integrates Compton and proximity imaging in a multi-modality system. These techniques have been successfully
in medical imaging applications, but they have never been combined in the same device in order to improve
sensitivity and image quality at the same time. To achieve this goal, we propose to quantitatively image Ac-225
in vivo the first time with a Cadmium Zinc Telluride dual-head camera that enables both Compton and proximity
imaging. To reach this goal we plan to 1) assemble Compton and proximity gamma camera; 2) develop a multi-
modality reconstruction algorithm for Compton and proximity imaging; 3) demonstrate in vivo imaging of 225Ac
with the final prototype and perform first in vivo pharmacokinetics study of two 225Ac radiopharmaceuticals,
providing a proof of principle in pre-clinical conditions using phantoms and mice. The outcome from this project
will be a prototype gamma camera able to image distributions of 225Ac TAT radiopharmaceuticals in-vivo (and
potentially other TAT isotopes), and thus, enabling the complete study of their pharmacokinetics to accelerate
their development. With our system, we expect to increase the understanding and confidence in TAT.

Grant Number: 5R01EB032324-04
NIH Institute/Center: NIH
Principal Investigator: Javier Caravaca