Radiopharmaceutical therapy with α-particle emitters (αRPT) is a highly effective cancer therapy modality; it delivers potent alpha-particle radiation to cancer cells and is therefore not susceptible to resistance seen with most other cancer therapies. It is also unique in that alpha-emitters also emit photons that can be imaged by nuclear medicine modalities. This allows for patient-specific treatment planning and optimization of patient therapy. These unique features of αRPT have not been used, however, because αRPT is so effective that the activity used to treat patient is too low to be imaged with conventional nuclear medicine imaging methods. In this project we will develop and implement accurate single photon emission computed tomography (SPECT) imaging methods that overcome this limitation. Our hypothesis is that enabling quantitative αRPT imaging and making it convenient so that it is widely adopted will improve the outcome of patients treated with αRPT. The distribution of the radionuclide in vivo is a prerequisite for estimating the absorbed dose distributions needed to plan and optimize αRPT’s. There are several significant challenges to imaging the distribution of α-emitters in patients. Due to their high linear energy transfer (LET) and resulting lethality, low administered activities are used. Typical decay chains include multiple daughter radionuclides that emit photons, and it is important to also determine their activity distribution. Also, the photon emission spectrum for α-emitters typically has many low-abundance gamma rays spread over a wide energy range. These properties have made imaging-based dosimetry difficult; the imaging that has been performed has not been quantitatively rigorous. We propose to develop imaging reconstruction methods applicable to clinical SPECT systems that will account for the complex imaging physics and allow for validated quantitative SPECT imaging of αRPT for accurate dosimetry calculations. The overall goal is to incorporate such quantitative SPECT imaging into a clinically implementable imaging workflow that can provide accurate dosimetry for treatment planning and efficacy monitoring. Our group, in collaboration with members of a Hopkins startup company, Radiopharmaceutical Imaging and Dosimetry, LLC (Rapid), have already made considerable progress on SPECT imaging of αRPT agents. In Aim1, we will extend this work to develop quantitative reconstruction methods for SPECT imaging of alpha emitters that produce accurate measures of activity distribution for dosimetry which will also be useful for SPECT diagnostic imaging in general. Another challenge for imaging αRPT is the requirement that patients return for several imaging sessions to obtain the needed pharmacokinetics in normal organs and tumors. Thus, in Aim 2 we will investigate the trade-off between number of imaging time-points and the accuracy of dosimetry. In Aim 3 we will apply the developed imaging method and statistically analyze the relationships between quantitative image measures, dosimetry, dose-response, and therapy outcome. In Aim 4, we consider several potential surrogate radionuclides and assess their utility for pre-therapy dosimetry.

Narrative Quantitative imaging of α-particle emitters is important for dosimetry needed to optimize patient therapy. Well validated methods for such imaging do not currently exist. We will develop and validate such methods while also considering different approaches to reduce the number of imaging sessions required for accurate dosimetry of αRPT