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Thorium-227-based alpha-particle radiopharmaceutical therapies({\alpha}-RPTs) are being investigated in several clinical and pre-clinicalstudies. After administration, Thorium-227 decays to Radium-223, anotheralpha-particle-emitting isotope, which redistributes within the patient.Reliable dose quantification of both Thorium-227 and Radium-223 is clinicallyimportant, and SPECT may perform this quantification as these isotopes alsoemit X- and gamma-ray photons. However, reliable quantification is challengedby the orders-of-magnitude lower activity compared to conventional SPECT,resulting in a very low number of detected counts, the presence of multiplephotopeaks, substantial overlap in the emission spectra of these isotopes, andthe image-degrading effects in SPECT. To address these issues, we propose amultiple-energy-window projection-domain quantification (MEW-PDQ) method thatjointly estimates the regional activity uptake of both Thorium-227 andRadium-223 directly using the SPECT projection from multiple energy windows. Weevaluated the method with realistic simulation studies using anthropomorphicdigital phantoms, in the context of imaging patients with bone metastases ofprostate cancer and treated with Thorium-227-based {\alpha}-RPTs. The proposedmethod yielded reliable (accurate and precise) regional uptake estimates ofboth isotopes and outperformed state-of-the-art methods across different lesionsizes and contrasts, in a virtual imaging trial, as well as with moderatelevels of intra-regional heterogeneous uptake and with moderate inaccuracies inthe definitions of the support of various regions. Additionally, wedemonstrated the effectiveness of using multiple energy windows and thevariance of the estimated uptake using the proposed method approached theCram\'er-Rao-lower-bound-defined theoretical limit.

Joint regional uptake quantification of Thorium-227 and Radium-223 using a multiple-energy-window projection-domain quantitative SPECT method