Reliable (accurate and precise) quantification of dose requires reliable absolute quantification of regional activity uptake. This is especially challenging for alpha-particle emitting radiopharmaceutical therapies ({alpha}-RPTs) due to the complex emission spectra, the very low number of detected counts, the impact of stray-radiation-related noise at these low counts, and other image-degrading processes such as attenuation, scatter, and collimator-detector response. The conventional reconstruction-based quantification methods are observed to be erroneous for {alpha}-RPT SPECT. To address these challenges, we developed an ultra-low-count quantitative SPECT (ULC-QSPECT) method that incorporates multiple strategies to perform reliable quantification. First, the method directly estimates the regional activity uptake from the projection data, obviating the reconstruction step. This makes the problem more well-posed and avoids reconstruction-related information loss. Next, the method compensates for radioisotope and SPECT physics, including the isotope spectra, scatter, attenuation, and collimator-detector response, using a Monte Carlo-based approach. Further, the method compensates for stray-radiation-related noise that becomes substantial at these low-count levels. The method was validated in the context of three-dimensional SPECT with 223Ra. Validation was performed using both realistic simulation studies, as well as synthetic and anthropomorphic physical-phantom studies. Across all studies, the ULC-QSPECT method yielded reliable estimates of regional uptake and outperformed conventional ordered subset expectation maximization (OSEM)-based reconstruction and geometric transfer matrix (GTM)-based partial-volume compensation methods. Further, the method yielded reliable estimates of mean uptake in lesions with varying intra-lesion heterogeneity in uptake.
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