We propose a novel framework of robust kinetic parameter estimation applied to absolute ow quanti cation in dynamic PET imaging. Kinetic parameter estimation is formulated as a nonlinear least squares with spatial constraints problem (NLLS-SC) where the spatial constraints are computed from a physiologically driven clustering of dynamic images, and used to reduce noise contamination. Resolution degradation is also substantially minimized as no spatial smoothing between heterogeneous functional regions is performed. The proposed framework is shown to improve the quantitative accuracy of Myocardial Perfusion (MP) PET imaging, and in turn, has the long-term potential to enhance capabilities of MP PET in the detection, staging and management of coronary artery disease.