AIM: [123]I-Ioflupane (DaTSCAN) binds to the presynaptic dopamine transporter (DAT) and with a lower affinity to the serotonin transporter (SERT). We aimed to develop a novel method to quantify absolute uptake in the striatal (predominantly DAT binding) and extra-striatal regions (mainly SERT binding) using single-photon computed tomography-computed tomography (SPECT-CT) DaTSCAN and to improve DaTSCAN image quality. METHOD: Twenty-six patients with Parkinsonism underwent DaTSCAN SPECT-CT prospectively. The scans were visually analyzed independently by two experienced reporters. Specific binding ratios (SBRs) from Chang attenuation corrected SPECT were obtained using GE DaTQuant. Normalized concentrations and specific uptakes (NSU) from measured attenuation and modelled scatter-corrected SPECT-CT were obtained using HERMES Hybrid Recon and Affinity and modified EARL volumes of interest. RESULTS: Striatal NSU and SBR positively correlate (R = 0.65-0.88, P = 0.00). SBR, normalized concentrations, and NSU box plots differentiated between scans without evidence of dopaminergic deficit and abnormal scans. Interestingly, body weight inversely correlated with normalized concentrations values in extra-striatal regions [frontal (R = 0.81, P = 0.00); thalamus (R = 0.58, P = 0.00); occipital (R = 0.69, P = 0.00)] and both caudate nuclei [R = 0.42, P = 0.03 (Right), R = 0.52, P = 0.01 (Left)]. Both reporters noted improved visual quality of SPECT-CT versus SPECT images for all scans. CONCLUSION: DaTSCAN SPECT-CT resulted in more accurate quantification, improved image quality, and enabled absolute quantification of extra-striatal regions. More extensive studies are required to establish the full value of absolute quantification for diagnosis and monitoring the progression of neurodegenerative disease, to assess an interplay between DAT and SERT, and to verify serotonin and DATs are potentially DATs are dysfunctional in obesity.