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The aim of this study was to evaluate the accuracy of different single-photon emission computed tomography (SPECT) reconstruction techniques in measuring striatal N-ω-fluoropropyl-2β-carbomethoxy-3β-4-[123I]iodophenyl-nortropane (123I-FP-CIT) binding in de novo Parkinson’s disease (PD) patients, in order to find a correlation with clinical scales of disease severity in the initial phases of disease. Thirty-six de novo PD patients underwent 123I-FP-CIT SPECT and MRI scan. SPECT data were reconstructed with filtered back projection (FBP), with an iterative algorithm (ordered subset expected maximization, OSEM) and with a method previously developed in our institution, called least-squares (LS) method. The ratio of specific to non-specific striatal 123I-FP-CIT binding (binding potential, BP) was used as the outcome measure with all the reconstruction methods (BPFBP, BPOSEM, BPLS). The range of values of striatal BPLS was significantly greater than BPFBP and BPOSEM. For all striatal regions, estimates of BPFBP correlated well with BPOSEM ( r = 0.84) and with BPLS ( r = 0.64); BPOSEM correlated significantly with BPLS ( r = 0.76). A good correlation was found between putaminal BPLS and Hoen and Yahr, Unified PD Rating Scale (UPDRS) and lateralized UPDRS motor scores ( r = −0.46, r = −0.42, r = −0.39, respectively). Neither putaminal BPFBP nor putaminal BPOSEM correlated with any of these motor scores. In de novo PD patients, 123I-FP-CIT BP values derived from FBP and OSEM reconstruction techniques do not permit to differentiate PD severity. The LS method instead finds a correlation between striatal BP and disease severity scores. The results of this study support the use of 123I-FP-CIT BP values estimated with the LS method as a biomarker of PD severity. [ABSTRACT FROM AUTHOR]