Image-derived input function (IDIF) obtained by manually drawing carotid arteries (manual-IDIF) can be reliably used in [11C](R)-rolipram positron emission tomography (PET) scans. However, manual-IDIF is time consuming and subject to inter-and intra-operator variability. To overcome this limitation, we developed a fully automated technique for deriving IDIF with a supervised clustering algorithm (SVCA). To validate this technique, 25 healthy controls and 26 patients with moderate to severe major depressive disorder (MDD) underwent T1-weighted brain magnetic resonance imaging (MRI) and a 90-minute [11C](R)-rolipram PET scan. For each subject, metabolite-corrected input function was measured from the radial artery. SVCA templates were obtained from 10 additional healthy subjects who underwent the same MRI and PET procedures. Cluster- IDIF was obtained as follows: 1) template mask images were created for carotid and surrounding tissue; 2) parametric image of weights for blood were created using SVCA; 3) mask images to the individual PET image were inversely normalized; 4) carotid and surrounding tissue time activity curves (TACs) were obtained from weighted and unweighted averages of each voxel activity in each mask, respectively; 5) partial volume effects and radiometabolites were corrected using individual arterial data at four points. Logan-distribution volume (VT/fP) values obtained by cluster-IDIF were similar to reference results obtained using arterial data, as well as those obtained using manual-IDIF; 39 of 51 subjects had a V T/fP error of ,5%, and only one had error >10%. With automatic voxel selection, cluster-IDIF curves were less noisy than manual-IDIF and free of operator-related variability. Cluster-IDIF showed widespread decrease of about 20% [11C](R)-rolipram binding in the MDD group. Taken together, the results suggest that cluster-IDIF is a good alternative to full arterial input function for estimating Logan-VT/fP in [11C](R)-rolipram PET clinical scans. This technique enables fully automated extraction of IDIF and can be applied to other radiotracers with similar kinetics.
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