PET imaging of neurokinin-1 receptors with [¹⁸F]SPA-RQ in human subjects: Assessment of reference tissue models and their test-retest reproducibility

[¹⁸F]SPA-RQ (substance P antagonist receptor quantifier) labels the substance P-preferring (NK₁) receptor in human brain. A prior study showed that [¹⁸F]SPA-RQ brain uptake can be quantified with a reference tissue method and thereby avoid invasive blood sampling. The purposes of this study were to compare three different reference tissue methods and to assess test-retest reproducibility. Eight healthy subjects underwent two [ ¹⁸F]SPA-RQ scans. We calculated the binding potential (BP), which is proportional to receptor density, from both regional volume of interest and voxel-wise data. We compared three reference tissue methods: simplified reference tissue model, multilinear reference tissue model (MRTM), and its two-parameter version (MRTM2). The three methods generated equivalent values of regional BP, but MRTM2 was the most resistant to noise. Temporally stable values of BP were obtained with 240 min of imaging data. MRTM2 had excellent test-retest reproducibility, with high reliability (intraclass correlation > 0.9) and low variability (< 10%). In addition to regional volume of interest analysis, we also created parametric images of BP, variability, and reliability based on voxel-wise time-activity data. The reproducibility of parametric BP was also good, with variability < 20% and reliability > 0.7 in gray matter regions. In conclusion, a two-parameter reference tissue method (MRTM2) provided reproducible and reliable measurements of [¹⁸F]SPA-RQ brain uptake using 240 min of both regional and voxel-wise data.