PET Imaging Evaluation of Four σ1 Radiotracers in Nonhuman Primates

The sigma(1) receptors (S1Rs) are implicated in a variety of diseases including Alzheimer disease and cancer. Previous PET S1R radiotracers are characterized by slow kinetics or off-target binding that impedes their use in humans. Here, we report the first PET imaging evaluation in rhesus monkeys of 4 F-18-labeled spirocyclic piperidine-based PET radiotracers (F-18-1 to F-18-4). Methods: Baseline scans for the 4 radiotracers were obtained on an adult male rhesus monkey. Blocking scans were obtained with the S1R-selective agonist SA4503 to assess binding specificity of F-18-2 and F-18-4. Arterial input functions were measured, and binding parameters were determined with kinetic modeling analysis. Results: In the rhesus brain, all 4 radiotracers showed high and fast uptake. Tissue activity washout was rapid for F-18-2 and F-18-4, and much slower for F-18-1 and F-18-3, in line with their respective in vitro S1R-binding affinities. Both the 1-tissue-compartment and multilinear analysis-1 kinetic models provided good fits of time-activity curves and reliable estimates of distribution volume. Regional distribution volume values were highest in the cingulate cortex and lowest in the thalamus for all radiotracers. F-18-4 showed greater differential uptake across brain regions and 3-fold-higher binding potential than F-18-2. SA4503 at the dose of 0.5 mg/kg blocked approximately 85% (F-18-2) and 95% (F-18-4) of radiotracer binding. Conclusion: Tracers F-18-2 and F-18-4 displayed high brain uptake and fast tissue kinetics, with F-18-4 having higher specific binding signals than F-18-2 in the same monkey. Taken together, these data indicate that both F-18-2 and F-18-4 possess the requisite kinetic and imaging properties as viable PET tracers for imaging S1R in the human brain.