PET Imaging Evaluation of Four σ₁ Radiotracers in Nonhuman Primates.

Abstract

The σ₁ 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 ¹⁸F-labeled spirocyclic piperidine-based PET radiotracers (¹⁸F-<b>1</b> to ¹⁸F-<b>4</b>). <b>Methods:</b> 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 ¹⁸F-<b>2</b> and ¹⁸F-<b>4</b> Arterial input functions were measured, and binding parameters were determined with kinetic modeling analysis. <b>Results:</b> In the rhesus brain, all 4 radiotracers showed high and fast uptake. Tissue activity washout was rapid for ¹⁸F-<b>2</b> and ¹⁸F-<b>4</b>, and much slower for ¹⁸F-<b>1</b> and ¹⁸F-<b>3</b>, 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. ¹⁸F-<b>4</b> showed greater differential uptake across brain regions and 3-fold-higher binding potential than ¹⁸F-<b>2</b> SA4503 at the dose of 0.5 mg/kg blocked approximately 85% (¹⁸F-<b>2</b>) and 95% (¹⁸F-<b>4</b>) of radiotracer binding. <b>Conclusion:</b> Tracers ¹⁸F-<b>2</b> and ¹⁸F-<b>4</b> displayed high brain uptake and fast tissue kinetics, with ¹⁸F-<b>4</b> having higher specific binding signals than ¹⁸F-<b>2</b> in the same monkey. Taken together, these data indicate that both ¹⁸F-<b>2</b> and ¹⁸F-<b>4</b> possess the requisite kinetic and imaging properties as viable PET tracers for imaging S1R in the human brain.