Design, synthesis, and characterization of F-18 sigma-1 receptor radiotracers for Alzheimer disease.

Sigma-1 receptor (σ1R) has been implicated in the pathogenesis of Alzheimer disease (AD). Positron emission tomography (PET) imaging of σ1R presents a novel strategy for the diagnosis and prognosis of AD. We previously reported a group of promising σ1R radiotracers. Continuing our efforts, we utilized an alternative labeling approach of our lead radiotracer (-)-[18F]TZ3108 to (-)-[18F]15, and facilitated the synthesis of three new radiotracers: (-)-[18F]13, (-)-[18F]14, and (-)-[18F]21. We performed systematic characterizations of these radiotracers including in vitro potency and selectivity, ex vivo biodistributions, autoradiography, immunohistology, PET for in vivo specificity, PET to assess σ1R expression in 3xTg-AD mice, PET in macaque brain, and radiometabolite analysis. We successfully synthesized all new F-18 labeled σ1R radiotracers with high yield and purity. In vitro and in vivo evaluations demonstrated all candidates were potent and selective for σ1R. PET studies in CD1 mice revealed high brain uptake and specificity for σ1R in vivo of all radiotracers. PET studies of 3xTg-AD and age-matched control mice showed reduced brain uptake of all σ1R radiotracers in AD mice. Immunohistology confirmed decreased expression of neuronal σ1R in 3xTg-AD mice. PET studies in macaque demonstrated (-)-[18F]13 has high brain uptake alongside elimination pharmacokinetics that are especially clinically favorable. Overall, our σ1R radiotracers can successfully quantify the reduction of σ1R in 3xTg-AD mice. (-)-[18F]13 is the most promising σ1R radiotracer of our discovery group, exhibiting high brain uptake, good in vivo specificity and stability, and clinically favorable brain washout pharmacokinetics that resolve prominent limitations of previously reported σ1R radiotracers.