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.