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

Sigma-1 receptor (σ 1 R) has been implicated in the pathogenesis of Alzheimer disease (AD). Positron emission tomography (PET) imaging of σ 1 R presents a novel strategy for the diagnosis and prognosis of AD. We previously reported a group of promising σ 1 R radiotracers. Continuing our efforts, we utilized an alternative labeling approach of our lead radiotracer ( - )-[ 18 F] TZ3108 to ( - )-[ 18 F] 15 , and facilitated the synthesis of three new radiotracers: ( - )-[ 18 F] 13 , ( - )-[ 18 F] 14 , and ( - )-[ 18 F] 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 σ 1 R expression in 3xTg-AD mice, PET in macaque brain, and radiometabolite analysis. We successfully synthesized all new F-18 labeled σ 1 R radiotracers with high yield and purity. In vitro and in vivo evaluations demonstrated all candidates were potent and selective for σ 1 R. PET studies in CD1 mice revealed high brain uptake and specificity for σ 1 R in vivo of all radiotracers. PET studies of 3xTg-AD and age-matched control mice showed reduced brain uptake of all σ 1 R radiotracers in AD mice. Immunohistology confirmed decreased expression of neuronal σ 1 R in 3xTg-AD mice. PET studies in macaque demonstrated ( - )-[ 18 F] 13 has high brain uptake alongside elimination pharmacokinetics that are especially clinically favorable. Overall, our σ 1 R radiotracers can successfully quantify the reduction of σ 1 R in 3xTg-AD mice. ( - )-[ 18 F] 13 is the most promising σ 1 R 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 σ 1 R radiotracers. • Mounting evidence highlights the association of Sigma 1 Receptor with AD. • PET with a σ1R-specific radioligand could assess σ1R expression in vivo. • Our σ1R PET tracers could detect the reduced σ1R expression in 3xTg-AD mice. • Our lead radioligand (-)-[ 18 F] 13 shows clinically favorable brain washout kinetics. • PET with (-)-[ 18 F] 13 shows promise in both rodent and nonhuman primate brains.