PET Neuroimaging Studies of [¹⁸F]CABS13 in a Double Transgenic Mouse Model of Alzheimer’s Disease and Nonhuman Primates

Fluorine-18 labeled 2-fluoro-8-hydroxyquinoline ([¹⁸F]CABS13) is a promising positron emission tomography (PET) radiopharmaceutical based on a metal chelator developed to probe the “metal hypothesis of Alzheimer’s disease”. Herein, a practical radiosynthesis of [¹⁸F]CABS13 was achieved by radiofluorination followed by deprotection of an <i>O</i>-benzyloxymethyl group. Automated production and formulation of [¹⁸F]CABS13 resulted in 19 ± 5% uncorrected radiochemical yield, relative to starting [¹⁸F]fluoride, with ≥95% chemical and radiochemical purities, and high specific activity (>2.5 Ci/μmol) within 80 min. Temporal PET neuroimaging studies were carried out in female transgenic B6C3-Tg(APPswe,PSEN 1dE9)85Dbo/J (APP/PS1) and age-matched wild-type (WT) B6C3F1/J control mice at 3, 7, and 10 months of age. [¹⁸F]CABS13 showed an overall higher uptake and retention of radioactivity in the central nervous system of APP/PS1 mice versus WT mice with increasing age. However, PET/magnetic resonance imaging in normal nonhuman primates revealed that the tracer had low uptake in the brain and rapid formation of a hydrophilic radiometabolite. Identification of more metabolically stable ¹⁸F-hydroxyquinolines that can be readily accessed by the radiochemical strategy presented herein is underway