PET neuroimaging studies of [(18)F]CABS13 in a double transgenic mouse model of Alzheimer's disease and nonhuman primates

Abstract

Fluorine-18 labeled 2-fluoro-8-hydroxyquinoline ([(18)F]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 [(18)F]CABS13 was achieved by radiofluorination followed by deprotection of an O-benzyloxymethyl group. Automated production and formulation of [(18)F]CABS13 resulted in 19 ± 5% uncorrected radiochemical yield, relative to starting [(18)F]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. [(18)F]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 (18)F-hydroxyquinolines that can be readily accessed by the radiochemical strategy presented herein is underway.

Keywords: APP/PS1; [18F]CABS13; metal hypothesis of Alzheimer’s disease; nonhuman primates; rodents; transgenic mice.

Figure 1

Longitudinal PET studies in APP/PS1 transgenic mice of AD versus wild-type controls. (A) PET images (axial, coronal and sagittal) summed at 5-10 min post-injection of 10 month-old transgenic mice (left) versus WT controls (right); (B) Time-activity curves and (C) AUC measurement in whole brain between transgenic mice of AD versus WT controls in 3, 7 and 10 months.

Figure 2

Summed PET (0-15 min) with structural MR images (top). Radioactivity is seen primarily in the confluence of the sinuses (torcula) with the highest intensity just inside the occipital protuberance (lower left). Time-activity curve for the radioactivity observed is also shown (bottom right).

Scheme 1

Improved radiosynthesis of [¹⁸F]CABS13 based on benzyloxymethyl precursor 1. (A) Reaction conditions and radiosynthesis results. (B) Plausible mechanism of trifluoroacetic acid mediated deprotection and formation of side products under aqueous acidic conditions.