PET imaging of early stages of Alzheimer’s disease (AD) in transgenic mice with F-18 hydroxy quinoline

Objectives To evaluate F-18 labeled hydroxy quinoline (HOQ) in PET imaging of plaques in AD transgenic (Tg) mice at early stages of the disease.

Methods F-18 HOQ was prepared as previously reported by us, reacting 8-benzyloxy-2-chloroquinoline with K222 and F-18 in DMSO. Control (B6) and Tg mice (n=4) (APP/PS1, strain B6C3-Tg, APPswe, PSEN1 dE9) ages 6, 12 and 15 months were imaged in a Siemens Inveon® PET-CT scanner. Mice were imaged for 20 min starting immediately after i.v. injection of the tracer (50-90 μCi). In a separate study, imaging studies were repeated a week later in 15 mo old Tg mice (n=3) with co-administration of 100 μg cold compound. Time activity curves were generated for cortex and cerebellum. Brain sections were stained with Aβ-42 specific antibody and plaque burden measured with Image J NIH software.

Results There was rapid initial brain uptake (8-10% ID/g) and fast washout from control mice brains whereas Tg mice had delayed washout. Cortex to cerebellum ratios were close to 1 at all times for control mice and 1.5 for the Tg mice 6 mo, >2.5 for 12 mo and >3.5 for 15 mo old mice at 5 min. Tg mice 6 mo old had increased but diffuse uptake in the cortex vs. cerebellum whereas older Tg mice had discrete uptake. Low sp. activity product in Tg mice showed no localization of the tracer in the brain and had rapid washout similar to control mice indicating in vivo blocking. Immunohistology confirmed the presence of plaques.

Conclusions Tg mice had increased tracer uptake in the cortex compared to cerebellum and this was observed in mice at an early age (6 mo). Brain uptake by PET correlated with amyloid burden assessed by immunohistology. F-18 labeled quinolines are neutral, lipophilic, weak metal chelators and appear promising molecules for targeting elevated metals in amyloid plaques. These studies warrant further evaluation of this class of molecules for early imaging of amyloid plaques.

Research Support Worsham Fund and NIH (NIA) Grant# 1RC1AG0330