Das BC, Das S, Elmaleh DR.
Design and synthesis of potential retinoid based PET imaging agents to study Alzheimer's disease biology.
Human Amyloid Imaging 2011 Meeting Abstrac. 2011 Jan 15;
The pathological hallmarks of Alzheimer's disease (AD) are the presence of senile plaques containing amyloid-beta
(Ab) peptide and the formation of neuronal tangles in the cerebral cortex. Several radiolabeled PET compounds
were reported as AD biomarkers, the most tested are PIB and AV45. Here we present a novel biomarker approach
for AD imaging. Retinoid signaling pathway is involved in mAD genetic linkages. This pathway is mediated by
retinoic acid (RA) receptors (RARs) and retinoid X receptors (RXRs), both of which have three types, ƒ¿, s and ƒÁ,
and various isoforms. RA is derived from vitamin A. Deficiency of this vitamin in rats leads to Ab brain vasculature
deposits and neuronal cell death. These were correlated with the lack of RARƒ¿ signaling, as this receptor is down
regulated in vitamin A deficient rats. Similar RARƒ¿ deficit was found in the cortices in pathology samples of AD
patients. Recent work has also shown that all-trans RA (atRA) applied intra peritoneally in a mouse model of AD
results in a decrease in Ab production, and the neuronal cell death associated with Ab can be prevented by RARƒ¿
signaling, and an RARƒ¿ agonist can cross the blood-brain barrier (BBB). We synthesized a small library of novel
retinoic acid analogues and tested their activity by evaluating phenotypic changes caused in developing zebrafish
embryos. We showed that several compounds showed receptor activity and specificity and significantly affect
development. Our reporter assays determined that BT10, interacts with RAR-ƒ¿ receptor sub-types and had no
activity for RXR receptors at the tested concentrations. We will report on the 18F labeled BT10 as PET tracer for
animal imaging to measure the concentration of RAR-alpha in normal neural cell and pathological AD neural cells.
Our approach may lead to an early indicator for predicting amyloid-beta production leading to AD. We are planning
to modify and our lead BT10 to improve receptor activity and specificity for in-vivo RAR receptor activity to study