[18F]Flotaza for Aß Plaque Diagnostic Imaging: Evaluation in Postmortem Human Alzheimer's Disease Brain Hippocampus and PET/CT Imaging in 5xFAD Transgenic Mice.

The diagnostic value of imaging Aß plaques in Alzheimer's disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [18F]flotaza, which shows high binding to Aß plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [18F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [18F]flotaza in transgenic 5xFAD mice expressing Aß plaques. [18F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aß and analyzed using QuPath. In vitro and in vivo [18F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aß. High [18F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WM♂/WM♀ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [18F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [18F]flotaza exhibited binding to Aß plaques in 5xFAD mice with SUVR~1.4. [18F]Flotaza is a new Aß plaque PET imaging agent that exhibited high binding to Aß plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [18F]flotaza to human PET studies may be worthwhile.

Development of [124/125I]IAZA as a New Proteinopathy Imaging Agent for Alzheimer's Disease.

Radioiodinated imaging agents for Aß amyloid plaque imaging in Alzheimer's disease (AD) patients have not been actively pursued. Our previous studies employed the "diaza" derivatives [11C]TAZA and [18F]flotaza in order to develop successful positron emission tomography (PET) imaging agents for Aß plaques. There is a need for radioiodinated imaging agents for Aß plaques for single photon emission computed tomography (SPECT) and PET imaging. We report our findings on the preparation of [124/125I]IAZA, a "diaza" analog of [11C]TAZA and [18F]flotaza, and the evaluation of binding to Aß plaques in the postmortem human AD brain. The binding affinity of IAZA for Aß plaques was Ki = 10.9 nM with weak binding affinity for neurofibrillary tangles (Ki = 3.71 µM). Both [125I]IAZA and [124I]IAZA were produced in >25% radiochemical yield and >90% radiochemical purity. In vitro binding of [125I]IAZA and [124I]IAZA in postmortem human AD brains was higher in gray matter containing Aß plaques compared to white matter (ratio of gray to white matter was >7). Anti-Aß immunostaining strongly correlated with [124/125I]IAZA in postmortem AD human brains. The binding of [124/125I]IAZA in postmortem human AD brains was displaced by the known Aß plaque imaging agents. Thus, radiolabeled [124/123I]IAZA may potentially be a useful PET or SPECT radioligand for Aß plaques in brain imaging studies.