P4‐296: COMPETITIVE BINDING OF [11C]PIB AND [18F]NAV4694 IN A TRANSGENIC RAT MODEL OF AMYLOIDOSIS

PET imaging with amyloid-targeting radiotracers constitute an increasingly important modality for Alzheimer's Disease. Pittsburgh compound B ([11 C]PiB), the first of these tracers, has a short half-life limiting its widespread use, which has led to the development of first-generation fluorine-18 imaging agents. These agents demonstrate increased non-specific white matter binding compared to [11 C]PiB, which can hinder interpretation of the PET image. In contrast, the second-generation [18 F]NAV4694 exhibits little white matter uptake and an excellent signal-to-noise ratio. Preliminary studies suggest that [18 F]NAV4694 has both mutual and exclusive binding sites when compared to [11 C]PiB. We aimed to further examine this hypothesis by measuring the blocking of [11 C]PiB by cold NAV4694 in the McGill-R-Thy1-APP rat, a transgenic (Tg) model expressing aggregation of human amyloid. We hypothesized a dose-dependent blocking effect of NAV4694 on [11 C]PiB specific binding. A total of four Tg rats (male; aged 19 months) were imaged using [11 C]PiB, once without any blockage and a second time with an injection of either 12nmol/kg (n = 2) or 200nmol/kg (n = 2) of NAV4694 (precursor provided by Navidea Biopharmaceuticals Inc.) 15 minutes before the scan. The effect of NAV4694 blockage was measured as the percentage difference of BP ND (generated using SRTM with cerebellum as reference) at the voxel level. Compared to the baseline scans, 12nmol/kg blocking induced small reductions (5-13%) of [11 C]PiB BP ND across the cortical mantle only. The 200nmol/kg dose of NAV4694 induced widespread reductions, with an average [11 C]PiB BP ND reduction of 23.2% in the frontal cortex, 9.7% in the temporo-parietal cortices, 14.7% in the hippocampus, 24.2% in the striatum and 20% in the thalamus. The significant reductions in [11 C]PiB binding as a result of cold NAV4694 further verify a partial overlap between the binding sites of these two compounds. However, the magnitude of decreases are lower than expected for the high doses of cold competitor injected (5 and 83.3 times K d of NAV4694, respectively). This implies that these two radiotracers either have high levels of non-specific binding in this animal model, or that [11 C]PiB and [18 F]NAV4694 bind not only to the same but also to different sites or conformations of amyloid.

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