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Introduction
Positron Emission Tomography (PET) imaging is the primary tool available to clinicians for assessing the presence and distribution of Aβ aggregates, a hallmark of Alzheimer’s Disease (AD) [1, 2–3], in the living human brain. Three 18F-imaging agents targeting Aβ plaques in the brain have been approved for clinical use by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA): [18F]AV-45 ([18F]florbetapir; Amyvid™) [4], [18F]AV-1 ([18F]florbetaben; Neuraceq™) [5], and [18F]3′-F-PIB ([18F]flutemetamol; Vizamyl™) [6]. Using these tracers, amyloid PET has demonstrated clinical utility in managing of patients with a diagnosis of either unexplained mild cognitive impairment (MCI) or dementia of uncertain origin [7].
There has been a renewed interest in amyloid PET due to the recent FDA approvals of lecanemab (Leqembi) [8] and Donanemab (Kisunla) [9], both monoclonal antibodies designed for removing soluble and insoluble Aβ in the brain. Both Kisunla and Leqembi are now commercially available for treatment of AD.
A prerequisite for any anti-plaque treatment is the detection of Aβ aggregates in the brain using PET imaging, particularly in cognitively normal aging individuals and patients with MCI or early dementia [9]. However, determining amyloid positivity in this population can be challenging due to the lower amyloid loads commonly observed and the high off-target binding to white matter, a characteristic of current amyloid PET tracers [10]. As part of our ongoing efforts to develop improved Aβ PET tracers, we have designed an N-deuterated version of AV-45. Recent preclinical studies suggest that this new N-deuterated radiotracer exhibits comparable affinity and selectivity for Aβ plaques to [18F]AV-45 in the brain [11]. Additionally, deuterium substitution is a well-established strategy in PET drug design to enhance pharmacokinetics, primarily by reducing the formation of radioactive metabolites that could degrade imaging performance [12]. Collectively, these properties of [18F]D3FSP may enhance the detectability of Aβ species compared to conventional AV-45. Reported herein are the results of a head-to-head comparison study using [18F]D3FSP and [18F]AV-45 in eight (8) AD patients to evaluate the effects of N-methyl deuteriation on imaging metrics of amyloid plaque specific binding. In addition, a separate biodistribution study was conducted using [18F]D3FSP in six healthy...