Positron emission tomography (PET) imaging of tau aggregation in Alzheimer’s disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [¹⁸F]OXD-2115, using ligand-based design. Over 150 analogues of OXD-2115 were synthesized and screened in post-mortem brain tissue for tau affinity against [³H]OXD-2115, and in silico models were used to predict brain uptake. [¹⁸F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies.

A chemical fingerprint search identified Z3777013540 (1-(5-(6-fluoro-1H-indol-2-yl)pyrimidin-2-yl)piperidin-4-ol; 1) as a potential 4R-tau binding ligand. Binding assays in post-mortem Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) brain with [³H]1 provided K_D (nM) values in AD = 4.0, PSP = 5.1, and CBD = 4.5. In vivo positron emission tomography (PET) imaging in rats with [¹⁸F]1 demonstrated good brain penetration and rapid clearance from normal brain tissues. A subsequent molecular similarity search using 1 as the query revealed an additional promising compound, Z4169252340 (4-(5-(6-fluoro-1H-indol-2-yl)pyrimidin-2-yl)morpholine; 21). Binding assays with [³H]21 provided K_D (nM) values in AD = 1.2, PSP = 1.6, and CBD = 1.7 and lower affinities for binding aggregated α-synuclein and amyloid-beta. PET imaging in rats with [¹⁸F]21 demonstrated a higher brain penetration than [¹⁸F]1 and rapid clearance from normal brain tissues. We anticipate that 1 and 21 will be useful for the identification of other potent novel 4R-tau radiotracers.

This paper describes pharmacokinetic analyses of the monoamine-oxidase-B (MAO-B) radiotracer [¹⁸F]( S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ([¹⁸F]SMBT-1) for positron emission tomography (PET) brain imaging. Brain MAO-B expression is widespread, predominantly within astrocytes. Reactive astrogliosis in response to neurodegenerative disease pathology is associated with MAO-B overexpression. Fourteen elderly subjects (8 control, 5 mild cognitive impairment, 1 Alzheimer’s disease) with amyloid ([¹¹C]PiB) and tau ([¹⁸F]flortaucipir) imaging assessments underwent dynamic [¹⁸F]SMBT-1 PET imaging with arterial input function determination. [¹⁸F]SMBT-1 showed high brain uptake and a retention pattern consistent with the known MAO-B distribution. A two-tissue compartment (2TC) model where the K₁/k₂ ratio was fixed to a whole brain value best described [¹⁸F]SMBT-1 kinetics. The 2TC total volume of distribution (V_T) was well identified and highly correlated (r²∼0.8) with post-mortem MAO-B indices. Cerebellar grey matter (CGM) showed the lowest mean V_T of any region and is considered the optimal pseudo-reference region. Simplified analysis methods including reference tissue models, non-compartmental models, and standard uptake value ratios (SUVR) agreed with 2TC outcomes (r² > 0.9) but with varying bias. We found the CGM-normalized 70–90 min SUVR to be highly correlated (r² = 0.93) with the 2TC distribution volume ratio (DVR) with acceptable bias (∼10%), representing a practical alternative for [¹⁸F]SMBT-1 analyses.

Structure-activity relationship studies were performed on a library of synthesized compounds based on previously identified tau ligands. The top 13 new compounds had K_i values in the range of 5-14 nM in Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) post-mortem brain tissues. One of the more promising new compounds ([³H]75) bound with high affinity in AD, PSP, and CBD tissues (K_D's = 1-1.5 nM) and Pick's disease tissue (K_D = 3.8 nM). Autoradiography studies with [³H]75 demonstrated specific binding in AD, PSP, and CBD post-mortem tissues. Nonhuman primate brain PET imaging with [¹⁸F]75 demonstrated a peak standardized uptake value (SUV) of ∼5 in the cerebellum, ∼4.5 in the cortex, and ∼4 in whole brain with SUV 2-to-90 min ratios of 3.9 in whole brain, 4.9 in cortex, and 4.5 in cerebellum. Compound [¹⁸F]75 is a promising candidate for translation to human brain PET imaging studies.

The development of positron emission tomography (PET) tracers targeting α-synuclein (α-syn) aggregates is critical for the early diagnosis, differential classification, and therapeutic monitoring of synucleinopathies such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Despite recent advances, challenges including the low abundance of α-syn aggregates (10–50× lower than amyloid-beta (Aβ) or Tau), structural heterogeneity (e.g., flat fibrils in PD vs. cylindrical forms in DLB), co-pathology with Aβ/Tau, and poor metabolic stability have hindered PET tracer development for this target. To optimize our previously reported pyridothiophene-based radiotracer, [¹⁸F]asyn-44, we present the synthesis and evaluation of novel S,N-heterocyclic scaffold derivatives for α-syn. A library of 49 compounds was synthesized, with 8 potent derivatives (LMD-006, LMD-022, LMD-029, LMD-044, LMD-045, LMD-046, LMD-051, and LMD-052) demonstrating equilibrium inhibition constants (K_i) of 6–16 nM in PD brain homogenates, all of which are amenable for radiolabeling with fluorine-18. This work advances the molecular toolkit for synucleinopathies and provides a roadmap for overcoming barriers in PET tracer development, with lead compounds that can be considered for biomarker-guided clinical trials and targeted therapies.

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer’s disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity 4-repeat (4R)-tau PET radiopharmaceutical for imaging non-AD tauopathies exists. Herein, the properties of analogues of a first-in-class 4R-tau lead, [¹⁸F]OXD-2115, are described. Over 150 analogues of OXD-2115 were synthesized and screened for tau affinity in vitro against [³H]OXD-2115, and in silico models were used to predict brain uptake. [¹⁸F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies.