Chemical synapses are the predominant neuron-to-neuron contact in the central nervous system. Presynaptic boutons of neurons contain hundreds of vesicles filled with neurotransmitters, the diffusible signaling chemicals. Changes in the number of synapses are associated with numerous brain disorders, including Alzheimer's disease and epilepsy. However, all current approaches for measuring synaptic density in humans require brain tissue from autopsy or surgical resection. We report the use of the synaptic vesicle glycoprotein 2A (SV2A) radioligand [(11)C]UCB-J combined with positron emission tomography (PET) to quantify synaptic density in the living human brain. Validation studies in a baboon confirmed that SV2A is an alternative synaptic density marker to synaptophysin. First-in-human PET studies demonstrated that [(11)C]UCB-J had excellent imaging properties. Finally, we confirmed that PET imaging of SV2A was sensitive to synaptic loss in patients with temporal lobe epilepsy. Thus, [(11)C]UCB-J PET imaging is a promising approach for in vivo quantification of synaptic density with several potential applications in diagnosis and therapeutic monitoring of neurological and psychiatric disorders.

Synaptic vesicle glycoprotein 2A (SV2A) is a 12-pass transmembrane glycoprotein ubiquitously expressed in presynaptic vesicles. In vivo imaging of SV2A using PET has potential applications in the diagnosis and prognosis of a variety of neuropsychiatric diseases, e.g., Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, autism, epilepsy, stroke, traumatic brain injury, post-traumatic stress disorder, depression, etc. Herein, we report the synthesis and evaluation of a new 18 Flabeled SV2A PET imaging probe, [ 18 F]SynVesT-2, which possesses fast in vivo binding kinetics and high specific binding signals in non-human primate brain.

The σ receptors (S1Rs) are implicated in a variety of diseases including Alzheimer disease and cancer. Previous PET S1R radiotracers are characterized by slow kinetics or off-target binding that impedes their use in humans. Here, we report the first PET imaging evaluation in rhesus monkeys of 4 F-labeled spirocyclic piperidine-based PET radiotracers (F- to F-). Baseline scans for the 4 radiotracers were obtained on an adult male rhesus monkey. Blocking scans were obtained with the S1R-selective agonist SA4503 to assess binding specificity ofF- and F- Arterial input functions were measured, and binding parameters were determined with kinetic modeling analysis. In the rhesus brain, all 4 radiotracers showed high and fast uptake. Tissue activity washout was rapid forF- and F-, and much slower for F- and F-, in line with their respective in vitro S1R-binding affinities. Both the 1-tissue-compartment and multilinear analysis-1 kinetic models provided good fits of time-activity curves and reliable estimates of distribution volume. Regional distribution volume values were highest in the cingulate cortex and lowest in the thalamus for all radiotracers. F- showed greater differential uptake across brain regions and 3-fold-higher binding potential than F- SA4503 at the dose of 0.5 mg/kg blocked approximately 85% (F-) and 95% (F-) of radiotracer binding. TracersF- and F- displayed high brain uptake and fast tissue kinetics, with F- having higher specific binding signals than F- in the same monkey. Taken together, these data indicate that both F- and F- possess the requisite kinetic and imaging properties as viable PET tracers for imaging S1R in the human brain.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of cortisone to cortisol and controls a key pathway in the regulation of stress. Studies have implicated 11β-HSD1 in metabolic diseases including type 2 diabetes and obesity, as well as stress-related disorders and neurodegenerative diseases, such as depression and Alzheimer's disease (AD). We have previously developed [ 11 C]AS2471907 as a PET radiotracer to image 11β-HSD1 in the brain of nonhuman primates and humans. However, the radiosynthesis of [ 11 C]AS2471907 was unreliable and low-yielding. Here, we report the development of the 18 F-labeled version [ 18 F]AS2471907, including the synthesis of two iodonium ylide precursors and the optimization of 18 F-radiosynthesis. Preliminary PET experiments, composed of a baseline scan of [ 18 F]AS2471907 and a blocking scan with the reversible 11β-HSD1 inhibitor ASP3662 (0.3 mg/kg), was also conducted in a rhesus monkey to verify the pharmacokinetics of [ 18 F]AS2471907 and its specific binding in the brain. The iodonium ylide precursors were prepared in a seven-step synthetic route with an optimized overall yield of ∼2%. [ 18 F]AS2471907 was synthesized in good radiochemical purity, with the ortho regioisomer of iodonium ylide providing greater radiochemical yield as compared with the para regioisomer. In monkey brain, [ 18 F]AS2471907 displayed high uptake and heterogeneous distribution, while administration of the 11β-HSD1 inhibitor ASP3662 significantly reduced radiotracer uptake, thus demonstrating the binding specificity of [ 18 F]AS2471907. Given the longer half-life of F-18 and feasibility for central production and distribution, [ 18 F]AS2471907 holds great promise to be a valuable PET radiotracer to image 11β-HSD1 in the brain.

We report a convenient radiosynthesis and the first positron emission tomography (PET) imaging evaluation of [ 18 F]FBFP as a potent sigma-1 (σ 1 ) receptor radioligand with advantageous characteristics. [ 18 F]FBFP was synthesized in one step from an iodonium ylide precursor. In cynomolgus monkeys, [ 18 F]FBFP displayed high brain uptake and suitable tissue kinetics for quantitative analysis. It exhibited heterogeneous distribution with higher regional volume of distribution (V T ) values in the amygdala, hippocampus, insula, and frontal cortex. Pretreatment with the σ 1 receptor agonist SA4503 (0.5 mg/kg) significantly reduced radioligand uptake in the monkey brain (>95%), indicating high binding specificity of [ 18 F]FBFP in vivo. Compared with (S)-[ 18 F]fluspidine, [ 18 F]FBFP possessed higher regional nondisplaceable binding potential (BP ND ) values across the brain regions. These findings demonstrate that [ 18 F]FBFP is a highly promising PET radioligand for imaging and quantification of σ 1 receptors in humans.