Background: Cyclooxygenase-2 (COX-2), which is rapidly upregulated by inflammation, is a key enzyme catalyzing the rate-limiting step in the synthesis of several inflammatory prostanoids. Successful positron emission tomography (PET) radioligand imaging of COX-2 in vivo could be a potentially powerful tool for assessing inflammatory response in the brain and periphery. To date, however, the development of PET radioligands for COX-2 has had limited success. Methods: The novel PET tracer [ 11 C]MC1 was used to examine COX-2 expression [1] in the brains of four rhesus macaques at baseline and after injection of the inflammogen lipopolysaccharide (LPS) into the right putamen, and [2] in the joints of two human participants with rheumatoid arthritis and two healthy individuals. In the primate study, two monkeys had one LPS injection, and two monkeys had a second injection 33 and 44 days, respectively, after the first LPS injection. As a comparator, COX-1 expression was measured using [ 11 C]PS13. Results: COX-2 binding, expressed as the ratio of specific to nondisplaceable uptake (BP ND) of [ 11 C]MC1, increased on day 1 post-LPS injection; no such increase in COX-1 expression, measured using [ 11 C]PS13, was observed. The day after the second LPS injection, a brain lesion (~0.5 cm in diameter) with high COX-2 density and high BP ND (1.8) was observed. Postmortem brain analysis at the gene transcript or protein level confirmed in vivo PET results. An incidental finding in an unrelated monkey found a line of COX-2 positivity along an incision in skull muscle, demonstrating that [ 11 C]MC1 can localize inflammation peripheral to the brain. In patients with rheumatoid arthritis,
Accumulation of hyper-phosphorylated tau, a microtubule-associated protein, plays an important role in the progression of Alzheimer's disease (AD). Animal studies suggest that one strategy for treating AD and related tauopathies may be inhibition of O-GlcNAcase (OGA), which may subsequently decrease pathological tau phosphorylation Here, we report the pharmacokinetics of a novel positron emission tomography (PET) radioligand, F-LSN3316612, which binds with high affinity and selectivity to OGA. PET imaging was performed in rhesus monkeys at baseline and after administration of either thiamet G, a potent OGA inhibitor, or nonradioactive LSN3316612. The density of the enzyme was calculated as distribution volume (VT) using a two-tissue compartment model and serial concentrations of parent radioligand in arterial plasma. The radiation burden for future studies was calculated based on whole-body imaging of monkeys. Oga∆Br, a mouse brain-specific knockout of Oga, was also scanned to assess the specificity of the radioligand for its target enzyme. Uptake of radioactivity in monkey brain was high (~5 SUV) and followed by slow washout. The highest uptake was in the amygdala, followed by striatum and hippocampus. Pretreatment with thiamet G or nonradioactive LSN3316612 reduced brain uptake to a low and uniform concentration in all regions, corresponding to an approximately 90% decrease in VT. Whole-body imaging in rhesus monkeys showed high uptake in kidney, spleen, liver, and testes. In Oga∆Br mice, brain uptake ofF-LSN3316612 was reduced by 82% compared to control mice. Peripheral organs were unaffected in Oga∆Br mice, consistent with loss of OGA expression exclusively in the brain. The effective dose of F- LSN3316612 in humans was calculated to be 22 µSv/MBq, which is typical forF-labeled radioligands. These results show thatF-LSN3316612 is an excellent radioligand for imaging and quantifying OGA in rhesus monkeys and mice. Based on these data, F-LSN3316612 merits evaluation in humans.
The use of nanometer-sized semiconductor crystals, known as quantum dots, allows us to directly observe individual biomolecular transactions through a fluorescence microscope. Here, we review the evolution of single quantum dot tracking over the past two decades, highlight key biophysical discoveries facilitated by quantum dots, briefly discuss biochemical and optical implementation strategies for a single quantum dot tracking experiment, and report recent accomplishments of our group at the interface of molecular neuroscience and nanoscience.
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