Molecules containing lysine-ureido-glutamate functional groups bind to the active site of prostate specific membrane antigen, which is overexpressed in prostate cancer. To prepare copper radiopharmaceuticals for the diagnosis and therapyofprostate cancer,macrobicyclic sarcophagine ligands tethered to either one or two lysine-ureido-glutamate functional groups through an appropriate linker have been prepared. Sarcophagine ligands can be readily radiolabeled with positron-emitting copper-64 at room temperature.T he bivalent agent, in which two targeting groups are tethered to as ingle copper complex, dramatically outperforms the monomeric agent with respect to tumor uptake and retention. The high tumor uptake,l ow background, and prolonged tumor retention, even at 24 hours post injection, suggest the bivalent agent is apromising diagnostic for prostate cancer and could be used for prospective dosimetry for therapywith acopper-67 variant.

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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.

Positron emission tomography (PET) is an immensely important imaging modality in biomedical research and drug development but must use selective radiotracers to achieve biochemical specificity. Such radiotracers are usually labeled with carbon-11 (t1/2 = 20 min) or fluorine-18 (t1/2 = 110 min), but these are only available from cyclotrons in a few simple chemical forms. [18F]Fluoroform has emerged for labeling tracers in trifluoromethyl groups but is severely limited in utility by low radioactivity per mass (low molar activity). Here we describe the synthesis of [11C]fluoroform, based on CoF3-mediated fluorination of cyclotron-produced [11C]methane. This process is efficient and repetitively reliable. [11C]Fluoroform shows versatility for labeling small molecules in very high molar activity (> 200 GBq/μmol), far exceeding that possible from [18F]fluoroform. Therefore, [11C]fluoroform represents a major breakthrough for labeling prospective PET tracers in trifluoromethyl groups at high molar activity.