[¹⁸F]THK-523 and [¹⁸F]807 are promising radioligands for imaging neurofibrillary tangles (NFTs) with positron emission tomography (PET) in neurodegenerative diseases, such as Alzheimer’s disease (AD) and traumatic brain injury. Although [¹⁸F]THK-523 and [¹⁸F]T807 are considered high-affinity selective radioligands for NFTs, uncertainty has existed as to whether PET radioligands for imaging NFTs bind to the same molecular site because in vitro assays for ligands binding to NFTs have been lacking. We labeled THK-523 and T807 with tritium to serve as reference radioligands for in vitro binding assays with AD brain homogenates for newly synthesized ligands. With these radioligands, we identified two distinct binding sites for small molecules, one site with high affinity for THK-523 and the other with high affinity for T807. Moreover, binding assays with [³H]PIB confirmed that the two newly identified binding sites are also distinct from the thioflavin-T binding site where all current clinically useful PET radioligands for imaging β-amyloid plaque bind with high affinity. The two newly identified binding sites are considered to reside on NFTs rather than on β-amyloid plaques. Furthermore, we applied all three binding assays to a set of newly prepared compounds, based on chain modifications to THK-523. Some compounds with high affinity and selectivity for the THK-523 binding site emerged from this set, including one with amenability to labeling with fluorine-18, namely, ligand 10b.

A new method is described for the synthesis of imidazo[1,2-a]pyridine derivatives from the reaction of 2-aminopyridines with α-haloketones. The critical reagent is titanium(IV) chloride, which appears to serve as a strong dehydrating agent to promote formation of putative Schiff base intermediates, which cyclize subsequently to form the products. The reactions were performed rapidly under microwave conditions. Multiple reaction conditions were evaluated, including reaction temperature, solvent and other Lewis acids. Various combinations of substitution patterns in both the α-haloketone and 2-aminopyridine substrates were examined to evaluate the scope of the reaction. The reaction is quite sensitive to substituents in both substrates, especially those with basicity or coordination ability.

[S-Methyl-¹¹C](±)-7-methoxy-3-(4-(4-(methylthio)phenyl)butyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol (¹¹C-NR2B-SMe) and its enantiomers were synthesized as candidates for imaging the NR2B subunit within the N-methyl-D-aspartate receptor with positron emission tomography (PET). Methods: Brains were scanned with PET for 90 min after intravenous injection of one of the candidate radioligands into rats. To detect any NR2B specific binding of radioligand in brain, various pre-blocking or displacing agents were evaluated for their impact on the PET brain imaging data. Radiometabolites from brain and other tissues were measured ex vivo and in vitro. Results: Each radioligand gave high early whole brain uptake of radioactivity, followed by a brief fast decline and then a slow final decline. ¹¹C-(S)-NR2B-SMe was studied extensively. Ex vivo measurements showed that radioactivity in rat brain at 30 min after radioligand injection was virtually unchanged radioligand. Only less lipophilic radiometabolites appeared in plasma. High-affinity NR2B ligands, Ro-25-6981, ifenprodil, and CO10124, showed increasing preblock of whole brain radioactivity retention with increasing dose (0.01 to 1.25 mg/kg, i.v.). Five σ1 antagonists (FTC146, BD1407, F3, F4, and NE100) and four σ1 agonists ((+)-pentazocine, (±)-PPCC, PRE-084, (+)-SKF10047) were ineffective preblocking agents, except FTC146 and F4 at high dose. Two potent σ1 receptor agonists, TC1 and SA4503, showed dose-dependent preblocking effects in the presence or absence of pharmacological σ1 receptor blockade with FTC146. Conclusion: ¹¹C-(S)-NR2B-SMe has adequate NR2B-specific PET signal in rat brain to warrant further evaluation in higher species. TC1 and SA4503 likely have off-target binding to NR2B in vivo.

In the field of ultra-precision manufacturing, such as lithography lenses, achieving nanometer-level errors across the entire frequency range is crucial. Magnetorheological finishing (MRF) technology, a high-precision processing method with high efficiency and low subsurface damage, often introduces mid-spatial frequency (MSF) error due to the removal attenuation effect and regular polishing trajectory in the long continuous polishing process. It causes various imaging and light transmission defects that limit the performance of precision optical instruments. The attenuation of material removal capacity of MRF is characterized by the attenuation of the tool influence function, which is obtained by an equal time interval point removal experiment. The variable optimal angle-step trajectory strategy is proposed to mitigate the removal attenuation effect of MRF and suppress MSF error. To validate the effectiveness and practicability of the proposed method, a uniform polishing experiment is performed on fused silica components. The experimental results show that the 90° grating trajectory introduces significant MSF error on surface shape with PV = 0.008 λ, and the variable optimal angle-step trajectory strategy does not introduce MSF error, which confirms the variable optimal angle-step trajectory strategy effectively eliminates the removal attenuation effect of MRF and suppresses MSF error. The study presents a general approach for ultra-precision optical processing and improves the manufacturing accuracy of optical components.