Monoacylglycerol lipase (MAGL) is one of the key enzymes in the endocannabinoid system. Inhibition of MAGL has been proposed as an attractive approach for the treatment of various diseases. In this study, we designed and successfully synthesized two series of piperazinyl pyrrolidin-2-one derivatives as novel reversible MAGL inhibitors. (R)-[18F]13 was identified through the preliminary evaluation of two carbon-11-labeled racemic structures [11C]11 and [11C]16. In dynamic positron-emission tomography (PET) scans, (R)-[18F]13 showed a heterogeneous distribution and matched the MAGL expression pattern in the mouse brain. High brain uptake and brain-to-blood ratio were achieved by (R)-[18F]13 in comparison with previously reported reversible MAGL PET radiotracers. Target occupancy studies with a therapeutic MAGL inhibitor revealed a dose-dependent reduction of (R)-[18F]13 accumulation in the mouse brain. These findings indicate that (R)-[18F]13 ([18F]­YH149) is a highly promising PET probe for visualizing MAGL non-invasively in vivo and holds great potential to support drug development.

Minimally invasive unilateral pedicle screw fixation for the treatment of degenerative lumbar diseases has won the support of many surgeons. However, few data are available regarding clinical research on unilateral pedicle screw fixation associated with minimally invasive techniques for the treatment of lumbar spinal diseases. The purpose of this study was to evaluate clinical outcomes in a selected series of patients with lumbar degenerative diseases treated with minimally invasive unilateral vs classic bilateral pedicle screw fixation and lumbar interbody fusion. Patients in the unilateral group (n=43) underwent minimally invasive unilateral pedicle screw fixation with the Quadrant system (Medtronic, Memphis, Tennessee). The bilateral group (n=42) underwent bilateral instrumentation via the classic approach. Visual analog scale pain scores, Oswestry Disability Index scores, fusion rate, operative time, blood loss, and complications were analyzed. Mean operative time was 75 minutes in the unilateral group and 95 minutes in the bilateral group. Mean blood loss was 220 mL in the unilateral group and 450 mL in the bilateral group. Mean postoperative visual analog scale pain score was 3.10±0.16 in the unilateral group and 3.30±1.10 in the bilateral group. Mean postoperative Oswestry Disability Index score was 15.67±2.3 in the unilateral group and 14.93±2.6 in the bilateral group. Successful fusion was achieved in 92.34% of patients in the unilateral group and 93.56% of patients in the bilateral group. Minimally invasive unilateral pedicle screw fixation is an effective and reliable option for the surgical treatment of lumbar degenerative disease. It causes less blood loss, requires less operative time, and has a fusion rate comparable with that of conventional bilateral fixation.

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We have designed and synthesized novel piperazine compounds with low lipophilicity as σ receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine (10) possessed a low nanomolar σ receptor affinity and a high selectivity toward the vesicular acetylcholine transporter (>2000-fold), σ receptors (52-fold), and adenosine A, adrenergic α, cannabinoid CB, dopamine D, D, γ-aminobutyric acid A (GABA), NMDA, melatonin MT, MT, and serotonin 5-HT receptors. The corresponding radiotracer [F]10 demonstrated high brain uptake and extremely high brain-to-blood ratios in biodistribution studies in mice. Pretreatment with the selective σ receptor agonist SA4503 significantly reduced the level of accumulation of the radiotracer in the brain. No radiometabolite of [F]10 was observed to enter the brain. Positron emission tomography and magnetic resonance imaging confirmed suitable kinetics and a high specific binding of [F]10 to σ receptors in rat brain. Ex vivo autoradiography showed a reduced level of binding of [F]10 in the cortex and hippocampus of the senescence-accelerated prone (SAMP8) compared to that of the senescence-accelerated resistant (SAMR1) mice, indicating the potential dysfunction of σ receptors in Alzheimer's disease.

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