ABSTRACT
We have discovered and synthesized a series of indole-based derivatives as novel sigma-2 (σ 2) receptor ligands. Two ligands with high σ 2 receptor affinity and subtype selectivity were then radiolabeled with F-18 in good radiochemical yields and purities, and evaluated in rodents. In biodistribution studies in male ICR mice, radioligand [18F]9, or 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[18F]fluoroethoxy)-1H-indole, was found to display high brain uptake and high brain-to-blood ratio. Pretreatment of animals with the selective σ 2 receptor ligand CM398 led to significant reductions in both brain uptake (29%-54%) and brain-to-blood ratio (60%-88%) of the radioligand in a dose-dependent manner, indicating high and saturable specific binding of [18F]9 to σ 2 receptors in the brain. Further, ex vivo autoradiography in male ICR mice demonstrated regionally heterogeneous specific binding of [18F]9 in the brain that is consistent with the distribution pattern of σ 2 receptors. Dynamic positron emission tomography imaging confirmed regionally distinct distribution and high levels of specific binding for [18F]9 in the rat brain, along with appropriate tissue kinetics. Taken together, results from our current study indicated the novel radioligand [18F]9 as the first highly specific and promising imaging agent for σ 2 receptors in the brain.
ABSTRACT
Objective To investigate the predictive factors affecting the efficacy of cyclophosphamide (CTX) combined with glucocorticoids in the treatment of idiopathic membranous nephropathy (IMN),and to evaluate the efficacy of calcineurin inhibitor (CNI) adjustment due to poor treatment.Methods A retrospective cohort study was conducted.Two hundreds and twenty-eight patients with IMN diagnosed by renal biopsy in the People's Hospital of Guangxi Zhuang Autonomous Region from January 1,2007 to December 1,2016 were enrolled.All subjects were treated with CTX in combination with glucocorticoids.The patients were divided into two groups:remission group and no remission group.Multivariable logistic regression analysis was used to determine the baseline clinical-pathological influencing factors for the remission of IMN in the enrolled patients.Results The number of total remission (including complete and partial remission) of the first CTX combined with glucocorticoid treatment in 228 patients with IMN was 188(82.5％).Among them,141 patients (61.8％) had complete remission (CR),the median time for CR was 8(6,12) months,and the median time for partial remission (PR) was 3(1,4) months.The median follow-up time for this study was 25(13,43) months.Compared with the remission group,the serum albumin level was lower in the non-remission group,the 24-hour urine protein content,the blood complement C3 and C4 levels were higher,and the pathological stage was milder (all P ＜ 0.05).Multivariate logistic regression analysis suggested that the levels of baseline serum albumin,complement C4,and pathological stage were independent predictors of clinical remission in IMN patients.Twenty-four non-remission patients were treated with CNI.The overall response rate was 66.7％(16/24) at 6 months and 77.3％(17/22) at 12 months.Conclusions The levels of baseline albumin,blood complement C4,and pathological stage were independent predictors of clinical remission in IMN patients treated with CTX plus glucocorticoids.The non-remission patients with CTX combined with glucocorticoid therapy can still achieve a higher response rate after adjusting for CNI.
ABSTRACT
Many brain disorders do not show visible lesions and most likely are resulted from abnormalities in regional brain activity or connectivity.Conventional diagnostic neuroimaging techniques are not capable of precisely localizing the abnormal brain activity,but the recently developed integrated PET/MR technology may have the potential to bridge this gap.Integrated PET/MR has been used in clinical practice.However,its primary application is still a combination of functional PET imaging and structural MRI.Simultaneous PET/fMRI,a "functional+functional" imaging technique,holds the advantages of high spatial and temporal resolution,high sensitivity and specificity,and non-invasiveness.Globally,simultaneous PET/fMRI research is still in its beginning stage,and a few initial PET/fMRI studies have shown that voxel-wise correlation between PET and fMRI metrics was not very high,indicating that they may reflect very different aspects of brain activity.To date more than 5 integrated PET/MR scanners have been set up in mainland China.China has the largest patient population,rapidly developing PET imaging techniques,and well-established capabilities in fMRI neuroimaging analytics.PET/fMRI studies require multi-disciplinary collaborations in nuclear medicine,radiology,chemistry,medical physics,computation science,and cognitive neuroscience.At the moment,the research management system in Chinese hospitals is not conducive to such collaborations and further improvement is needed to encourage multi-disciplinary research such as PET/fMRI.Given the known advantages in patient population and other resources,multi-center and multi-disciplinary studies hold the potential to put China at the leading edge of PET/fMRI research and produce high value results that will advance both neuroimaging sciences and future patient care in brain disorders.