狒狒中F-FP-DTBZ的活性和非活性对映体与胰腺VMAT2结合的评估。
Evaluation of pancreatic VMAT2 binding with active and inactive enantiomers of F-FP-DTBZ in baboons.
作者信息
Naganawa Mika, Lin Shu-Fei, Lim Keunpoong, Labaree David, Ropchan Jim, Harris Paul, Huang Yiyun, Ichise Masanori, Carson Richard E, Cline Gary W
机构信息
Yale University, 801 Howard Avenue, PO Box 208048, New Haven, CT, United States, 06520.
Columbia University, New York, NY, United States.
出版信息
Nucl Med Biol. 2016 Dec;43(12):743-751. doi: 10.1016/j.nucmedbio.2016.08.018. Epub 2016 Sep 2.
INTRODUCTION
F-Fluoropropyl-(+)-dihydrotetrabenazine (F-FP-(+)-DTBZ) is a vesicular monoamine transporter type 2 (VMAT2) radiotracer for positron emission tomography (PET) imaging to quantify human β-cell mass. Renal cortex and spleen have been suggested as reference regions, however, little is known about F-FP-(+)-DTBZ binding in these regions including the fraction of radiometabolite. We compared the kinetics of F-FP-(+)-DTBZ and its inactive enantiomer F-FP-(-)-DTBZ in baboons, estimated the non-displaceable binding (V) of the tracers, and used ex vivo studies to measure radiometabolite fractions.
METHODS
PET scans were conducted for up to 4h with (+) and (-) enantiomers. Displacement experiments using unlabeled (+) and (-) enantiomers of FP-DTBZ and fluvoxamine (to evaluate sigma-1 receptor binding) were performed. SUV curves were used to calculate displacement values in the pancreas, renal cortex, and spleen. Distribution volumes (V) were computed, and three approaches for calculation of V were compared: (1) F-FP-(+)-DTBZ reference V, (2) F-FP-(-)-DTBZ pancreatic V, and (3) a scaled F-FP-(+)-DTBZ reference V values. Ex vivo study was conducted to measure radiometabolite fraction in homogenized tissue samples from baboons at 90min post-injection.
RESULTS
Spleen uptake was lowest for both tracers. Highest uptake was in the pancreas with F-FP-(+)-DTBZ and renal cortex with F-FP-(-)-DTBZ. Substantial displacement effect was observed only with unlabeled FP-(+)-DTBZ in the F-FP-(+)-DTBZ studies. Radiometabolite fraction was higher in the renal cortex than the spleen. Approaches (1) and (3) with spleen to estimate V provided lowest inter-subject variability of BP.
CONCLUSIONS
V differences among organs and between enantiomers indicated that scaling of reference region values is needed for quantification of VMAT2 binding in the pancreas with F-FP-(+)-DTBZ. Since the kidney PET signal has greater partial volume averaging and more radiometabolites, the spleen was considered a more practical candidate for use as a scaled-reference region in the quantification of F-FP-(+)-DTBZ in the pancreas.
引言
F - 氟丙基 -（+）- 二氢丁苯那嗪（F - FP -（+）- DTBZ）是一种用于正电子发射断层扫描（PET）成像的囊泡单胺转运体2（VMAT2）放射性示踪剂，用于量化人体β细胞质量。肾皮质和脾脏已被提议作为参考区域，然而，关于F - FP -（+）- DTBZ在这些区域的结合情况，包括放射性代谢物的比例，人们了解甚少。我们比较了狒狒体内F - FP -（+）- DTBZ及其无活性对映体F - FP -（-）- DTBZ的动力学，估计了示踪剂的非置换性结合（V），并通过体外研究测量放射性代谢物比例。
方法
使用（+）和（-）对映体进行长达4小时的PET扫描。使用未标记的FP - DTBZ和氟伏沙明（用于评估σ-1受体结合）的对映体进行置换实验。SUV曲线用于计算胰腺、肾皮质和脾脏中的置换值。计算分布容积（V），并比较三种计算V的方法：（1）F - FP -（+）- DTBZ参考V，（2）F - FP -（-）- DTBZ胰腺V，以及（3）缩放后的F - FP -（+）- DTBZ参考V值。在注射后90分钟对狒狒的匀浆组织样本进行体外研究，以测量放射性代谢物比例。
结果
两种示踪剂在脾脏中的摄取量最低。F - FP -（+）- DTBZ在胰腺中的摄取量最高，F - FP -（-）- DTBZ在肾皮质中的摄取量最高。在F - FP -（+）- DTBZ研究中，仅未标记的FP -（+）- DTBZ观察到显著的置换效应。肾皮质中的放射性代谢物比例高于脾脏。用脾脏估计V的方法（1）和（3）提供了最低的心间变异性BP。
结论
各器官之间以及对映体之间的V差异表明，在用F - FP -（+）- DTBZ量化胰腺中VMAT2结合时，需要对参考区域值进行缩放。由于肾脏PET信号具有更大的部分容积平均效应和更多的放射性代谢物，脾脏被认为是在量化胰腺中F - FP -（+）- DTBZ时更实用的缩放参考区域候选者。
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