健康人体中5-羟色胺转运体放射性配体11C-DASB和11C-McN 5652的比较评估

Comparative evaluation of serotonin transporter radioligands 11C-DASB and 11C-McN 5652 in healthy humans.

作者信息

Frankle W Gordon, Huang Yiyun, Hwang Dah-Ren, Talbot Peter S, Slifstein Mark, Van Heertum Ronald, Abi-Dargham Anissa, Laruelle Marc

机构信息

Department of Psychiatry, Columbia University College of Physicians and Surgeons, and the New York State Psychiatric Institute, New York, New York, USA.

出版信息

J Nucl Med. 2004 Apr;45(4):682-94.

PMID:15073266

Abstract

UNLABELLED

Alterations of serotonin transporters (SERT) are implicated in a large number of psychiatric conditions. (11)C-(+)-6beta-(4-Methylthiophenyl)-1,2,3,5,6alpha,10beta-hexahydropyrrolo[2,1-a]isoquinoline ((11)C-McN 5652) was the first PET radiotracer successfully developed as a SERT imaging agent. Recently, (11)C-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile ((11)C-DASB) was introduced as an alternative to (11)C-McN 5652. Comparative evaluation of (11)C-DASB and (11)C-McN 5652 in baboons indicates that (11)C-DASB is associated with (a) lower nonspecific binding in the brain, (b) higher plasma free fraction, and (c) faster plasma clearance and brain uptake kinetics, enabling measurement of SERT parameters in a shorter scanning time. The purpose of this study was to compare these 2 agents in healthy humans.

METHODS

Six healthy volunteers underwent 2 PET scans on the same day, one with (11)C-DASB and one with (11)C-McN 5652, in counterbalanced order. Regional distribution volumes (V(T)) were derived for 16 brain regions by kinetic analysis using the arterial input function.

RESULTS

Both (11)C-DASB and (11)C-McN 5652 displayed similar patterns of accumulation: highest levels in the midbrain, thalamus and striatum; intermediate in the limbic regions; low in the neocortex; and lowest in the cerebellum. (11)C-DASB cerebellar V(T) (10.1 +/- 2.0 mL g(-1)) was lower than that of (11)C-McN 5652 (20.8 +/- 3.6 mL g(-1)), indicating lower nonspecific binding. As a result, regional specific-to-nonspecific equilibrium partition coefficients (V(3)") of (11)C-DASB were higher compared with those of (11)C-McN 5652 (for example, midbrain V(3)" of (11)C-DASB and (11)C-McN 5652 were 2.04 +/- 0.44 and 1.20 +/- 0.34, respectively). The plasma free fraction was 8.9% +/- 1.6% for (11)C-DASB and was not measurable for (11)C-McN 5652. In contrast to the situation observed in baboons, plasma clearances of both compounds were similar in humans, and the minimal scanning times required to derive time-invariant distribution volumes in all regions were comparable for both tracers (95 min).

CONCLUSION

With the exception of the scanning time, predictions from baboon studies were confirmed in humans. The higher specific-to-nonspecific ratios of (11)C-DASB are a critical advantage. This property will be especially important for the measurement of SERT in regions with moderate density, such as the limbic regions, where alterations of serotonin transmission might be associated with anxiety and depression.

摘要

未标注

血清素转运体（SERT）的改变与大量精神疾病有关。（11）C-（+）-6β-（4-甲基硫苯基）-1,2,3,5,6α,10β-六氢吡咯并[2,1-a]异喹啉（（11）C-McN 5652）是首个成功开发的作为SERT成像剂的正电子发射断层扫描（PET）放射性示踪剂。最近，（11）C-3-氨基-4-（2-二甲基氨基甲基苯硫基）苄腈（（11）C-DASB）作为（11）C-McN 5652的替代品被引入。对狒狒体内（11）C-DASB和（11）C-McN 5652的比较评估表明，（11）C-DASB具有以下特点：（a）在脑中的非特异性结合较低；（b）血浆游离分数较高；（c）血浆清除和脑摄取动力学较快，从而能够在更短的扫描时间内测量SERT参数。本研究的目的是在健康人体内比较这两种药物。

方法

6名健康志愿者在同一天接受2次PET扫描，一次使用（11）C-DASB，一次使用（11）C-McN 5652，顺序相互平衡。通过使用动脉输入函数的动力学分析得出16个脑区的区域分布容积（V（T））。

结果

（11）C-DASB和（11）C-McN 5652均表现出相似的聚集模式：中脑、丘脑和纹状体中的水平最高；边缘区域中等；新皮质中较低；小脑中最低。（11）C-DASB的小脑V（T）（10.1±2.0 mL g-1）低于（11）C-McN 5652（20.8±3.6 mL g-1），表明非特异性结合较低。因此，与（11）C-McN 5652相比，（11）C-DASB的区域特异性与非特异性平衡分配系数（V（3）"）更高（例如，（11）C-DASB和（11）C-McN 5652的中脑V（3）"分别为2.04±0.44和1.20±0.34）。（11）C-DASB的血浆游离分数为8.9%±1.6%，而（11）C-McN 5652的血浆游离分数无法测量。与在狒狒中观察到的情况相反，两种化合物在人体内的血浆清除率相似，并且两种示踪剂在所有区域得出时间不变分布容积所需的最短扫描时间相当（95分钟）。