[F]JNJ-64326067的临床评估，一种用于检测阿尔茨海默病中tau蛋白病理的新型正电子发射断层显像（PET）示踪剂。
Clinical evaluation of [F] JNJ-64326067, a novel candidate PET tracer for the detection of tau pathology in Alzheimer's disease.
作者信息
Schmidt Mark E, Janssens Luc, Moechars Diederik, Rombouts Frederik J R, Timmers Maarten, Barret Olivier, Constantinescu Cristian C, Madonia Jennifer, Russell David S, Sandiego Christine M, Kolb Hartmuth
机构信息
Janssen Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium.
Invicro, a Konica Minolta company, New Haven, CT, USA.
出版信息
Eur J Nucl Med Mol Imaging. 2020 Dec;47(13):3176-3185. doi: 10.1007/s00259-020-04880-1. Epub 2020 Jun 13.
PURPOSE
The accumulation of misfolded tau is a common feature of several neurodegenerative disorders, with Alzheimer's disease (AD) being the most common. Earlier we identified JNJ-64326067, a novel isoquinoline derivative with high affinity and selectivity for tau aggregates from human AD brain. We report the dosimetry of [F] JNJ-64326067 and results of a proof-of-concept study comparing subjects with probable Alzheimer's disease to age-matched healthy controls.
METHODS
[F] JNJ-64326067 PET scans were acquired for 90 min and then from 120 to 180 min in 5 participants with [F]-florbetapir PET amyloid positive probable AD (73 ± 9 years) and 5 [F]-florbetapir PET amyloid negative healthy controls (71 ± 7 years). Whole-body [F] JNJ-64326067 PET CT scans were acquired in six healthy subjects for 5.5 h in 3 scanning sessions. Brain PET scans were visually reviewed. Regional quantification included kinetic analysis of distribution volume ration (DVR) estimated by Logan graphical analysis over the entire scan and static analysis of SUVr in late frames. Both methods used ventral cerebellar cortex as a reference region.
RESULTS
One of the healthy controls had focal areas of PET signal in occipital and parietal cortex underlying the site of a gunshot injury as an adolescent; the other four healthy subjects had no tau brain signal. Four of the 5 AD participants had visually apparent retention of [F] JNJ-64326067 in relevant cortical regions. One of the AD subjects was visually negative. Cortical signal in visually positive subjects approached steady state by 120 min. Temporal and frontal cortical SUVr/DVR values in visually positive AD subjects ranged from 1.21 to 3.09/1.2 to 2.18 and from 0.92 to 1.28/0.91 to 1.16 in healthy controls. Whole-body effective dose was estimated to be 0.0257 mSv/MBq for females and 0.0254 mSv/MBq for males.
CONCLUSIONS
[F] JNJ-64326067 could be useful for detection and quantitation of tau aggregates.
目的
错误折叠的tau蛋白积累是几种神经退行性疾病的共同特征，其中阿尔茨海默病（AD）最为常见。我们之前鉴定出JNJ-64326067，这是一种新型异喹啉衍生物，对来自人类AD脑的tau聚集体具有高亲和力和选择性。我们报告了[F]JNJ-64326067的剂量测定以及一项概念验证研究的结果，该研究将可能患有阿尔茨海默病的受试者与年龄匹配的健康对照进行了比较。
方法
对5名[F] - 氟代贝他吡PET淀粉样蛋白阳性的可能患有AD的参与者（73±9岁）和5名[F] - 氟代贝他吡PET淀粉样蛋白阴性的健康对照（71±7岁）进行了90分钟的[F]JNJ-64326067 PET扫描，然后在120至180分钟进行扫描。对6名健康受试者进行了3次扫描，每次扫描5.5小时，获取全身[F]JNJ-64326067 PET CT扫描图像。对脑部PET扫描图像进行了视觉评估。区域定量分析包括通过Logan图形分析在整个扫描过程中估计分布容积比（DVR）的动力学分析以及晚期图像中标准化摄取值（SUVr）的静态分析。两种方法均使用小脑腹侧皮质作为参考区域。
结果
一名健康对照在青少年时期曾遭受枪伤，其枕叶和顶叶皮质下方存在PET信号的局灶性区域；其他四名健康受试者脑部无tau蛋白信号。5名AD参与者中有4名在相关皮质区域可见[F]JNJ-64326067的滞留。一名AD受试者在视觉上为阴性。视觉上阳性的受试者皮质信号在120分钟时接近稳态。视觉上阳性的AD受试者颞叶和额叶皮质的SUVr / DVR值范围为1.21至3.09 / 1.2至2.18，而健康对照的范围为0.92至1.28 / 0.91至1.16。全身有效剂量估计女性为0.0257 mSv/MBq，男性为0.0254 mSv/MBq。
结论
[F]JNJ-64326067可用于检测和定量tau聚集体。
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