In vivo imaging of vesicular monoamine transporter 2 in pancreas using an (18)F epoxide derivative of tetrabenazine.
In vivo imaging of vesicular monoamine transporter 2 in pancreas using an (18)F epoxide derivative of tetrabenazine.
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DOI：
10.1016/j.nucmedbio.2008.08.004
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发表时间：
2008-11
影响因子：
3.1
通讯作者：
Kilbourn, Michael
中科院分区：
文献类型：
--
作者：
Kung, Hank F.;Lieberman, Brian P.;Zhuang, Zhi-Ping;Oya, Shunichi;Kung, Mei-Ping;Choi, Seok Rye;Poessl, Karl;Blankemeyer, Eric;Hou, Catherine;Skovronsky, Daniel;Kilbourn, Michael
胰腺β细胞团显像剂的开发可能为研究胰岛素分泌β细胞及其与糖尿病的关系提供工具。本文报道了一种新的显像剂[18F]（+）-2-环氧乙烷基-3-异丁基-9-（3-氟丙氧基）-10-甲氧基-2，3，4，6，7，11 b-六氢-1H-吡啶并[2，1-a]异喹啉[18 F]（+）4，其显示靶向胰腺中β细胞的囊泡单胺转运蛋白2（VMAT 2）结合位点的性质，作为PET（正电子发射断层扫描）剂用于估计体内β细胞质量。（+）4的可水解环氧基团可提供将生物分布从肝脏转移到肾脏的机制，从而降低背景信号。合成并评价了18F和19 F标记的4的（+）和（−）异构体。在正常大鼠中进行器官分布。测量正常大鼠胰腺中[18 F]（+）4的摄取，并与使用竞争药物（+）二氢丁苯那嗪、（+）-DTBZ或9-氟丙基-（+）二氢丁苯那嗪（FP-（+）-DTBZ，（+）2）的阻断研究相关联。使用大鼠脑纹状体进行的VMAT 2体外结合研究显示，（+）4和（±）4的Ki值分别为0.08和0.15 nM。[18 F]（+）4在大鼠体内的生物分布显示胰腺中的摄取最高（注射后60 min时为2.68% ID/g）。用冷FP-（+）-DTBZ，（+）2（3.5 mg/kg，5 min iv预处理）进行的体内竞争实验导致胰腺摄取显著减少（60 min时阻断85%）。非活性异构体[18F]（−）4显示出显著较低的胰腺摄取（注射后30分钟为0.22%ID/g）。在正常大鼠中进行的[18F]（+）4的动物PET成像研究表明，大鼠中存在积极的胰腺摄取。初步结果表明，环氧化物[18F]（+）4与VMAT 2的结合具有高度选择性，并且在大鼠胰腺中具有良好的摄取。通过使用环氧基团，肝脏摄取显著降低。因此，它可能是潜在的有用的成像β细胞质量在胰腺。
Development of imaging agents for pancreatic beta cell mass may provide tools for studying insulin-secreting beta cells and their relationship with diabetes mellitus. In this paper a new imaging agent, [18F](+)-2-oxiranyl-3-isobutyl-9-(3-fluoropropoxy)-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline [18F](+)4, which displays properties targeting vesicular monoamine transporter 2 (VMAT2) binding sites of beta cells in the pancreas, was evaluated as a PET (positron emission tomography) agent for estimating beta cell mass in vivo. The hydrolyzable epoxide group of (+)4 may provide a mechanism for shifting biodistribution from liver to kidney thus, reducing the background signal. Both 18F and 19F labeled (+) and (−) isomers of 4 were synthesized and evaluated. Organ distribution was carried out in normal rats. Uptake of [18F](+)4 in pancreas of normal rats was measured and correlated with blocking studies using competing drugs, (+)dihydrotetrabenazine, (+)-DTBZ or 9-fluoropropyl-(+)dihydro tetrabenazine (FP-(+)-DTBZ, (+)2). In vitro binding study of VMAT2 using rat brain striatum showed a Ki value of 0.08 and 0.15 nM for the (+)4 and (±)4, respectively. The in vivo biodistribution of [18F](+)4 in rats showed the highest uptake in the pancreas (2.68 %ID/g at 60 min post-injection). In vivo competition experiments with cold FP-(+)-DTBZ, (+)2, (3.5 mg/kg, 5 min iv pretreatment) led to a significant reduction of pancreas uptake (85 % blockade at 60 min). The inactive isomer [18F](−)4 showed significantly lower pancreas uptake (0.22 %ID/g at 30 min post-injection). Animal PET imaging studies of [18F](+)4 in normal rats demonstrated an avid pancreatic uptake in rats. The preliminary results suggest that the epoxide, [18F](+)4, is highly selective in binding to VMAT2 and it has an excellent uptake in the pancreas of rats. The liver uptake was significantly reduced through the use of the epoxide group. Therefore, it may be potentially useful for imaging beta cell mass in the pancreas.
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影响因子：
3.1
作者：
Goswami, Rajesh;Ponde, Datta E.;Kung, Hank F.
通讯作者：
Kung, Hank F.
影响因子：
4.8
作者：
Maffei, A;Liu, ZR;Harris, PE
通讯作者：
Harris, PE
影响因子：
3.2
作者：
Anlauf, M;Schäfer, MKH;Weihe, E
通讯作者：
Weihe, E
影响因子：
0.9
作者：
Briones, R. M.;Miranda, J. M.;Frutos, M. A.
通讯作者：
Frutos, M. A.
影响因子：
3.6
作者：
DAVIS, R;KLUGE, AF;SPARACINO, ML
通讯作者：
SPARACINO, ML