Wey Shiaw-Pyng, Weng Chi-Chang, Lin Kun-Ju, Yao Cheng-Hsiang, Yen Tzu-Chen, Kung Hank F, Skovronsky Daniel, Kung Mei-Ping
Department of Medical Imaging and Radiological Sciences, Graduate Institute of Medical Physics and Imaging Science, Chang Gung University, Taoyuan, 333 Taiwan.
Nucl Med Biol. 2009 May;36(4):411-7. doi: 10.1016/j.nucmedbio.2009.01.013. Epub 2009 Mar 26.
Recently, the feasibility of detecting amyloid plaques in the living brain by positron emission tomography (PET) imaging has been successfully demonstrated. As such, imaging beta-amyloid (A beta) plaques in the brain may further advance the differential diagnosis of the disease and allow clinicians to measure the effectiveness of therapeutic drugs aimed at lowering plaques in the brain. We report herein the preclinical validation of a potential (18)F-labeled biphenylalkyne, AV-138, as a preliminary step toward developing the imaging agent for patients suspected of having Alzheimer's disease.
In vitro binding was carried out in the homogenates prepared from postmortem AD brains with [(125)I]IMPY as the radioligand. [(18)F]AV-138 was successfully prepared using a tosylate precursor and Sumitomo modules for radiosynthesis. Similarly, specific binding of [(18)F]AV-138 (0.02-0.05 nM) to homogenates, prepared from gray and white matters of pooled AD patients and control subjects, was performed. Specific binding to A beta plaques was measured by autoradiography in AD brain sections (n=11), and the same brain sections were fluorescently stained with thioflavin-S (TF-S). Images of both radiolabeling and fluorescent staining of plaques obtained by a phosphor imager were used for correlation image analysis.
As expected, AV-138 displayed a high binding affinity (K(i)=2.4+/-0.7 nM) in AD gray matter homogenates (due to its high level of A beta plaque accumulation). Specific binding can be clearly measured in the AD gray matter homogenates, but not in the AD white matters. Control brain homogenates, due to a lack of A beta plaques, also showed no specific binding. Furthermore, in vitro autoradiography of postmortem AD brain sections showed that the high binding signal of [(18)F]AV-138 was specifically due to A beta plaques. Fluorescent staining of plaques with TF-S correlated well with the radiolabeling of [(18)F]AV-138 in AD brain sections (r>0.90).
Taken together, these preliminary results strongly suggest that [(18)F]AV-138 is potentially useful for imaging A beta plaques in the living human brain.
最近，正电子发射断层扫描（PET）成像在活体大脑中检测淀粉样斑块的可行性已得到成功证实。因此，对大脑中的β-淀粉样蛋白（Aβ）斑块进行成像可能会进一步推动该疾病的鉴别诊断，并使临床医生能够评估旨在降低大脑中斑块的治疗药物的疗效。我们在此报告一种潜在的（18）F标记的联苯炔AV-138的临床前验证，这是朝着为疑似患有阿尔茨海默病的患者开发成像剂迈出的初步步骤。
以[(125)I]IMPY作为放射性配体，在取自死后AD大脑的匀浆中进行体外结合实验。使用甲苯磺酸酯前体和住友模块进行放射性合成，成功制备了[(18)F]AV-138。同样，对取自合并的AD患者和对照受试者的灰质和白质制备的匀浆进行了[(18)F]AV-138（0.02 - 0.05 nM）的特异性结合实验。通过放射自显影法在AD脑切片（n = 11）中测量对Aβ斑块的特异性结合，并用硫黄素-S（TF-S）对相同的脑切片进行荧光染色。通过磷光成像仪获得的斑块放射性标记和荧光染色图像用于相关图像分析。
正如预期的那样，AV-138在AD灰质匀浆中显示出高结合亲和力（K(i)=2.4±0.7 nM）（由于其Aβ斑块积累水平较高）。在AD灰质匀浆中可以清楚地测量到特异性结合，但在AD白质中则没有。由于缺乏Aβ斑块，对照脑匀浆也未显示出特异性结合。此外，死后AD脑切片的体外放射自显影表明，[(18)F]AV-138的高结合信号 specifically due to Aβ斑块。在AD脑切片中，用TF-S对斑块进行的荧光染色与[(18)F]AV-138的放射性标记相关性良好（r>0.90）。
综上所述，这些初步结果强烈表明[(18)F]AV-138在活体人脑中对Aβ斑块进行成像具有潜在用途。
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