Characterisation of radioiodinated flavonoid derivatives for SPECT imaging of cerebral prion deposits.

Prion diseases are fatal neurodegenerative diseases characterised by deposition of amyloid plaques containing abnormal prion protein aggregates (PrPSc). This study aimed to evaluate the potential of radioiodinated flavonoid derivatives for single photon emission computed tomography (SPECT) imaging of PrPSc. In vitro binding assays using recombinant mouse PrP (rMoPrP) aggregates revealed that the 4-dimethylamino-substituted styrylchromone derivative (SC-NMe2) had higher in vitro binding affinity (Kd = 24.5 nM) and capacity (Bmax = 36.3 pmol/nmol protein) than three other flavonoid derivatives (flavone, chalcone, and aurone). Fluorescent imaging using brain sections from mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice demonstrated that SC-NMe2 clearly labelled PrPSc-positive prion deposits in the mice brain. Two methoxy SC derivatives, SC-OMe and SC-(OMe)2, also showed high binding affinity for rMoPrP aggregates with Ki values of 20.8 and 26.6 nM, respectively. In vitro fluorescence and autoradiography experiments demonstrated high accumulation of [125I]SC-OMe and [125I]SC-(OMe)2 in prion deposit-rich regions of the mBSE-infected mouse brain. SPECT/computed tomography (CT) imaging and ex vivo autoradiography demonstrated that [123I]SC-OMe showed consistent brain distribution with the presence of PrPSc deposits in the mBSE-infected mice brain. In conclusion, [123I]SC-OMe appears a promising SPECT radioligand for monitoring prion deposit levels in the living brain.

朊病毒疾病是致命的神经退行性疾病，其特征是含有异常朊病毒蛋白聚集体（PrP^{Sc}）的淀粉样斑块沉积。本研究旨在评估放射性碘标记的黄酮类衍生物用于PrP^{Sc}单光子发射计算机断层扫描（SPECT）成像的潜力。使用重组小鼠朊病毒蛋白（rMoPrP）聚集体进行的体外结合试验表明，4 - 二甲基氨基取代的苯乙烯基色酮衍生物（SC - NMe₂）比其他三种黄酮类衍生物（黄酮、查耳酮和橙酮）具有更高的体外结合亲和力（Kd = 24.5 nM）和结合能力（Bmax = 36.3 pmol/nmol蛋白质）。使用感染小鼠适应性牛海绵状脑病（mBSE）小鼠的脑切片进行的荧光成像显示，SC - NMe₂能清晰标记小鼠脑中PrP^{Sc}阳性的朊病毒沉积物。两种甲氧基SC衍生物，SC - OMe和SC - (OMe)₂，对rMoPrP聚集体也显示出高结合亲和力，Ki值分别为20.8和26.6 nM。体外荧光和放射自显影实验表明，[¹²⁵I]SC - OMe和[¹²⁵I]SC - (OMe)₂在感染mBSE的小鼠脑内富含朊病毒沉积物的区域有高积聚。SPECT/计算机断层扫描（CT）成像和离体放射自显影表明，[¹²³I]SC - OMe在感染mBSE的小鼠脑中的分布与PrP^{Sc}沉积物的存在一致。总之，[¹²³I]SC - OMe似乎是一种有前景的SPECT放射性配体，可用于监测活体大脑中的朊病毒沉积水平。