DEVELOPMENT OF NEW PET AND SPECT RADIOTRACERS AND NEW APPROACHES TO PET DATA

在亚型选择性和毒性方面，进一步研究了新型放射性示踪剂（特别是A-85380的5-碘、2-和6-氟类似物）的特征，这些示踪剂用于正电子发射断层扫描（PET）和单光子发射计算机断层扫描（SPECT）成像烟碱乙酰胆碱受体（nAChR）。详细的动力学和饱和度分析证实，5-[I-125]碘- A85380以极高的亲和力标记同质结合位点群体，推测为nAChR的α 4-β 2亚型。四种不同类型受体的竞争试验结果表明，5-碘A-85380对α 4-β 2受体的亲和力超过其对哺乳动物α 7、肌肉和α 3-β 4亚型的亲和力3 - 5个数量级。此外，5- [I-125] iodo-A85380在缺乏nAChR β 2亚基的敲除小鼠的任何脑区均未显示结合。总的来说，这些发现表明5-[I-125]碘-A85380上级可用于选择性成像α 4-β 2 nAChR的其他放射性配体。毒理学研究表明，在相对高的剂量下，这些配体具有惊厥特性并影响心血管系统。小鼠惊厥的剂量比nAChR成像所需的剂量大约5000倍，表明A-85380相关化合物比作为毒素地棘蛙素衍生物的新成像配体具有更宽的安全范围。在未麻醉大鼠的初步心血管研究中，5-碘A-85380和尼古丁产生了等效的、适度的短暂血压升高，但只有尼古丁产生了显著的心率降低，表明5-碘A- 85380的心脏毒性可能低于尼古丁。另一个目标是通过使用静脉而不是动脉血液采样来计算CMRglc，从而改进PET/[F-18]氟脱氧葡萄糖（FDG）方法。在麻醉的非人灵长类动物（NHP）中，从动脉和静脉血样获得的FDG和葡萄糖浓度的时间曲线与使用动脉和静脉血计算的CMRglc值之间有很好的一致性。用静脉采血替代动脉采血将简化应用于人类和NHP的实验程序，而不会显著损失准确性，并扩展了对同一受试者进行多次PET-FDG研究的能力。- 放射性示踪剂，正电子发射断层扫描，烟碱受体

The features of novel radiotracers, specifically the 5-iodo, 2- and 6- fluoro analogs of A-85380, developed to image the nicotinic acetylcholine receptors (nAChRs) with positron emission tomography (PET) and single photon emission computed tomography (SPECT) have been further investigated in terms of subtype selectivity and toxicity. Detailed kinetic and saturation analyses confirmed that 5-[I-125] iodo- A85380 labels with extremely high affinity a homogeneous population of binding sites, presumably the alpha4-beta2 subtype of nAChRs. Results of competition assays for four different types of receptors demonstrated that the affinity of 5-iodo A-85380 for alpha4-beta2 receptors exceeds its affinity for the mammalian alpha7, muscular, and alpha3-beta4 subtypes by three to five orders of magnitude. Further, 5- [I-125] iodo-A85380 shows no binding in any brain region in knockout mice lacking the beta2 subunit of nAChRs. Collectively, these findings demonstrate that 5-[I-125]iodo-A85380 is superior to other radioligands available for selectively imaging alpha4-beta2 nAChRs. Toxicology studies demonstrated that at relatively high doses these ligands have convulsant properties and affect the cardiovascular system. Convulsions in mice were manifested at doses approximately 5000 times larger than doses needed to image nAChRs, demonstrating that the A-85380-related compounds have a wider margin of safety than new imaging ligands that are derivatives of the toxin epibatidine. In preliminary cardiovascular studies in unanesthetized rats, 5-iodo A-85380 and nicotine produced equivalent, modest transient increases in blood pressure, but only nicotine produced marked decreases in heart rate suggesting 5-iodo A- 85380 may be less cardiotoxic than nicotine. Another goal has been to improve PET/[F-18]fluorodeoxyglucose (FDG) methodology by using venous instead of arterial blood sampling to calculate CMRglc. There was a good agreement between the time curves of FDG and glucose concentration obtained from arterial and venous blood samples and values of CMRglc calculated using arterial and venous blood in anesthetized non human primates (NHPs). Substitution of arterial blood sampling by venous sampling will simplify the experimental procedure as applied to both humans and NHPs without a significant loss of accuracy and expands the ability to conduct multiple PET-FDG studies on the same subject. - radiotracers, positron emission tomography, nicotinic receptors