Traditional nuclear medicine ligands were designed to target cellular receptors or transporters with a binding pocket and a defined structure–activity relationship. More recently, tracers have been developed to target pathological protein aggregations, which have less well-defined structure–activity relationships. Aggregations of proteins such as tau, α-synuclein, and β-amyloid (Aβ) have been identified in neurodegenerative diseases, including Alzheimer’s disease (AD) and other dementias, and Parkinson’s disease (PD). Indeed, Aβ deposition is a hallmark of AD, and detection methods have evolved from coloured dyes to modern 18F-labelled positron emission tomography (PET) tracers. Such tracers are becoming increasingly established in routine clinical practice for evaluation of Aβ neuritic plaque density in the brains of adults who are being evaluated for AD and other causes of cognitive impairment. While similar in structure, there are key differences between the available compounds in terms of dosing/dosimetry, pharmacokinetics, and interpretation of visual reads. In the future, quantification of Aβ-PET may further improve its utility. Tracers are now being developed for evaluation of tau protein, which is associated with decreased cognitive function and neurodegenerative changes in AD, and is implicated in the pathogenesis of other neurodegenerative diseases. While no compound has yet been approved for tau imaging in clinical use, it is a very active area of research. Development of tau tracers comprises in-depth characterisation of existing radiotracers, clinical validation, a better understanding of uptake patterns, test-retest/dosimetry data, and neuropathological correlations with PET. Tau imaging may allow early, more accurate diagnosis, and monitoring of disease progression, in a range of conditions. Another marker for which imaging modalities are needed is α-synuclein, which has potential for conditions including PD and dementia with Lewy bodies. Efforts to develop a suitable tracer are ongoing, but are still in their infancy. In conclusion, several PET tracers for detection of pathological protein depositions are now available for clinical use, particularly PET tracers that bind to Aβ plaques. Tau-PET tracers are currently in clinical development, and α-synuclein protein deposition tracers are at early stage of research. These tracers will continue to change our understanding of complex disease processes.

中文翻译：

---

新的蛋白质沉积示踪剂正在研发中。


传统的核医学配体被设计为具有结合口袋和明确的结构-活性关系的靶向细胞受体或转运蛋白。最近，示踪剂被开发用于靶向病理性蛋白质聚集，这些蛋白质聚集的结构-活性关系不太明确。 tau、α-突触核蛋白和 β-淀粉样蛋白 (Aβ) 等蛋白质的聚集已在神经退行性疾病中被发现，包括阿尔茨海默病 (AD) 和其他痴呆症以及帕金森病 (PD)。事实上，Aβ 沉积是 AD 的一个标志，检测方法已经从有色染料发展到现代 18F 标记的正电子发射断层扫描 (PET) 示踪剂。此类示踪剂在常规临床实践中日益普及，用于评估正在评估 AD 和其他认知障碍原因的成人大脑中的 Aβ 神经炎斑块密度。虽然结构相似，但现有化合物在剂量/剂量测定、药代动力学和视觉读数的解释方面存在关键差异。未来，Aβ-PET的定量可能会进一步提高其实用性。目前正在开发用于评估 tau 蛋白的示踪剂，tau 蛋白与 AD 中认知功能下降和神经退行性变化有关，并且与其他神经退行性疾病的发病机制有关。虽然尚未批准用于临床 tau 成像的化合物，但它是一个非常活跃的研究领域。 tau 示踪剂的开发包括对现有放射性示踪剂的深入表征、临床验证、更好地理解摄取模式、重测/剂量测定数据以及与 PET 的神经病理学相关性。 Tau 成像可以在多种情况下实现早期、更准确的诊断和疾病进展监测。另一个需要成像方式的标记物是 α-突触核蛋白，它有可能用于治疗 PD 和路易体痴呆等疾病。开发合适的示踪剂的努力正在进行中，但仍处于起步阶段。总之，几种用于检测病理蛋白沉积的 PET 示踪剂现已可供临床使用，特别是与 Aβ 斑块结合的 PET 示踪剂。 Tau-PET 示踪剂目前正处于临床开发阶段，α-突触核蛋白沉积示踪剂正处于研究的早期阶段。这些示踪剂将继续改变我们对复杂疾病过程的理解。