PET Radiopharmaceuticals for Alzheimer's Disease and Parkinson's Disease Diagnosis, the Current and Future Landscape

Abstract

Ironically, population aging which is considered a public health success has been accompanied by a myriad of new health challenges, which include neurodegenerative disorders (NDDs), the incidence of which increases proportionally to age. Among them, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common, with the misfolding and the aggregation of proteins being common and causal in the pathogenesis of both diseases. AD is characterized by the presence of hyperphosphorylated τ protein (tau), which is the main component of neurofibrillary tangles (NFTs), and senile plaques the main component of which is β-amyloid peptide aggregates (Aβ). The neuropathological hallmark of PD is α-synuclein aggregates (α-syn), which are present as insoluble fibrils, the primary structural component of Lewy body (LB) and neurites (LN). An increasing number of non-invasive PET examinations have been used for AD, to monitor the pathological progress (hallmarks) of disease. Notwithstanding, still the need for the development of novel detection tools for other proteinopathies still remains. This review, although not exhaustively, looks at the timeline of the development of existing tracers used in the imaging of Aβ and important moments that led to the development of these tracers.

Keywords: Alzheimer’s disease; Parkinson’s disease; diagnostic imaging probes; neurofibrillary tangles; positron emission tomography (PET); α-synucleinopathy; β-amyloid plaques.

Figure 1

Structures of thioflavin-T, [¹¹C]PiB, and the FDA approved Aβ-PET tracers: [¹⁸F]florbetaben, [¹⁸F]florbetapir, and [¹⁸F]flutemetamol.

Figure 2

Structures of the predecessors of FDA approved Aβ-PET tracers: [¹¹C]6-Me-BTA-1, [¹¹C]SB-13, [¹⁸F]FMAPO.

Figure 3

Structures of second generation Aβ-PET tracers: [¹⁸F]AZD4694, [¹⁸F]MK-3328, [¹⁸F]AD-269, [¹⁸F]FIBT.

Figure 4

Exemplary sagittal PET images of the FDA approved Aβ PET-tracers of Alzheimer’s disease patients with other select featured tracers, [¹¹C]PiB, [¹⁸F]Florbetaben, [¹⁸F]Flutemetamol, [¹⁸F]Florbetapir, [¹⁸F]Flutafuranol, and [¹⁸F]FIBT (reproduced with permission as agreed by Newlands Press Ltd. [135]).

Figure 5

Structures of the first generation tau-PET tracers: BF-158, BF-170, [¹⁸F]THK-523, [¹⁸F]THK-5105, [¹⁸F]THK-5117, [¹⁸F]THK-5317(17), (S)-[¹⁸F]THK-5117 ([¹⁸F]THK-5351), [¹¹C]PBB3, [¹⁸F]Flortaucipir (AV-1451, [¹⁸F]T807), [¹⁸F]T808.

Figure 6

Structures of the selected second-generation tau-PET tracers. [¹⁸F]GTP1, [¹⁸F]PM-PBB3 (APN-1607), *9, [¹⁸F]MK-6240, *12, [¹⁸F]RO-948 (RO6958948), [¹⁸F]PI-2620, [¹⁸F]JNJ64349311(JNJ311).

Figure 7

Structures of selective α-syn-PET tracers: [¹¹C]SIL5, [¹²⁵I]SIL23, [¹⁸F]SIL26, *6a, *14, *20, *46a, *11a, *11b, [¹²⁵I]IDP-4, [¹⁸F]FS3-1 ([¹⁸F]DABTA-11). *numbers given to the tracers in their respective publications.