PET/SPECT imaging agents for neurodegenerative diseases

Abstract

Single photon emission computed tomography (SPECT) or positron emission computed tomography (PET) imaging agents for neurodegenerative diseases have a significant impact on clinical diagnosis and patient care. The examples of Parkinson's Disease (PD) and Alzheimer's Disease (AD) imaging agents described in this paper provide a general view on how imaging agents, i.e. radioactive drugs, are selected, chemically prepared and applied in humans. Imaging the living human brain can provide unique information on the pathology and progression of neurodegenerative diseases, such as AD and PD. The imaging method will also facilitate preclinical and clinical trials of new drugs offering specific information related to drug binding sites in the brain. In the future, chemists will continue to play important roles in identifying specific targets, synthesizing target-specific probes for screening and ultimately testing them by in vitro and in vivo assays.

Figure 1

Radiolabeling reactions for production of [¹⁸F]FDG (2-fluoro-2-deoxy-D-glucose). A. The original method for preparation of [¹⁸F]FDG employed fluorine gas ([¹⁸F]F₂. B. The improved synthesis of [¹⁸F]FDG uses [¹⁸F]fluoride ion, potassium carbonate and K[2.2.2], a cryptand, to activate the fluoride ion. This nucleophilic reaction leads to a cleaner product and is a more efficient and higher yield reaction.

Figure 2

FDG PET-CT fusion images of a cancer patient (melanoma) can provide both anatomical and functional information as well as pinpoint the cancerous tissue, which shows higher glucose metabolism (arrows). (Images provided by David Mankoff M.D. Ph.D. University of Pennsylvania). (Reprinted with permission from The American Association for the Advancement of Science)

Figure 3

A schematic drawing of a dopamine neuron shows that the dopamine is synthesized in the pre-synaptic neuron starting from tyrosine to L-DOPA and then aromatic amino acid decarboxylase (AADC) catalyses the formation of dopamine. The SPECT/PET imaging agents for mapping dopamine neurons include: 1. 6-fluoro-[¹⁸F]DOPA (FDOPA), an analogue of L-DOPA which is a false substrate for AADC. 2. [¹²³I]FP-β-CIT and [^99mTc]TRODAT-1, which target the pre-synaptic dopamine transporter (DAT). 3. 9-fluoropropyl-(+)-DTBZ (AV-133), which binds to the vesicular monoamine transporter 2 (VMAT2).

Figure 4

Chemical structures of three types of imaging agents for studying nigrastriatal neuron degeneration in Parkinson’s disease (PD): 1. Enzymatic activity (aromatic amino acid decarboxylase, AADC); 2. Dopamine transporters (DAT); 3. Vesicular monoamine transporters (VMAT2).

Figure 5

Transaxial images of normal control and PD patients using different imaging agents: 5A: [¹⁸F]6-FDOPA/PET imaging of differential activity of a presynaptic enzyme, aromatic amino acid decarboxylase (AADC) (Reprinted with permission from Elsevier); 5B: [¹²³I]F-β-CIT (DatScan)/SPECT (GE Health; http://www3.gehealthcare.com/en/Products/Categories/Nuclear_Imaging_Agents/DaTscan); 5C: [^99mTc]TRODAT-1/SPECT (Authors thank Dr. David Mozley for providing the images); 5D: [¹⁸F]FP-(+)-DTBZ (AV-133). ^, (Reprinted with permission from JAMA)

Figure 6

A schematic drawing for the β-amyloid hypothesis is shown. It is suggested that Aβ aggregates participate in the pathogenesis of AD. The Aβ peptides, produced by neurons and other brain cells, transform β-sheet structures into a variety of toxic assemblies, neurofibrillary tangles and neuritic plaques. The Aβ oligomers as well as aggregates damage the neurons. The presence of Aβ plaques in the brain may suggest a risk factor of developing Alzheimer’s disease (modified from). (Reprinted with permission from ACS Med Chem Lett 2012. 3: p. 265-267; Copyright 2012 American Chemical Society.)

Figure 7

Chemical structures of the benzothiazole series of AD imaging agents: [¹¹C]PIB was the first agent to be tested in humans. [¹⁸F]FPIB was developed later, using the same core structure. The stilbene and styrylpyridine series of agents were discovered by modifying SB-13. Three units of polyethylene glycol chains were attached to the core, which reduce the lipophilicity without reducing brain penetration. This is a useful approach for adjusting the lipophilicity and providing a suitable position for fluorine substitution.

Figure 8

Results of a phase III clinical study suggest that the Amyvid/PET images are correlated with β-amyloid deposition seen in post-mortem studies. PET images are shown for three subjects (where red is highest uptake, blue the lowest): (top row) a normal subject with no β-amyloid plaques; (middle row) moderate loading of β-amyloid plaques associated with an early stage of Alzheimer’s Disease); and (bottom row) high β-amyloid plaques (white arrows) indicative of a late stage of Alzheimer’s Disease.^, (Reprinted with permission from JAMA)