Innovative Molecular Imaging for Clinical Research, Therapeutic Stratification, and Nosography in Neuroscience

Abstract

Over the past few decades, several radiotracers have been developed for neuroimaging applications, especially in PET. Because of their low steric hindrance, PET radionuclides can be used to label molecules that are small enough to cross the blood brain barrier, without modifying their biological properties. As the use of 11C is limited by its short physical half-life (20 min), there has been an increasing focus on developing tracers labeled with 18F for clinical use. The first such tracers allowed cerebral blood flow and glucose metabolism to be measured, and the development of molecular imaging has since enabled to focus more closely on specific targets such as receptors, neurotransmitter transporters, and other proteins. Hence, PET and SPECT biomarkers have become indispensable for innovative clinical research. Currently, the treatment options for a number of pathologies, notably neurodegenerative diseases, remain only supportive and symptomatic. Treatments that slow down or reverse disease progression are therefore the subject of numerous studies, in which molecular imaging is proving to be a powerful tool. PET and SPECT biomarkers already make it possible to diagnose several neurological diseases in vivo and at preclinical stages, yielding topographic, and quantitative data about the target. As a result, they can be used for assessing patients' eligibility for new treatments, or for treatment follow-up. The aim of the present review was to map major innovative radiotracers used in neuroscience, and explain their contribution to clinical research. We categorized them according to their target: dopaminergic, cholinergic or serotoninergic systems, β-amyloid plaques, tau protein, neuroinflammation, glutamate or GABA receptors, or α-synuclein. Most neurological disorders, and indeed mental disorders, involve the dysfunction of one or more of these targets. Combinations of molecular imaging biomarkers can afford us a better understanding of the mechanisms underlying disease development over time, and contribute to early detection/screening, diagnosis, therapy delivery/monitoring, and treatment follow-up in both research and clinical settings.

Keywords: PET; SPECT; clinical research; molecular imaging; neurology; psychiatry.

Figure 1

Comparison of [123I]-IBZM image (A) and [18F]-fallypride image (B) within the same individual.

Figure 2

Schematic illustration of PET and SPECT techniques for assessing presynaptic and postsynaptic dopaminergic targets. L-DOPA is converted to dopamine by DOPA decarboxylase, then stored in vesicles by a vesicular monoamine transporter. Dopamine reuptake into presynaptic neurons occurs via a dopamine transporter (DAT). Two different types of dopamine receptors are expressed on postsynaptic neurons: D1 and D2.

Figure 3

[18F]-DPA-714 images obtained from two clinical studies: (A) Comparison between Amyotrophic Lateral Sclerosis (ALS) patients and healthy individuals, and (B) stroke patient.

Figure 4

Images from first-in-man injection of [18F]-FNM in a Tourette's syndrome patient (GlutaTour project).

Figure 5

Schematic illustration of the main cholinergic PET and SPECT radioligands, and their presynaptic or postsynaptic targets. Acetylcholine (ACh) is synthesized by choline acetyltransferase from choline and acetylCoA. ACh is released into the synaptic cleft, where it can bind to two types of receptors expressed on postsynaptic neurons: nicotinic receptors (nAChR) and muscarinic receptors (mAChR). ACh is degraded to choline and acetate by acetylcholinesterase (AChE). The reuptake of choline into presynaptic neurons occurs via a choline transporter. Choline is recycled within presynaptic neurons to form ACh, and stored in vesicles by a presynaptic vesicular ACh transporter (VAChT).