Strategies to facilitate the discovery of novel CNS PET ligands

Abstract

Positron Emission Tomography (PET), as a non-invasive translatable imaging technology, can be incorporated into various stages of the CNS drug discovery process to provide valuable information for key preclinical and clinical decision-making. Novel CNS PET ligand discovery efforts in the industry setting, however, are facing unique challenges associated with lead design and prioritization, and budget constraints. In this review, three strategies aiming toward improving the central nervous system (CNS) PET ligand discovery process are described: first, early determination of receptor density (Bmax) and bio-distribution to inform PET viability and resource allocation; second, rational design and design prioritization guided by CNS PET design parameters; finally, a cost-effective in vivo specific binding assessment using a liquid chromatography-mass spectrometry (LC-MS/MS) “cold tracer” method. Implementation of these strategies allowed a more focused and rational CNS PET ligand discovery effort to identify high quality PET ligands for neuroimaging.

In Vitro Pharmacological Characterization and In Vivo Validation of LSN3172176 a Novel M1 Selective Muscarinic Receptor Agonist Tracer Molecule for Positron Emission Tomography

“…One of the most significant issues with advancing a therapeutic for treatment of cognitive deficit in AD is the lack of robust, translatable, and validated biomarkers. The gold standard for assessing target engagement is to use PET tracers (Zhang and Villalobos, 2017); however, to date there has been no reported use of a PET tracer to guide clinical dosesetting for mAChR therapies, particularly for agonist ligands. Several companies have reported incorporation of pharmacodynamic biomarkers including reversal of scopolamine or nicotine abstinence-induced memory deficits or electroencephalography (EEG)-related measures (Nathan et al, 2013; https://www.heptares.com/news/261/74/Heptares-Announces-Positive-Results-from-Phase-1b-Clinical-Trial-with-HTL9936-a-First-In-Class-Selective-Muscarinic-M1-Receptor-Agonistfor-Improving-Cognition-in-Dementia-and-Schizophrenia.html; Voss et al, 2016).…”

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

“…Target selectivity an important trait depends on factors such as the relative affinities of the tracer to target (specific binding) and non-target (nonspecific binding) sites, its brain distribution and the relative concentration of the binding sites. Both target and non-target binding sites should be considered when developing a brain tracer [77,81,82,85,86]. Additionally, a slow and reversible off-rates coupled (koff) with relatively high on-rates (kon), which is reflected by an equilibrium dissociation constant (Kd) in the range of 1 nM.…”

“…A standard uptake value (SUV) in the brain > 1.0 within a few min of intravenous injection is also required. Large molecules, antibodies, and nanobodies can cross the BBB, however they are unable to attain an SUV value > 1.0 a few min post-injection (p.i), and this has been a disqualifying criterion for large ligands labeled with short-lived radioisotopes [81,85,86]. The development of amyloid-specific imaging compounds is based mostly on conjugated dyes like Th-T ( Figure 1) and Congo red, that are used in postmortem AD brain sections for the staining of plaques and tangles [87][88][89][90].…”

Preparation of a First 18F-Labeled Agonist for M1 Muscarinic Acetylcholine Receptors

“…These findings have spurred interest into M 1 receptors as a target for experimental or clinical applications. In this context, functional imaging techniques and especially positron emission tomography (PET) have an enormous potential for in vivo assessment of target engagement [ 6 ]. A lot of effort spent in the development of PET tracers for mAChRs led to the discovery of several subtype selective 11 C-labeled radioligands [ 7 , 8 ].…”