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Is There a Role for GPCR Agonist Radiotracers in PET Neuroimaging?

ABSTRACT: Positron emission tomography (PET) is a molecular imaging modality that enables in vivo exploration of metabolic processes and especially the pharmacology of neuroreceptors. G protein-coupled receptors (GPCRs) play an important role in numerous pathophysiologic disorders of the central nervous system. Thus, they are targets of choice in PET imaging to bring proof concept of change in density in pathological conditions or in pharmacological challenge. At present, most radiotracers are antagonist ligands. In vitro data suggest that properties differ between GPCR agonists and antagonists: antagonists bind to receptors with a single affinity, whereas agonists are characterized by two different affinities: high affinity for receptors that undergo functional coupling to G-proteins, and low affinity for those that are not coupled. In this context, agonist radiotracers may be useful tools to give functional images of GPCRs in the brain, with high sensitivity to neurotransmitter release. Here, we review all existing PET radiotracers used from animals to humans and their role for understanding the ligand-receptor paradigm of GPCR in comparison with corresponding antagonist radiotracers.

SUBMITTER: Colom M

PROVIDER: S-EPMC6813225 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Is There a Role for GPCR Agonist Radiotracers in PET Neuroimaging?

Colom Matthieu M Vidal Benjamin B Zimmer Luc L

Frontiers in molecular neuroscience 20191018

Positron emission tomography (PET) is a molecular imaging modality that enables <i>in vivo</i> exploration of metabolic processes and especially the pharmacology of neuroreceptors. G protein-coupled receptors (GPCRs) play an important role in numerous pathophysiologic disorders of the central nervous system. Thus, they are targets of choice in PET imaging to bring proof concept of change in density in pathological conditions or in pharmacological challenge. At present, most radiotracers are anta ...[more]

PMID: 31680859

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Project description:IntroductionThere is a growing need in clinical research domains for direct comparability between amyloid-beta (Aβ) Positron Emission Tomography (PET) measures obtained via different radiotracers and processing methodologies. Previous efforts to provide a common measurement scale fail to account for non-linearities between measurement scales that can arise from these differences. We introduce a new application of distribution mapping, based on well established statistical orthodoxy, that we call Nonlinear Distribution Mapping (NoDiM). NoDiM uses cumulative distribution functions to derive mappings between Aβ-PET measurements from different tracers and processing streams that align data based on their location in their respective distributions.MethodsUtilizing large datasets of Florbetapir (FBP) from the Alzheimer's Disease Neuroimaging Initiative (n = 349 female (%) = 53) and Pittsburgh Compound B (PiB) from the Harvard Aging Brain Study (n = 305 female (%) = 59.3) and the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (n = 184 female (%) = 53.3), we fit explicit mathematical models of a mixture of two normal distributions, with parameter estimates from Gaussian Mixture Models, to each tracer's empirical data. We demonstrate the accuracy of these fits, and then show the ability of NoDiM to transform FBP measurements into PiB-like units.ResultsA mixture of two normal distributions fit both the FBP and PiB empirical data and provides a strong basis for derivation of a transfer function. Transforming Aβ-PET data with NoDiM results in FBP and PiB distributions that are closely aligned throughout their entire range, while a linear transformation does not. Additionally the NoDiM transform better matches true positive and false positive profiles across tracers.DiscussionThe NoDiM transformation provides a useful alternative to the linear mapping advocated in the Centiloid project, and provides improved correspondence between measurements from different tracers across the range of observed values. This improved alignment enables disparate measures to be merged on to continuous scale, and better enables the use of uniform thresholds across tracers.

Project description:PurposeA new PET radiotracer 18F-AF78 showing great potential for clinical application has been reported recently. It belongs to a new generation of phenethylguanidine-based norepinephrine transporter (NET)-targeting radiotracers. Although many efforts have been made to develop NET inhibitors as antidepressants, systemic investigations of the structure-activity relationships (SARs) of NET-targeting radiotracers have rarely been performed.MethodsWithout changing the phenethylguanidine pharmacophore and 3-fluoropropyl moiety that is crucial for easy labeling, six new analogs of 18F-AF78 with different meta-substituents on the benzene-ring were synthesized and evaluated in a competitive cellular uptake assay and in in vivo animal experiments in rats. Computational modeling of these tracers was established to quantitatively rationalize the interaction between the radiotracers and NET.ResultsUsing non-radiolabeled reference compounds, a competitive cellular uptake assay showed a decrease in NET-transporting affinity from meta-fluorine to iodine (0.42 and 6.51 µM, respectively), with meta-OH being the least active (22.67 µM). Furthermore, in vivo animal studies with radioisotopes showed that heart-to-blood ratios agreed with the cellular experiments, with AF78(F) exhibiting the highest cardiac uptake. This result correlates positively with the electronegativity rather than the atomic radius of the meta-substituent. Computational modeling studies revealed a crucial influence of halogen substituents on the radiotracer-NET interaction, whereby a T-shaped π-π stacking interaction between the benzene-ring of the tracer and the amino acid residues surrounding the NET binding site made major contributions to the different affinities, in accordance with the pharmacological data.ConclusionThe SARs were characterized by in vitro and in vivo evaluation, and computational modeling quantitatively rationalized the interaction between radiotracers and the NET binding site. These findings pave the way for further evaluation in different species and underline the potential of AF78(F) for clinical application, e.g., cardiac innervation imaging or molecular imaging of neuroendocrine tumors.

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Is There a Role for GPCR Agonist Radiotracers in PET Neuroimaging?

Publications

Is There a Role for GPCR Agonist Radiotracers in PET Neuroimaging?

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