New potent A1 adenosine receptor radioligands for positron emission tomography

Kreft, Sabrina; Bier, Dirk; Holschbach, M.; Schulze, Annette; Coenen, Heinrich Hubert

doi:10.1016/j.nucmedbio.2016.09.004

Cited by 12 publications

(12 citation statements)

References 37 publications

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“…Taking into account the results obtained with these derivatives, Kreft and coworkers developed other 18 F-CPFPX structurally-related derivatives named CBCPM (8-cyclobutyl-1-cyclopropymethyl-3-(3-fluoropropyl)xanthine, 7) and CPMMCB (1-cyclopropylmethyl-3-(3-fluoropropyl)-8-(1-methylcyclobutyl) xanthine, 8), respectively, which showed similar behavior to the reference compound in preliminary PET studies [36].…”

Section: Radioligands and Radiotracersmentioning

confidence: 99%

“…As shown in Figure 10, among agonists, the only other compound that was conjugated to a fluorophore in order to obtain, in this case, an agonist for the A 2A AR subtype was APEC (36) showed affinity towards both A 2A (K i = 149 nM) and A 3 (K i = 240 nM) ARs and was used to demonstrate that A 2A agonist-induced internalization is mediated by a clathrin-dependent mechanism [80]. Instead, the APEC-Alexa Fluor 532 conjugate MRS5424 (37) was developed to be applied in FRET experiments.…”

Section: Fluorescent Ligandsmentioning

confidence: 99%

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Chemical Probes for the Adenosine Receptors

2019

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Research on the adenosine receptors has been supported by the continuous discovery of new chemical probes characterized by more and more affinity and selectivity for the single adenosine receptor subtypes (A1, A2A, A2B and A3 adenosine receptors). Furthermore, the development of new techniques for the detection of G protein-coupled receptors (GPCR) requires new specific probes. In fact, if in the past radioligands were the most important GPCR probes for detection, compound screening and diagnostic purposes, nowadays, increasing importance is given to fluorescent and covalent ligands. In fact, advances in techniques such as fluorescence resonance energy transfer (FRET) and fluorescent polarization, as well as new applications in flow cytometry and different fluorescence-based microscopic techniques, are at the origin of the extensive research of new fluorescent ligands for these receptors. The resurgence of covalent ligands is due in part to a change in the common thinking in the medicinal chemistry community that a covalent drug is necessarily more toxic than a reversible one, and in part to the useful application of covalent ligands in GPCR structural biology. In this review, an updated collection of available chemical probes targeting adenosine receptors is reported.

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Section: Radioligands and Radiotracersmentioning

confidence: 99%

Section: Fluorescent Ligandsmentioning

confidence: 99%

Chemical Probes for the Adenosine Receptors

2019

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“…[ 11 C] PET radioligands of adenosine A 1 R. As shown in Figure 2, several 11 C PET radioligands of the A 1 R have been developed and tested thus far. The first PET radiotracer was developed by 11 C radiolabeling of the xanthene-derived A 1 R antagonist KF15372, [ 11 C]KF15372, and showed a specific and reversible brain uptake but an unacceptable high fraction of nonspecific binding that limited its use in preclinical evaluation of the A 1 R. 83,84 [ 11 C]MPDX, another analog of A 1 R antagonist KF15372, was developed to measure regional A 1 R densities in the brain of rodent and in patients with diffuse axonal injury, a model for TBI. 85 It detected an increase in A 1 R expression in areas surrounding the injuries in the brain, emphasizing on neuroprotective and neuromodulatory effects of A 1 R in TBI.…”

Section: Adenosine Receptors and Functions In The Cnsmentioning

confidence: 99%

“…Of these, [ 18 F]CPFPX has shown high affinity and selectivity for A 1 R 6,92 ; however, due to the high in vivo metabolism, this radiotracer exhibited a short biological half-life of only about 10 minutes. 84 Despite this fact, [ 18 F]CPFPX has been used for imaging of A 1 Rs in the human brain 93 and is currently a standard PET radioligand for evaluation of the A 1 R density in CNS disorders such as sleep-wake research. 84,[94][95][96] In order to improve metabolic stability inherent in [ 18 88 Despite stated limitations, these tracers 85 have presented promising imaging tools for mapping of A 1 R in the brain 86,87,96 .…”

Section: Adenosine Receptors and Functions In The Cnsmentioning

confidence: 99%

Purinergic Receptors of the Central Nervous System: Biology, PET Ligands, and Their Applications

Zarrinmayeh

Territo

2020

Mol Imaging

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Purinergic receptors play important roles in central nervous system (CNS). These receptors are involved in cellular neuroinflammatory responses that regulate functions of neurons, microglial and astrocytes. Based on their endogenous ligands, purinergic receptors are classified into P1 or adenosine, P2X and P2Y receptors. During brain injury or under pathological conditions, rapid diffusion of extracellular adenosine triphosphate (ATP) or uridine triphosphate (UTP) from the damaged cells, promote microglial activation that result in the changes in expression of several of these receptors in the brain. Imaging of the purinergic receptors with selective Positron Emission Tomography (PET) radioligands has advanced our understanding of the functional roles of some of these receptors in healthy and diseased brains. In this review, we have accumulated a list of currently available PET radioligands of the purinergic receptors that are used to elucidate the receptor functions and participations in CNS disorders. We have also reviewed receptors lacking radiotracer, laying the foundation for future discoveries of novel PET radioligands to reveal these receptors roles in CNS disorders.

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“…To date, the 18 F-labeled compound 8-cyclopentyl-3-(3-[ 18 F]fluoropropyl)-1-propylxanthine ([ 18 F]CPFPX, Figure 1) [10,11], which was the first radiolabeled A 1 AR ligand used in human PET studies [12], is still considered the gold standard for in vivo imaging of the A 1 AR. Numerous human and animal imaging studies have been successfully conducted using [ 18 F]CPFPX [13,14,15,16]; however, since this radiotracer undergoes rapid metabolic degradation [17,18], continuous efforts have been made to develop metabolically stable analogs that may provide higher image quality during PET scans [19]. Recognizing the C8-substituent at the xanthine core as a main target of metabolic enzymes [17], the development process concentrated predominantly on the synthesis of C8-substituted analogs of [ 18 F]CPFPX.…”

Section: Introductionmentioning

confidence: 99%

Relevance of In Vitro Metabolism Models to PET Radiotracer Development: Prediction of In Vivo Clearance in Rats from Microsomal Stability Data

et al. 2019

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The prediction of in vivo clearance from in vitro metabolism models such as liver microsomes is an established procedure in drug discovery. The potentials and limitations of this approach have been extensively evaluated in the pharmaceutical sector; however, this is not the case for the field of positron emission tomography (PET) radiotracer development. The application of PET radiotracers and classical drugs differs greatly with regard to the amount of substance administered. In typical PET imaging sessions, subnanomolar quantities of the radiotracer are injected, resulting in body concentrations that cannot be readily simulated in analytical assays. This raises concerns regarding the predictability of radiotracer clearance from in vitro data. We assessed the accuracy of clearance prediction for three prototypical PET radiotracers developed for imaging the A1 adenosine receptor (A1AR). Using the half-life (t1/2) approach and physiologically based scaling, in vivo clearance in the rat model was predicted from microsomal stability data. Actual clearance could be accurately predicted with an average fold error (AFE) of 0.78 and a root mean square error (RMSE) of 1.6. The observed slight underprediction (1.3-fold) is in accordance with the prediction accuracy reported for classical drugs. This result indicates that the prediction of radiotracer clearance is possible despite concentration differences of more than three orders of magnitude between in vitro and in vivo conditions. Consequently, in vitro metabolism models represent a valuable tool for PET radiotracer development.

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New potent A1 adenosine receptor radioligands for positron emission tomography

Cited by 12 publications

References 37 publications

Chemical Probes for the Adenosine Receptors

Chemical Probes for the Adenosine Receptors

Purinergic Receptors of the Central Nervous System: Biology, PET Ligands, and Their Applications

Relevance of In Vitro Metabolism Models to PET Radiotracer Development: Prediction of In Vivo Clearance in Rats from Microsomal Stability Data

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