Development of [ 18 F]-Labeled Pyrazolo[4,3- e ]-1,2,4- triazolo[1,5- c ]pyrimidine (SCH442416) Analogs for the Imaging of Cerebral Adenosine A 2A Receptors with Positron Emission Tomography (original) (raw)
Related papers
Journal of medicinal chemistry, 2014
2-(2-Furanyl)-7-[2-[4-[4-(2-[(11)C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine [(11)C]-3 ([(11)C]Preladenant) was developed for mapping cerebral adenosine A2A receptors (A2ARs) with PET. The tracer was synthesized in high specific activity and purity. Tissue distribution was studied by PET imaging, ex vivo biodistribution (BD), and in vitro autoradiography (ARG) experiments. Regional brain uptake of [(11)C]-3 was consistent with known A2ARs distribution, with highest uptake in striatum. The results indicate that [(11)C]-3 has favorable brain kinetics and exhibits suitable characteristics as an A2AR PET tracer.
Adenosine A2A Receptor Antagonists as Positron Emission Tomography (PET) Tracers
Current Medicinal Chemistry, 2013
The adenosine A 2A receptor (A 2A R) is highly concentrated in the striatum, and a therapeutic target for Parkinson's disorder (PD) and Huntington's disease. High affinity and selective radiolabeled A 2A R antagonists can be important research and diagnostic tools for PD. Positron Emission Tomography (PET) can play an important role by measuring radiolabeled A 2A antagonists non-invasively in the brain. However, till date no complete review on A 2A R PET ligands is available. The present article has been therefore focused on available PET tracers for A 2A R and their detailed biological evaluation in rodents, nonhuman primates and humans. Drug design and development by molecular modeling including new lead structures that are potential candidates for radiolabeling and mapping of cerebral A 2A Rs is discussed in the present article. A brief overview of functions of adenosine in health and disease, including the relevance of A 2A R for PD has also been presented.
International Journal of Molecular Sciences, 2021
The adenosine A2A receptor (A2AR) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the A2AR-tailored therapy, we designed a library of fluorinated analogs based on a recently published lead compound (PPY). Among those, the highly affine 4-fluorobenzyl derivate (PPY1; Ki(hA2AR) = 5.3 nM) and the 2-fluorobenzyl derivate (PPY2; Ki(hA2AR) = 2.1 nM) were chosen for 18F-labeling via an alcohol-enhanced copper-mediated procedure starting from the corresponding boronic acid pinacol ester precursors. Investigations of the metabolic stability of [18F]PPY1 and [18F]PPY2 in CD-1 mice by radio-HPLC analysis revealed parent fractions of more than 76% of total activity in the brain. Specific binding of [18F]PPY2 on mice brain slices was demonstrated by in vitro autoradiography. In vivo PET/magnetic resonance imaging (MRI) studies in C...
Journal of medicinal chemistry, 2018
Central adenosine A receptor (AR) is implicated in pain, sleep, substance use disorders, and neurodegenerative diseases, and is an important target for pharmaceutical development. Radiotracers for AR positron emission tomography (PET) would enable measurement of dynamic interaction of endogenous adenosine and AR during the sleep-awake cycle. Although several human AR PET tracers have been developed, most are xanthine-based antagonists that failed to demonstrate competitive binding against endogenous adenosine. Herein, we explored nonnucleoside (3,5-dicyanopyridine and 5-cyanopyrimidine) templates for developing an agonist AR PET radiotracer. We synthesized novel analogues, including 2-amino-4-(3-methoxyphenyl)-6-(2-(6-methylpyridin-2-yl)ethyl)pyridine-3,5-dicarbonitrile (MMPD, 22b), a partial AR agonist of sub-nanomolar affinity. [C]22b showed suitable blood-brain barrier (BBB) permeability and test-retest reproducibility. Regional brain uptake of [C]22b was consistent with known br...
Bioorganic & Medicinal Chemistry Letters, 2010
Movement disorders such as Parkinson's disease and Huntington's disease are serious life-limiting and debilitating movement disorders. Their onset typically occurs from mid-life to late in life, and effective diagnostic techniques for detecting and following the disease course are lacking. Our goal is to develop receptor imaging agents for positron emission tomography (PET) that selectively target the most relevant subtype of adenosine receptors (AR) that are highly expressed in the striatum, i.e. the A 2A AR. To further this goal, we have synthesized and characterized pharmacologically a family of high affinity A 2A AR ligands, based on the known antagonist, SCH 442416 (R = -Me), which have structural variability on the terminus (R = -Et, -i-Pr, -allyl, and others). A O-fluoroethyl analogue suitable for use as a PET tracer had a K i value of 12.4 nM and was highly selective for the A 2A AR in comparison to the A 1 and A 3 ARs.
Characterization in Humans of 18F-MNI-444, a PET Radiotracer for Brain Adenosine 2A Receptors
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2015
PET with selective adenosine 2A receptor (A2A) radiotracers can be used to study a variety of neurodegenerative and neuropsychiatric disorders in vivo and to support drug-discovery studies targeting A2A. The aim of this study was to describe the first in vivo evaluation of (18)F-MNI-444, a novel PET radiotracer for imaging A2A, in healthy human subjects. Ten healthy human volunteers were enrolled in this study; 6 completed the brain PET studies and 4 participated in the whole-body PET studies. Arterial blood was collected for invasive kinetic modeling of the brain PET data. Noninvasive methods of data quantification were also explored. Test-retest reproducibility was evaluated in 5 subjects. Radiotracer distribution and dosimetry was determined using serial whole-body PET images acquired over 6 h post-radiotracer injection. Urine samples were collected to calculate urinary excretion. After intravenous bolus injection, (18)F-MNI-444 rapidly entered the brain and displayed a distribut...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2017
11 C-preladenant was developed as a novel PET ligand for the adenosine A 2A receptors (A 2A Rs). The present study aimed to evaluate the suitability of 11 C-preladenant PET for the quantification of striatal A 2A Rs and the assessment of A 2A R occupancy in the conscious monkey brain. Methods: 11 C-preladenant was intravenously injected into conscious monkeys (n 5 4, 18 PET scans), and a 91-min dynamic scan was started. Arterial blood samples in combination with metabolite analysis were obtained during the scan to provide the input function for kinetic modeling. The distribution volume (V T) was obtained by kinetic modeling with a 2-tissue-compartment model. The simplified reference tissue model (SRTM) with selected reference regions (cerebellum, cingulate, parietal cortex, and occipital cortex) was tested to estimate the binding potential (BP ND) in A 2A R-rich regions. BP ND obtained from the SRTM was compared with distribution volume ratio (DVR)-1. The effects of blood volume, blood delay, and scan duration on BP ND and DVR-1 were investigated. V T and BP ND were also obtained after preblocking with unlabeled preladenant (1 mg/kg), A 2A R-selective KW-6002 (0.5-1 mg/kg), and nonselective adenosine receptor antagonist caffeine (2.5-10 mg/kg). A 2A R occupancy was studied with caffeine blockade. Results: Regional uptake of 11 C-preladenant was consistent with the distribution of A 2A Rs in the monkey brain, with the highest uptake in the putamen, followed by the caudate, and the lowest uptake in the cerebellum. Tracer kinetics were well described by the 2-tissue-compartment model with a lower constraint on k 4 to stabilize fits. The highest V T was observed in A 2A R-rich regions (;5.8-7.4) and lowest value in the cerebellum (;1.3). BP ND values estimated from the SRTM with different scan durations were comparable and were in agreement with DVR-1 (;4.3-5.3 in A 2A R-rich regions). Preladenant preinjection decreased the tracer uptake in A 2A R-rich regions to the level of the reference regions. Caffeine pretreatment reduced the tracer uptake in the striatum in a dose-dependent manner. Conclusion: 11 C-preladenant PET is suitable for noninvasive quantification of A 2A Rs and assessment of A 2A R occupancy in A 2A R-rich regions in the monkey brain. SRTM using the cerebellum as the reference tissue is the applicable model for A 2A R quantification.
International Journal of Molecular Sciences, 2020
The adenosine A2B receptor has been proposed as a novel therapeutic target in cancer, as its expression is drastically elevated in several tumors and cancer cells. Noninvasive molecular imaging via positron emission tomography (PET) would allow the in vivo quantification of this receptor in pathological processes and most likely enable the identification and clinical monitoring of respective cancer therapies. On the basis of a bicyclic pyridopyrimidine-2,4-dione core structure, the new adenosine A2B receptor ligand 9 was synthesized, containing a 2-fluoropyridine moiety suitable for labeling with the short-lived PET radionuclide fluorine-18. Compound 9 showed a high binding affinity for the human A2B receptor (Ki(A2B) = 2.51 nM), along with high selectivities versus the A1, A2A, and A3 receptor subtypes. Therefore, it was radiofluorinated via nucleophilic aromatic substitution of the corresponding nitro precursor using [18F]F-/K2.2.2./K2CO3 in DMSO at 120 °C. Metabolic studies of [1...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2005
Adenosine is an endogenous modulator of synaptic functions in the central nervous system. To investigate the physiologic and pathologic roles of the adenosine receptors in the human brain, PET is a powerful in vivo technique. In this study, we quantitatively evaluated the distribution of a major subtype A(1) adenosine receptor in the human brain by PET with a newly developed radioligand, 8-dicyclopropylmethyl-1-(11)C-methyl-3-propylxanthine ((11)C-MPDX). In 5 healthy volunteers, after PET measurement of the regional cerebral blood flow (rCBF) with (15)O-H(2)O, a 60-min PET scan with (11)C-MPDX was performed. The distribution volume (DV) of (11)C-MPDX was quantitatively evaluated by Logan's graphical analysis. (11)C-MPDX was taken up at a high level, reaching a peak at 2-2.5 min, followed by a rapid decrease. The unchanged form of (11)C-MPDX in plasma was 75% at 60 min after injection. The DV of (11)C-MPDX was large in the striatum and thalamus, moderate in the cerebral cortices ...
Synapse, 2005
[ 11 C]TMSX is a new positron emission tomography (PET) radioligand that provides visualization of adenosine A 2A receptors (A 2A Rs) in the brain, heart and skeletal muscle. Here we report on the first visualization of the A 2A Rs in the human brain by PET and [ 11 C]TMSX in a male healthy volunteer, compared with the adenosine A 1 receptors (A 1 Rs) and dopamine D 2 receptors (D 2 Rs) which were measured by PET with [ 11 C]MPDX and [ 11 C]raclopride, respectively. The distribution volume (DV) of [ 11 C]TMSX in the baseline was relatively high in the head of caudate nucleus, putamen, and thalamus and relatively low in the cortical regions. Infusion of theophylline, a nonselective A 2A R antagonist (K i for A 2A Rs ϭ 16000 nM for theophylline vs 5.9 nM for TMSX), slightly reduced the DVs in the head of caudate nucleus (8.0% reduction) and putamen (4.5% reduction), but not in the other regions having much lower levels of A 2A Rs, demonstrating the A 2A R-specific binding of [ 11 C]TMSX. On the other hand, the A 1 Rs were widely distributed in the whole brain except for the cerebellum, while the binding potential of [ 11 C]raclopride was predominantly high in the striatum. We concluded that [ 11 C]TMSX is an applicable PET ligand for mapping the A 2A Rs in the caudate nucleus and putamen in clinical studies because of no availability of other radioligands until now. The [ 11 C]TMSX PET is of great interest for studying the pathophysiology of neurological and psychiatric disorders together with the [ 11 C]raclopride PET for D 2 Rs evaluation and/or the [ 11 C]MPDX PET for A 1 Rs evaluation. Synapse 55: 133-136, 2005.