Synthesis of in vivo Metabolites of the New Adenosine A3 Receptor PET-Radiotracer [18F]FE@SUPPY (original) (raw)
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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...
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...
The Open Nuclear Medicine Journal, 2009
Introduction: Since the Adenosine-A 3 -receptor was identified in the late 1990´s, there is little data available describing its distribution in vivo. Recently, we introduced [ 18 F]FE@SUPPY as the first PET-tracer for this receptor. In the present investigation we translated this fluoroethyl-ester into the fluoroethyl-thioester [ 18 F]FE@SUPPY:2 (5-ethyl 2,4diethyl-3-((2-[ 18 F]fluoroethyl) sulfanylcarbonyl)-6-phenylpyridine-5-carboxylate). Aims of the present study were the evaluation of (1) the automatized preparation of both [ 18 F]FE@SUPPY-derivatives, (2) the biodistribution of [ 18 F]FE@SUPPY:2, (3) the lipophilicity and the comparison of the findings of [ 18 F]FE@SUPPY and [ 18 F]FE@SUPPY:2. Methods: The automated preparations of both [ 18 F]FE@SUPPY-analogs were performed on a GE TRACERlab Fx FN synthesizer using suitable precursors. Biodistribution experiments were performed using Sprague-Dawley rats/Him:OFA. Lipophilicity of the compounds was determined using an HPLC assay. Results: 22 automated radiosyntheses were performed for both radiotracers. Specific radioactivity was 70 ± 26GBq/ mol for [ 18 F]FE@SUPPY and 340 ± 140GBq/ mol for [ 18 F]FE@SUPPY:2. Biodistribution experiments evinced bowels and liver as organs with highest uptake and intermediate uptake in kidney, lung and heart. LogP values of both molecules ranged from 3.99 to 4.12 at different pH. Conclusion: From a radiopharmaceutical perspective, drastically better specific radioactivities would militate in favour of [ 18 F]FE@SUPPY:2; preclinical evaluations, so far, do not permit the decision upon the selection of the optimum [ 18 F]FE@SUPPY-derivative. With [ 18 F]FE@SUPPY:2, we are able to provide a second potential tracer that could help to further characterize the still quite unexplored Adenosine-A 3 -receptor. © Mitterhauser et al.; Licensee Bentham Open.
Bioorganic & Medicinal Chemistry, 2006
pyrimidinediones have previously been found to bind to adenosine A 1 and A 2A receptors in micromolar concentrations. The present study was aimed at studying the structure-activity relationships of this class of compounds in more detail. Most of the investigated compounds were provided with polar substituents, such as ethoxycarbonyl groups and basic amino functions, in order to improve their water-solubility. The compounds were synthesized starting from 6-amino-1,3-dimethyluracil via different reaction sequences involving (cyano)acetylation, Vilsmeier formylation, or reaction with diethyl ethoxymethylenemalonate (EMME). The most potent and selective compound of the present series was 6-carbethoxy-1,2,3,4-tetrahydro-1,3-dimethyl-5-(2-naphthylmethyl)aminopyrido[2,3-d]pyrimidine-2,4-dione (11c) with a K i value of 5 nM at rat and 25 nM at human A 1 receptors. The compound was more than 60-fold selective versus A 3 and more than 300-fold selective versus A 2A receptors. It showed an over 300-fold improvement with respect to the lead compound. In GTPcS binding studies at membranes of Chinese hamster ovary cells recombinantly expressing the human adenosine A 1 receptor, 11c behaved as an antagonist with inverse agonistic activity. A regioisomer of 11c, 6-carbethoxy-1,2,3,4-tetrahydro-1,3-dimethyl-7-(2-naphthylmethyl)aminopyrido[2,3-d]pyrimidine-2,4-dione (7a) in which the 2-naphthylmethylamino substituent at position 5 of 11c was moved to the 7-position, was a relatively potent (K i = 226 nM) and selective (>20-fold) A 3 ligand. In the series of compounds lacking an electron-withdrawing ethoxycarbonyl or cyano substituent in the 6-position, compounds with high affinity for adenosine A 2A receptors were identified, such as 1,2,3,4-tetrahydro-1,3-dimethyl-5-(1-naphthyl)aminopyrido[2,3-d]pyrimidine-2,4-dione 16b (K i human A 2A = 81.3 nM, K i human A 1 = 153 nM, and K i human A 3 > 10,000 nM).
European journal of medicinal chemistry, 2015
An efficient synthetic procedure was adopted to synthesize a series of new molecules containing the pyrazolo[3,4-d]pyrimidine (PP) scaffold, which have been evaluated as promising human adenosine receptor (AR) antagonists. The effect of substitutions at the N(2), C(4) and C(6) positions of PPs on the affinity and selectivity towards the adenosine receptors were explored. Most of the pyrazolo[3,4-d]pyrimidine-4-carboxylates displayed from moderate to good affinity at the human A3AR (hA3AR), as indicated by the low micromolar range of Ki values (Ki hA3AR = 0.7-34 μM). In particular, compounds 60 and 62 displayed good affinity at the hA3AR (60, Ki hA3AR = 2.2 μM and 62, Ki hA3AR = 2.9 μM) and selectivity towards the other AR subtypes (60, >46-fold selective and 62, >34-fold selective, respectively). In view of these results, these novel PP analogues were docked both in the crystallographic structure of the hA2AAR and in a homology model of the hA3AR in order to support the struct...
Archiv der Pharmazie, 2013
A series of novel pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 5 was prepared from 2-amino-3cyano-4-trifluoromethyl-6-phenylpyridine 1 in two steps via formation of iminoether 3 followed by reaction with different aroylhydrazides 4. Representative products 5 were evaluated for their affinity towards all four subtypes of human adenosine receptors. Compounds 2-(3-fluorophenyl)-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5b), 2-(furan-2-yl)-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5d), and 2-(furan-2-yl)-5-methyl-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5j) showed high affinity for the A 3 receptors, with K i values of 8.1, 10.4, and 12.1 nM, respectively, and were >1000-fold selective versus all other adenosine receptor subtypes.
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.
Medicinal Chemistry Research, 2017
A series of new fluorine containing pyrido[2,3-d] pyrimidines and imidazo[1,2-c]pyrido[3,2-e]pyrimidines along with a series of bioisosteric fluorinated quinazolines were synthesised following appropriate synthetic schemes and characterised by spectral analytical means. X-ray crystal structure of the key precursor 1 (2-amino-3-cyano-4-trifluoro-methyl-6-phenyl-pyridine) was also determined to gain insight into its reactivity. Binding affinity data of all the compounds for adenosine receptors (ARs) showed that pyrido[2,3-d]pyrimidine scaffold with free amino (NH 2) group at 2-and 4-position (2a) exhibited the maximum binding affinity for hA 3 AR with similar affinity for the hA 1 and somewhat lower affinity for hA 2A ARs resulting in a compound with no A 3 selectivity vs. A 1 and moderate selectivity vs. A 2A AR (K i hA 1 = 0.62 µM, hA 2A = 3.59 µM and hA 3 = 0.42 µM). Interestingly, the replacement of both the amino groups with carbonyl (C=O) groups (compound 4) resulted in significantly improved affinity for hA 1 AR but with moderate selectivity against hA 2A and hA 3 ARs (K i hA 1 = 0.17 µM, hA 2A = 0.67 µM and hA 3 = 0.68 µM). In case of fluorinated quinazolines, only compound 18a showed remarkable affinity for hA 1 AR with significant selectivity against hA 2A and hA 3 ARs (K i hA 1 = 0.73 µM, hA 2A > 30 µM and hA 3 = 9.27 µM). The preliminary results of these compounds demonstrate that the fluorinated pyrido [2,3-d]pyrimidine and imidazo[1,2-c]pyrido[3,2-e]pyrimidine can be considered as promising scaffolds for further optimisation in search of potential antagonists with better affinity and selectivity towards hA 1 and hA 3 ARs.