Studies towards the development of a PET radiotracer for imaging of the P2Y1 receptors in the brain: synthesis, 18F-labeling and preliminary biological evaluation (original) (raw)
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Journal of Labelled Compounds and Radiopharmaceuticals, 2004
4-Fluoro-N-{2-[4-(6-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethyl}benzamide is a full 5-HT 1A agonist with high affinity (pK i =9.3), selectivity and a c log P of 3.045. The corresponding PET radioligand 4-[ 18 F]fluoro-N-{2-[4-(6-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethyl}benzamide was synthesized by nucleophilic aromatic substitution on the nitro precursor. The fluorinating agent K[ 18 F]F/Kryptofix 2.2.2 was both dried (9 min, 700 W) and incorporated in the precursor (5 min, 700 W) using a commercially available microwave oven. In a total synthesis time of 60 min, an overall radiochemical yield of 18% (SD=5, n=7, EOS) was obtained. Radiochemical purity was always higher than 99% and specific activity always higher than 81.4 GBq/mmol (2.2 Ci/mmol). Initial brain uptake in mice was 2.19% ID (5.47% ID/g, 2 min) but decreased rapidly (0.17% ID, 0.45% ID/g (60 min)). During the first 20 min p.i., radioactivity concentration of the brain was significantly higher than that of blood demonstrating good brain entry of the tracer.
Journal of Nuclear Medicine, 2012
11 C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11 C-methyl-oxime), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. Methods: ABP688 was radiolabeled with 11 C by reacting 11 Cmethyl iodide with the sodium salt of desmethyl-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime). The affinity of 11 C-ABP688 for mGluR5 was determined by Scatchard analysis using rat whole-brain membranes (without cerebellum). Ex vivo autoradiography, biodistribution, and PET studies with 11 C-ABP688 were performed on rats, wild-type mice, and mGluR5-knock-out mice. Results: The overall synthesis time was 45250 min from the end of radionuclide production. 11 C-ABP688 was obtained in good radiochemical yield (35% 6 8%, n 5 17, decay corrected), and the specific radioactivity was 150 6 50 GBq/mmol (n 5 17) at the end of the synthesis. Scatchard analysis revealed a single high-affinity binding site with a dissociation constant of 1.7 6 0.2 nmol/L and a maximum number of binding sites of 231 6 18 fmol/mg of protein. Ex vivo autoradiography in wild-type mice and rats showed a heterogeneous distribution pattern consistent with the known distribution of mGluR5 in the brain, with the highest uptake in hippocampus, striatum, and cortex. Blocking studies by coinjection of 11 C-ABP688 and unlabeled 2-methyl-6-(3-methoxyphenyl)ethynylpyridine (1 mg/kg), an antagonist for mGluR5, revealed up to 80% specific binding in rat brain. In mGluR5-knock-out mouse brain, a homogeneous and markedly reduced accumulation of 11 C-ABP688 was observed. PET studies on rats and mice using a small-animal PET scanner also demonstrated radioactivity uptake in the brain regions known to be rich in mGluR5. In contrast, radioactivity uptake in mGluR5-knock-out mice was fairly uniform, substantiating the specificity of 11 C-ABP688 binding to mGluR5. Conclusion: 11 C-ABP688 is a selective tracer for imaging mGluR5 in vivo in rodents and may offer a future tool for imaging mGluR5 in humans using PET.
Molecules
The need for increasingly personalized medicine solutions (precision medicine) and quality medical treatments, has led to a growing demand and research for image-guided therapeutic solutions. Positron emission tomography (PET) is a powerful imaging technique that can be established using complementary imaging systems and selective imaging agents—chemical probes or radiotracers—which are drugs labeled with a radionuclide, also called radiopharmaceuticals. PET has two complementary purposes: selective imaging for diagnosis and monitoring of disease progression and response to treatment. The development of selective imaging agents is a growing research area, with a high number of diverse drugs, labeled with different radionuclides, being reported nowadays. This review article is focused on the use of pyrazoles as suitable scaffolds for the development of 18F-labeled radiotracers for PET imaging. A brief introduction to PET and pyrazoles, as key scaffolds in medicinal chemistry, is pres...
Journal of medicinal …, 2007
2-Fluoromethyl analogs of (3-[(2-methyl-1,3-thiazol-4yl)ethynyl]pyridine) were synthesized as potential ligands for metabotropic glutamate subtype-5 receptors (mGluR5s). One of these, namely, 3-fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile (3), was found to have exceptionally high affinity (IC 50 ) 36 pM) and potency in a phosphoinositol hydrolysis assay (IC 50 ) 0.714 pM) for mGluR5. Compound 3 was labeled with fluorine-18 (t 1/2 ) 109.7 min) in high radiochemical yield (87%) by treatment of its synthesized bromomethyl analog with [ 18 F]fluoride ion and its radioligand behavior was assessed with positron emission tomography (PET). Following intravenous injection of [ 18 F]3 into rhesus monkey, radioactivity was avidly taken up into brain with high uptake in mGluR5 receptor-rich regions such as striata. [ 18 F]3 was stable in monkey plasma and human whole blood in vitro and in monkey and human brain homogenates. In monkey in vivo, a single polar radiometabolite of [ 18 F]3 appeared rapidly in plasma.
Bioorganic & Medicinal Chemistry, 2006
FPhEP (1, (+/À)-2-exo-(2 0 -fluoro-3 0 -phenyl-pyridin-5 0 -yl)-7-azabicyclo[2.2.1]heptane) belongs to a recently described novel series of 3 0 -phenyl analogues of epibatidine, which not only possess subnanomolar affinity and high selectivity for brain a4b2 neuronal nicotinic acetylcholine receptors (nAChRs), but also were reported as functional antagonists of low toxicity (up to 15 mg/kg in mice). FPhEP (1, K i of 0.24 nM against [ 3 H]epibatidine) as reference as well as the corresponding N-Boc-protected chloro-and bromo derivatives (3a,b) as precursors for labelling with fluorine-18 were synthesized in eight and nine steps, respectively, from commercially available N-Boc-pyrrole (overall yields = 17% for 1, 9% for 3a and 8% for 3b). FPhEP (1) was labelled with fluorine-18 using the following two-step radiochemical process: (1) no-carrier-added nucleophilic heteroaromatic ortho-radiofluorination from the corresponding N-Boc-protected chloro-or bromo derivatives (3a,b-1 mg) and the activated K[ 18 F]F-Kryptofix Ò 222 complex in DMSO using microwave activation at 250 W for 1.5 min, followed by (2) quantitative TFA-induced removal of the N-Boc-protective group. Radiochemically pure (>99%) [ 18 F]FPhEP ([ 18 F]-1, 2.22-3.33 GBq, 66-137 GBq/lmol) was obtained after semi-preparative HPLC (Symmetry Ò C18, eluent aq 0.05 M NaH 2 PO 4 /CH 3 CN, 80:20 (v:v)) in 75-80 min starting from a 18.5 GBq aliquot of a cyclotron-produced [ 18 F]fluoride production batch (10-20% nondecay-corrected overall yield). In vitro binding studies on rat whole-brain membranes demonstrated a subnanomolar affinity (K D 660 pM) of [ 18 F]FPhEP ([ 18 F]-1) for nAChRs. In vitro autoradiographic studies also showed a good contrast between nAChR-rich and -poor regions with a low non-specific binding. Comparison of in vivo Positron Emission Tomography (PET) kinetics of [ 18 F]FPhEP ([ 18 F]-1) and [ 18 F]F-A-85380 in baboons demonstrated faster brain kinetics of the former compound (with a peak uptake at 20 min post injection only). Taken together, the preliminary data obtained confirm that [ 18 F]FPhEP ([ 18 F]-1) has potential for in vivo imaging nAChRs in the brain with PET.
Nuclear medicine and biology, 2014
The N-methyl-D-Aspartate (NMDA) receptor plays an important role in learning and memory. Overactivation is thought to play an important role in neurodegenerative disorders such as Alzheimer's disease. Currently, it is not possible to assess N-methyl-D-aspartate receptor (NMDAr) bio-availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NR2B binding site of the NMDA receptor. N-((5-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was radiolabelled with carbon-11 in the phenyl moiety. Biodistribution and blocking studies were carried out in anaesthetized mice and in non-anaesthetized rats. N-((5-(4-fluoro-2-[(11)C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was prepared in 49±3% (decay-corrected) yield, affording 4.1±0.3 GBq of formulated product at the end of synthesis with a radiochemical purity of >99% and with a specific activity of 78±10 GBq/μmol. A new NR2B PET ligand was developed in high yi...
Fluorine-18 chemistry for PET: A concise introduction
2010
Fluorine-18 is the most important radionuclide used in positron emission tomography (PET) today, largely due to its attractive physical and nuclear characteristics. Agents such as the clinical oncology tracer 2-[ 18 F]fluoro-2-deoxy-Dglucose ([ 18 F]FDG), the most widely used PET-radiopharmaceutical, are driving an increasing interest in the chemistry of radiopharmaceuticals utilizing fluorine-18. This review outlines the methods for production of fluorine-18, and the development of agents for performing radiofluorination reactions. With a few exceptions, radiofluorinations can be classified as either electrophilic or nucleophilic. The electrophilic reactions mainly use molecular [ 18 F]fluorine of moderately low specific radioactivity, or reagents prepared from it, and include additions to alkenes, reactions with carbanions and especially fluorodehydrogenation and fluorodemetallation. The nucleophilic reactions usually involve no-carrier-added (highspecific-radioactivity) [ 18 F]fluoride as its K[ 18 F]F-K 222 complex and include S N 2-type substitutions in the aliphatic series and S N Ar-type substitutions in the aromatic and heteroaromatic series. Key examples from each class of radiofluorination reaction will be described, highlighting the potential of this radioisotope in the design and preparation of fluorine-18labeled probes for PET imaging.