Improved Automated Radiosynthesis of [F]Dolutegravir: Toward Clinical Applications.

Positron emission tomography imaging using radiolabeled dolutegravir (DTG) is an interesting approach to understand the biodistribution of this antiretroviral drug at HIV-1 sanctuary sites. In the course of clinical translation, we depict herein an improved and pharmaceutically compliant radiosynthesis of [F]DTG from an original tin precursor. The radiosynthesis was achieved in two steps by copper-mediated radiofluorination, followed by enol ether deprotection using a kit-based AllInOne module.

Nalmefene alleviates the neuroimmune response to repeated binge-like ethanol exposure: A TSPO PET imaging study in adolescent rats.

A large body of preclinical research has shown that neuroimmunity plays a key role in the deleterious effects of alcohol (ethanol) to the brain. Translational imaging techniques are needed to monitor the efficacy of strategies to prevent or mitigate neuroinflammation and alleviate ethanol-induced neurotoxicity. Opioid receptor antagonists such as nalmefene are antagonists of the toll-like receptor 4, which may block the proinflammatory signaling cascade induced by ethanol at this specific target.

Automated two-step manufacturing of [C]glyburide radiopharmaceutical for PET imaging in humans.

Introduction: Glyburide is an approved anti-diabetes drug binding to the sulfonylurea receptors-1 (SUR-1) and substrate of solute carrier (SLC) transporters, which can be isotopically radiolabelled with carbon-11 for PET imaging. The aim of this work is to present an original and reproducible automated radiosynthesis of [C]glyburide and a full European Pharmacopeia 9.7 compliant quality control to use [C]glyburide in PET imaging clinical trials.

Intravenous infusion for the controlled exposure to the dual ABCB1 and ABCG2 inhibitor elacridar in nonhuman primates.

Elacridar (GF120918) is a highly potent inhibitor of both P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), the main efflux transporters expressed at the blood-brain barrier (BBB). Elacridar shows very low aqueous solubility, which complicates its formulation for i.v.

Imaging the neuroimmune response to alcohol exposure in adolescent baboons: a TSPO PET study using F-DPA-714.

The effects of acute alcohol exposure to the central nervous system are hypothesized to involve the innate immune system. The neuroimmune response to an initial and acute alcohol exposure was investigated using translocator protein 18 kDa (TSPO) PET imaging, a non-invasive marker of glial activation, in adolescent baboons. Three different alcohol-naive adolescent baboons (3-4 years old, 9 to 14 kg) underwent F-DPA-714 PET experiments before, during and 7-12 months after this initial alcohol exposure (0.

Difficulties in dopamine transporter radioligand PET analysis: the example of LBT-999 using [18F] and [11C] labelling: part II: Metabolism studies.

Introduction: LBT-999, (E)-N-(4-fluorobut-2-enyl)-2β-carbomethoxy-3β-(4'-tolyl)nortropane, has been developed for PET imaging of the dopamine transporter. [(18)F]LBT-999 PET studies in baboons showed a lower brain uptake than [(11)C]LBT-999 and a high bone uptake, suggesting the presence of interfering metabolites. Therefore, in vitro and in vivo metabolism of these radiotracers was investigated.

[18F]DPA-714, [18F]PBR111 and [18F]FEDAA1106-selective radioligands for imaging TSPO 18 kDa with PET: automated radiosynthesis on a TRACERLAb FX-FN synthesizer and quality controls.

Imaging of TSPO 18 kDa with PET is more and more considered as a relevant biomarker of inflammation in numerous diseases. Development of new radiotracers for TSPO 18 kDa has seen acceleration in the last years and the challenge today is to make available large amounts of such a radiotracer in compliance with GMP standards for application in humans. We present in this technical note automated productions of [(18)F]DPA-714, [(18)F]PBR111 and [(18)F]FEDAA1106, three promising radiotracers for TSPO 18 kDa imaging, using a TRACERlab FX-FN synthesizer.

[(11)C]SL25.1188, a new reversible radioligand to study the monoamine oxidase type B with PET: preclinical characterisation in nonhuman primate.

[(11)C]SL-25.1188 [(S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)-benzo[d]isoxazol-3-yl]-oxazolidin-2-one], an oxazolidinone derivative, was characterized in baboons as a radioligand for the in vivo visualization of MAO-B using positron emission tomography (PET). After i.

Decrease of nicotinic receptors in the nigrostriatal system in Parkinson's disease.

Smoking is associated with a lower incidence of Parkinson's disease (PD), which might be related to a neuroprotective action of nicotine. Postmortem studies have shown a decrease of cerebral nicotinic acetylcholine receptors (nAChRs) in PD. In this study, we evaluated the decrease of nAChRs in PD in vivo using positron emission tomography (PET), and we explored the relationship between nAChRs density and PD severity using both clinical scores and the measurement of striatal dopaminergic function.

Dopamine D1 receptor imaging in the rodent and primate brain using the isoquinoline +-[11C]A-69024 and positron emission tomography.

In vivo pharmacokinetic and brain binding characteristics of (+)-[(11)C]A-69024, a high-affinity-D1-selective dopamine receptor antagonist, were assessed with micro-PET and beta-microprobes in the rat and PET in the baboon. The biodistribution of (+)-[(11)C]A-69024 in rats and baboons showed a rapid brain uptake (reaching a maximal value at 5 and 15 min postinjection in rats and baboons, respectively), followed by a slow wash out. The region/cerebellum concentration ratio was characterized by a fourfold higher uptake in striatum and a twofold higher uptake in cortical regions, consistent with in vivo specific binding of the radiotracer in these cerebral regions.

[18F]FPhEP and [18F]F2PhEP, two new epibatidine-based radioligands: evaluation for imaging nicotinic acetylcholine receptors in baboon brain.

The radioligand 2-[(18)F]fluoro-A-85380 has been developed for imaging alpha(4)beta(2) nAChRs with PET. However, it has slow kinetics and a large fraction of bound activity is nondisplaceable. In an attempt to address these problems, two epibatidine-based alpha(4)beta(2) nicotinic antagonists, coded FPhEP and F(2)PhEP, were evaluated in vivo in baboons.

Altered cerebral glucose metabolism in an animal model of diabetes insipidus: a micro-PET study.

The Brattleboro rat is an animal model of genetically induced central diabetes insipidus. These rats show cognitive and behavioral disorders, but no neurodegenerative disease has been observed. We studied brain glucose uptake, a marker of neuronal activity, in 6 Brattleboro rats, in comparison with 6 matched Long-Evans (LE) control rats.

Quantification of cerebral nicotinic acetylcholine receptors by PET using 2-[18F]fluoro-A-85380 and the multiinjection approach.

The multiinjection approach was used to study in vivo interactions between alpha4beta2(*) nicotinic acetylcholine receptors and 2-[(18)F]fluoro-A-85380 in baboons. The ligand kinetics was modeled by the usual nonlinear compartment model composed of three compartments (arterial plasma, free and specifically bound ligand in tissue). Arterial blood samples were collected to generate a metabolite-corrected plasma input function.

[11C]LBT-999: a suitable radioligand for investigation of extra-striatal dopamine transporter with PET.

A new tropane derivative, (E)-N-(4-fluorobut-2-enyl)-2beta-carbomethoxy-3beta-(4'-tolyl)nortropane (LBT-999), was evaluated in baboons as a carbon-11 radioligand for studies of the dopamine transporter (DAT) using positron emission tomography (PET). Brain uptake was high in the striatum (17 and 13% ID/100 mL tissue in the putamen and the caudate, respectively), moderate in the midbrain and thalamus (5 and 3% ID/100 mL tissue, respectively), and low in the cortex and cerebellum (2% ID/100 mL tissue) at 30 min post injection. The striatum-to-cerebellum ratio was high (30 at 110 min post injection).

Synthesis and radiolabeling of N-[4-[4-(2-[11C]methoxyphenyl)piperazin-1-yl]butyl]benzo[b]thiophene-2-carboxamide -- a potential radiotracer for D3 receptor imaging with PET.

FAUC346 (N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]benzo[b]thiophene-2-carboxamide), an in vitro D(3)-selective ligand, and its normethyl derivative have been synthesized from commercially available 1-(2-substituted-phenyl)piperazines. FAUC346 has been labeled using [(11)C]methyl triflate in acetone containing aqueous NaOH (5 Eq) at -10 degrees C for 1 min, purified on semipreparative reverse-phase high-performance liquid chromatography (HPLC) and formulated as an intravenous injectable solution using a Sep-Pak Plus C(18) device. Up to 5.

Synthesis and radiosynthesis of [(18)F]FPhEP, a novel alpha(4)beta(2)-selective, epibatidine-based antagonist for PET imaging of nicotinic acetylcholine receptors.

FPhEP (1, (+/-)-2-exo-(2'-fluoro-3'-phenyl-pyridin-5'-yl)-7-azabicyclo[2.2.1]heptane) belongs to a recently described novel series of 3'-phenyl analogues of epibatidine, which not only possess subnanomolar affinity and high selectivity for brain alpha4beta2 neuronal nicotinic acetylcholine receptors (nAChRs), but also were reported as functional antagonists of low toxicity (up to 15 mg/kg in mice).

Multiinjection approach for D2 receptor binding quantification in living rats using [11C]raclopride and the beta-microprobe: crossvalidation with in vitro binding data.

The purpose of this study was to quantify D2 receptors density and affinity in living rats using [11C]raclopride and to validate the multiinjection modelling approach. To this aim, we used an intracerebral beta+-sensitive probe as a highly sensitive system to quantify the radioligand activity using a single three-injection experimental paradigm. The study was divided into three main parts: (i) [11C]raclopride catabolism evaluation without and with cimetidine pretreatment (cytochrome P450 inhibitor); (ii) quantification of kinetics parameters in the striatum, enthorinal cortex, and cerebellum of living rats using a three-compartment model with an arterial input function; (iii) correlation study of in vivo and in vitro binding density and affinity values in the same striatal tissues.

Acute inhibition of cardiac monoamine oxidase A after tobacco smoke inhalation: validation study of [11C]befloxatone in rats followed by a positron emission tomography application in baboons.

The in vivo characteristics of [11C]befloxatone were assessed in myocardium of rats and monkeys. A complete multicompartmental model was developed to quantify monkey cardiac monoamine oxidase A (MAO-A) binding sites using positron emission tomography (PET) and was applied to assess the acute effects of inhalation of tobacco smoke. Unknown compounds contained in tobacco smoke inhibit brain MAO.

Acute effects of physostigmine and galantamine on the binding of [18F]fluoro-A-85380: a PET study in monkeys.

2-[18F]fluoro-3-[2S-2-azetidinylmethoxy]pyridine ([18F]fluoro-A-85380) is an alpha4beta2 subtype selective nicotinic cholinergic agonist with potential suitability for studying changes in endogenous acetylcholine synaptic concentration. Physostigmine, a potent AChE inhibitor, and galantamine, an allosteric modulator of nAChRs, are widely used for the treatment of Alzheimer's disease. Before studying patients with this neurodegenerative disease, positron emission tomography (PET) studies in monkeys were performed to assess the impact of these two compounds on the radiotracer distribution volumes.

In vivo imaging of human cerebral nicotinic acetylcholine receptors with 2-18F-fluoro-A-85380 and PET.

Unlabelled: 2-(18)F-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine (2-(18)F-fluoro-A-85380) is a PET radioligand that is specific for nicotinic acetylcholine receptors (nAChRs) and has a high affinity for the alpha(4)beta(2) subtype. The purpose of this study was to evaluate different strategies to quantify 2-(18)F-fluoro-A-85380 binding in healthy nonsmoking human volunteers.

Methods: After intravenous injection of 189 +/- 30 MBq (0.

Synthesis, radiosynthesis and in vivo evaluation of 5-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzoimidazol-2-[(11)C]one, as a potent NR(1A)/2B subtype selective NMDA PET radiotracer.

Recently, a new series of potent and highly subtype-selective 1-(heteroarylalkynyl)-4-benzylpiperidine antagonists of the NMDA receptors has been described by Pfizer Laboratories. In this series, 5-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzoimidazol-2-one (1) was identified as a selective antagonist for the NR1(A)/2B subtype, displaying IC(50) values for inhibition of the NMDA responses of 5.3 nM for this subtype (compared to NR1(A)/2A: 35 microM and NR1(A)/2C>100 microM) and was active in rat at a relatively low dosage (10mg/kg po).

Synthesis of a [2-pyridinyl-18F]-labelled fluoro derivative of (-)-cytisine as a candidate radioligand for brain nicotinic alpha4beta2 receptor imaging with PET.

In recent years, there has been considerable effort to design and synthesize radiotracers suitable for use in Positron Emission Tomography (PET) imaging of the alpha4beta2 neuronal nicotinic acetylcholine receptor (nAChR) subtype. A new fluoropyridinyl derivative of (-)-cytisine (1), namely (-)-9-(2-fluoropyridinyl)cytisine (3, K(i) values of 24 and 3462 nM for the alpha4beta2 and alpha7 nAChRs subtypes, respectively) has been synthesized in four chemical steps from (-)-cytisine and labelled with fluorine-18 (T(1/2): 119.8 min) using an efficient two-step radiochemical process [(a).

Synthesis and in vivo imaging properties of [11C]befloxatone: a novel highly potent positron emission tomography ligand for mono-amine oxidase-A.

Befloxatone (1, (5R)-5-(methoxymethyl)-3-[4-[(3R)-4,4,4-trifluoro-3-hydroxybutoxy]phenyl]-2-oxazolidinone) is an oxazolidinone derivative belonging to a new generation of reversible and selective mono-amine oxidase-A (MAO-A) inhibitors. In vitro and ex vivo studies have demonstrated that befloxatone is a potent, reversible and competitive MAO-A inhibitor with potential antidepressant properties. Befloxatone (1) was labelled with carbon-11 (t(12): 20.

Biodistribution and radiation dosimetry of 18F-fluoro-A-85380 in healthy volunteers.

Unlabelled: This study reports on the biodistribution and radiation dosimetry of 2-(18)F-Fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine ((18)F-fluoro-A-85380), a promising radioligand for the imaging of central nicotinic acetylcholine receptors (nAChRs).

Methods: Whole-body scans were performed in 3 healthy male volunteers up to 2 h after intravenous injection of 137-238 MBq (18)F-fluoro-A-85380. Transmission scans (3 min per step, 8 or 9 steps according to the height of the subject) in 2-dimensional mode were used for subsequent correction of attenuation of emission scans.

Long-lasting occupancy of central nicotinic acetylcholine receptors after smoking: a PET study in monkeys.

The aim of this study was to compare the degree of occupancy of central nicotinic acetylcholine receptors (nAChR) in isoflurane anaesthetized baboon brain following inhalation of tobacco smoke (one cigarette containing 0.9 mg nicotine) or i.v.