The first synthesis of [11C]SB-216763, a new potential PET agent for imaging of glycogen synthase kinase-3 (GSK-3)

Wang, Min; Gao, Mingzhang; Miller, Kathy D.; Sledge, George W.; Hutchins, Gary D.; Zheng, Qi

doi:10.1016/j.bmcl.2010.11.026

Cited by 33 publications

(25 citation statements)

References 19 publications

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“…[ 11 C]SB-216763 showed good brain uptake in rodents and non-human primates (NHPs) but was not selective against other structurally similar kinases. [11] [ 11 C]PyrATP-1 [12] and 11 C-oxadiazole [13] -based radiotracers failed to show appreciable uptake in vivo.N one of the PET radiotracers for GSK-3 has yet proven to be successful for in vivo imaging studies with specificity and/or suitable brain uptake ( Figure 1). Thus an acute need for PET neuroimaging of GSK-3 remains, specifically for clinical research applications in AD and non-AD tauopathies.…”

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confidence: 99%

Discovery of a Highly Selective Glycogen Synthase Kinase‐3 Inhibitor (PF‐04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging

et al. 2016

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Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology and neurology. We have identified N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. We demonstrated its efficacy in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A 11 Cisotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.Correspondence to: Ravi G. Kurumbail, ravi.g.kurumbail@pfizer.com; Neil Vasdev, vasdev.neil@mgh.harvard.edu. † These authors contributed equally to this work. # See the supplementary materials for current affiliations. Glycogen synthase kinase 3 (GSK-3) is a serine and threonine kinase that regulates a plethora of physiological functions in the periphery and central nervous system ranging from differentiation and development, to metabolism, cell cycle regulation, and neuroprotection. [1] GSK-3 plays a significant role in several pathologies including Alzheimer's disease (AD), mood disorders, type-II diabetes, and in some cancers. [2] Specifically for neurodegenerative diseases, molecular imaging of GSK-3 can indicate target engagement by GSK-3 therapeutics and offer a path to diagnostic agents that not only correlates with early cognitive impairment, but also increased tau hyperphosphorylation, [2a, 3] increased amyloid-production [4] and local plaque-associated glial-mediated inflammatory responses; all of which are hallmarks of AD and non-AD tauopathies. GSK-3 plays a key role in AD evident from: (i) the abundance and dysregulation of GSK-3 in the AD brain, [5] (ii) reduced tau phosphorylation (pTau) induced by treatment with GSK-3β inhibitors [6] and, (iii) genetic studies suggesting GSK-3 is fundamental in the pathogenesis of sporadic and familial AD. These and related findings have led to the "GSK-3 Hypothesis of Alzheimer's Disease". [7] The pertinence of GSK-3 in diverse diseases has led to longstanding, world-wide efforts by major pharmaceutical companies to develop small molecule inhibitors as therapeutics for this target. [8] Clinical translation of potent GSK-3 therapeutics for neurodegenerative disease have faced three major hurdles: 1) poor GSK-3 selectivity over other central nervous system (CNS) targets and closely related kinases; 2) low blood-brain barrier (BBB) penetration and 3) chronic toxicity. A positron emission tomography (PET) radiotracer for GSK-3 could aid many ongoing clinical research efforts to develop GSK-3 targeted therapeutics by indicating the success and extent of engagement by GSK-3 inh...

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Discovery of a Highly Selective Glycogen Synthase Kinase‐3 Inhibitor (PF‐04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging

et al. 2016

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“…Vasdev and co-workers prepared [11C]AR-A014418 ( 1 ), but unfortunately the radiotracer did not cross the blood-brain barrier (BBB) despite a log P of 2.44 and previously reported central nervous system (CNS) effects [11, 12]. Recently, two syntheses of [ 11 C]SB-216763 ( 2 ) have been reported [13, 14], and Aigbirhio and co-workers reported preliminary evidence for BBB permeability [14]. For that radiotracer, no further studies of imaging properties or brain pharmacokinetics have been reported.…”

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confidence: 99%

Synthesis and evaluation of [11C]PyrATP-1, a novel radiotracer for PET imaging of glycogen synthase kinase-3β (GSK-3β)

Cole

Shao

Sherman

et al. 2014

Nuclear Medicine and Biology

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Introduction The dysfunction of glycogen synthase kinase-3β(GSK-3β) has been implicated in a number of diseases, including Alzheimer’s disease. The ability to non-invasively quantify GSK-3βactivity in vivo is therefore of critical importance, and this work is focused upon development of inhibitors of GSK-3βradiolabeled with carbon-11 to examine quantification of the enzyme using positron emission tomography (PET) imaging. Methods [11C]PyrATP-1 was prepared from the corresponding desmethyl-piperazine precursor in an automated synthesis module. In vivo rodent and primate imaging studies were conducted on a Concorde MicroPET P4 scanner to evaluate imaging properties, and in vitro autoradiography studies with rat brain samples were carried out to examine specific binding. Results 2035 ± 518 MBq (55 ± 14 mCi) of [11C]PyrATP-1 were obtained (1–2% noncorrected radiochemical yield at end-of-synthesis based upon [11C]CO2) with high chemical (>95%) and radiochemical (>99%) purities, and good specific activities (143 ± 52 GBq/µmol (3874 ± 1424 Ci/mmol)), n = 5. In vivo microPET imaging studies revealed poor brain uptake in rodents and non-human primates. Pretreatment of rodents with cyclosporin A resulted in moderately increased brain uptake suggesting Pgp transporter involvement. Autoradiography demonstrated high levels of specific binding in areas of the rodent brain known to be rich in GSK-3β. Conclusion [11C]PyrATP-1 is readily synthesized using standard carbon-11 radiochemistry. However, the poor brain uptake in rodents and non-human primates indicates that the radiotracer is not suitable for the purposes of quantifying GSK-3βin neurological and psychiatric disorders.

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“…Our efforts toward the development of PET agents for AD diagnosis have been ongoing quite some time, and a series of enzyme-or receptor-based PET agents has been developed in this laboratory. For example, we have targeted the enzyme glycogen synthase kinase-3 (GSK-3) and developed carbon-11-labeled GSK-3 inhibitors 12,13 as PET AD imaging agents (Figure 1). In this continued effort, we revisit α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), which is a novel and attractive molecular target for treatment and PET imaging of AD.…”

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Radiosynthesis of a carbon-11-labeled AMPAR allosteric modulator as a new PET radioligand candidate for imaging of Alzheimer’s disease

Miao

Dong

Jia

et al. 2019

Bioorganic & Medicinal Chemistry Letters

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To develop PET tracers for imaging of Alzheimer's disease, a new carbon-11-labeled AMPAR allosteric modulator 4cyclopropyl-7-(3-[ 11 C]methoxyphenoxy)-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide ([ 11 C]8) has been synthesized. The reference standard 4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (8) and its corresponding desmethylated precursor 4-cyclopropyl-7-(3-hydroxyphenoxy)-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (9) were synthesized from 4-methoxyabiline and chlorosulfonyl isocyanate in eight and nine steps with 3% and 1% overall chemical yield, respectively. The target tracer [ 11 C]8 was prepared from the precursor 9 with [ 11 C]CH 3 OTf through O-[ 11 C]methylation and isolated by HPLC combined with SPE in 10-15% radiochemical yield, based on [ 11 C]CO 2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (A M) at EOB was 370-740 GBq/mol with a total synthesis time of 35-40-minutes from EOB.

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The first synthesis of [11C]SB-216763, a new potential PET agent for imaging of glycogen synthase kinase-3 (GSK-3)

Cited by 33 publications

References 19 publications

Discovery of a Highly Selective Glycogen Synthase Kinase‐3 Inhibitor (PF‐04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging

Discovery of a Highly Selective Glycogen Synthase Kinase‐3 Inhibitor (PF‐04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging

Synthesis and evaluation of [11C]PyrATP-1, a novel radiotracer for PET imaging of glycogen synthase kinase-3β (GSK-3β)

Radiosynthesis of a carbon-11-labeled AMPAR allosteric modulator as a new PET radioligand candidate for imaging of Alzheimer’s disease

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