Binding characteristics of [3H]ucb 30889 to levetiracetam binding sites in rat brain

Gillard, Michel; Fuks, B. B.; Vertongen, Pascale; Massingham, R.; Chatelain, Pierre

doi:10.1016/j.ejphar.2003.08.032

Cited by 57 publications

(57 citation statements)

References 23 publications

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“…Binding assays were performed as previously described (17)(18)(19). The selectivity of UCB-J was assessed by its ability to interact with various receptors, transporters, enzymes, and ion channels (.55 targets) when tested at a concentration of 10 mM.…”

Section: In Vitro Binding Assaysmentioning

confidence: 99%

“…UCB-A has been radiolabeled with 11 C and tested in mini-pigs (12), rats (13), and rhesus monkeys (Nabulsi et al, unpublished data, 2012) but showed slow kinetics (prolonged retention in brain tissue) and may therefore not be suitable for PET imaging (unpublished data). UCB-H was radiolabeled with 18 F and displayed good kinetics in rats (14) and nonhuman primates (15) and acceptable dosimetry in humans (16); however, its radiosynthesis has proven challenging and specific binding was relatively low. In this study, we report the radiosynthesis and characterization of 11 C-UCB-J as a best-in-class SV2A PET tracer.…”

mentioning

confidence: 99%

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Synthesis and Preclinical Evaluation of¹¹C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain

et al. 2016

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The synaptic vesicle glycoprotein 2A (SV2A) is found in secretory vesicles in neurons and endocrine cells. PET with a selective SV2A radiotracer will allow characterization of drugs that modulate SV2A (e.g., antiepileptic drugs) and potentially could be a biomarker of synaptic density (e.g., in neurodegenerative disorders). Here we describe the synthesis and characterization of the SV2A PET radiotracer 11 C-UCB-J ((R)-1-((3-( 11 C-methyl-11 C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) in nonhuman primates, including whole-body biodistribution. Methods: 11 C-UCB-J was prepared by C-11 C-methylation of the 3-pyridyl trifluoroborate precursor with 11 C-methyl iodide via the Suzuki-Miyaura cross-coupling method. Rhesus macaques underwent multiple scans including coinjection with unlabeled UCB-J (17, 50, and 150 μg/kg) or preblocking with the antiepileptic drug levetiracetam at 10 and 30 mg/kg. Scans were acquired for 2 h with arterial sampling and metabolite analysis to measure the input function. Regional volume of distribution (V T ) was estimated using the 1-tissue-compartment model. Target occupancy was assessed using the occupancy plot; the dissociation constant (K d ) was determined by fitting self-blocking occupancies to a 1-site model, and the maximum number of receptor binding sites (B max ) values were derived from baseline V T and from the estimated K d and the nondisplaceable distribution volume (V ND ). Results: 11 C-UCB-J was synthesized with greater than 98% purity. 11 C-UCB-J exhibited high free fraction (0.46 ± 0.02) and metabolized at a moderate rate (39% ± 5% and 24% ± 3% parent remaining at 30 and 90 min) in plasma. In the monkey brain, 11 C-UCB-J displayed high uptake and fast kinetics. V T was high (∼25-55 mL/cm 3 ) in all gray matter regions, consistent with the ubiquitous expression of SV2A. Preblocking with 10 and 30 mg/kg of levetiracetam resulted in approximately 60% and 90% occupancy, respectively. Analysis of the self-blocking scans yielded a K d estimate of 3.4 nM and B max of 125-350 nM, in good agreement with the in vitro inhibition constant (K i ) of 6.3 nM and regional B max in humans. Whole-body biodistribution revealed that the liver and the brain are the dose-limiting organs for males and females, respectively. Conclusion: 11 C-UCB-J exhibited excellent characteristics as an SV2A PET radiotracer in nonhuman primates. The radiotracer is currently undergoing first-in-human evaluation.

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Section: In Vitro Binding Assaysmentioning

confidence: 99%

mentioning

confidence: 99%

Synthesis and Preclinical Evaluation of¹¹C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain

et al. 2016

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“…The mechanism of action of this drug is not fully understood. Several studies have identified a binding site in the central nervous system, the synaptic vesicle protein 2A, which seems to boost neurotransmission by increasing the number of secretory vesicles [Gillard et al, 2003;Lynch et al, 2004]. Unfortunately, the role of LEV as an antiepileptic agent is unclear.…”

Section: Levetiracetam (Keppra)mentioning

confidence: 99%

Antiepileptic Drugs and Pregnancy Outcomes

Wlodarczyk

Palacios

George³

et al. 2012

Obstetrical &Amp; Gynecological Survey

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The treatment of epilepsy in women of reproductive age remains a clinical challenge. While most women with epilepsy require anticonvulsant drugs for adequate control of their seizures, the teratogenicity associated with some antiepileptic drugs is a risk that needs to be carefully addressed. Antiepileptic medications are also used to treat an ever broadening range of medical conditions such as bipolar disorder, migraine prophylaxis, cancer and neuropathic pain. Despite the fact that the majority of pregnancies of women with epilepsy who are receiving pharmacological treatment are normal, studies have demonstrated that the risk of having a pregnancy complicated by a major congenital malformation is doubled when comparing the risk of untreated pregnancies. Furthermore, when antiepileptic drugs (AEDs) are used in polytherapy regimens, the risk is tripled, especially when valproic acid (VPA) is included. However, it should be noted that the risks are specific for each anticonvulsant drug. Some investigations have suggested that the risk of teratogenicity is increased in a dose-dependent manner. More recent studies have reported that in utero exposure to AEDs can have detrimental effects on the cognitive functions and language skills in later stages of life. In fact, the FDA just issued a safety announcement on the impact of VPA on cognition (Safety Announcement 6-30-2011). The purpose of this document is to review the most commonly used compounds in the treatment of women with epilepsy, and to provide information on the latest experimental and human epidemiological studies of the effects of antiepileptic drugs in the exposed embryos.

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“…8,9 SV2A has already proved an effective therapeutic target in reducing seizures and also holds promise for therapeutic application in conditions characterized by excessive neurotransmitter release in pathologically active neuronal circuits such as bipolar disorder 10 and chronic neuropathic pain. 11,12 WHAT IS SV2A?…”

Section: Psychopharmacologymentioning

confidence: 99%

“…8,9,[13][14][15] A protein specific to synaptic vesicles, denoted SV2, is a 12 transmembrane region glycoprotein present in all neural cells and occurring in 3 isoforms, SV2A, SV2B, and SV2C. [13][14][15] SV2A is the most widely distributed isoform and is ubiquitous not only throughout the CNS, but also in endocrine cells.…”

Section: Psychopharmacologymentioning

confidence: 99%

Psychopharmacology of Anticonvulsants: Levetiracetam as a Synaptic Vesicle Protein Modulator.

Stahl¹

2004

J. Clin. Psychiatry

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Binding characteristics of [3H]ucb 30889 to levetiracetam binding sites in rat brain

Cited by 57 publications

References 23 publications

Synthesis and Preclinical Evaluation of¹¹C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain

Synthesis and Preclinical Evaluation of¹¹C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain

Antiepileptic Drugs and Pregnancy Outcomes

Psychopharmacology of Anticonvulsants: Levetiracetam as a Synaptic Vesicle Protein Modulator.

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Binding characteristics of [3H]ucb 30889 to levetiracetam binding sites in rat brain

Cited by 57 publications

References 23 publications

Synthesis and Preclinical Evaluation of11C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain

Synthesis and Preclinical Evaluation of11C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain

Antiepileptic Drugs and Pregnancy Outcomes

Psychopharmacology of Anticonvulsants: Levetiracetam as a Synaptic Vesicle Protein Modulator.

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Product

Resources

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Synthesis and Preclinical Evaluation of¹¹C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain

Synthesis and Preclinical Evaluation of¹¹C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain