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1.
Synapse ; 71(7)2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28245513

RESUMO

ONO-2952, a novel antagonist of translocator protein 18 kDa (TSPO), binds with high affinity to TSPO in rat brain and human tumor cell line membrane preparations. This study used the TSPO-specific PET radioligand [11 C]PBR28 to confirm binding of ONO-2952 to brain TSPO in human subjects, and evaluate brain TSPO occupancy and its relationship with ONO-2952 plasma concentration. Sixteen healthy subjects received a single oral dose of 200, 60, 20, or 6 mg ONO-2952 (n = 4 per dose). Two PET scans with [11 C]PBR28 were conducted ≤7 days apart: at baseline and 24 h after ONO-2952 administration. [11 C]PBR28 regional distribution volume (VT ) was derived with kinetic modeling using the arterial input function and a two tissue compartment model. Nonspecific binding (VND ) was obtained on an individual basis for each subject using linear regression as the x-intercept of the Lassen plot. The binding potential relative to VND (BPND ) was derived as the difference between VT in the ROI (VT ROI) and VND , normalized to VND ; BPND = (VT ROI - VND )/VND . TSPO occupancy was calculated as the change in BPND (ΔBPND ) from individual's baseline scan to the on-medication scan to the baseline BPND value. TSPO occupancy by ONO-2952 was dose dependent between 20-200 mg, approaching saturation at 200 mg both in the whole brain and in 15 anatomic regions of interest (ROI). Estimated Ki values ranged from 24.1 to 72.2 nM. This open-label, single-center, single-dose study demonstrated engagement of ONO-2952 to brain TSPO. The relationship between pharmacokinetics and TSPO occupancy observed in this study support the hypothesis that ONO-2952 could potentially modulate neurosteroid production by binding to brain TSPO.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Ciclopropanos/farmacologia , Antagonistas GABAérgicos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Receptores de GABA/metabolismo , Acetamidas , Adulto , Radioisótopos de Carbono , Ciclopropanos/efeitos adversos , Ciclopropanos/sangue , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Antagonistas GABAérgicos/efeitos adversos , Antagonistas GABAérgicos/sangue , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/sangue , Humanos , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Piridinas , Compostos Radiofarmacêuticos , Adulto Jovem
2.
J Neurol Neurosurg Psychiatry ; 74(5): 667-70, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12700317

RESUMO

BACKGROUND: The neuroactive steroid 3alpha, 5alpha-tetrahydroprogesterone is the most potent endogenous positive modulator of gamma-amino-butyric acid (GABA)(A) receptors. There is evidence for a relation between neuroactive steroids and seizure susceptibility. OBJECTIVE: To evaluate the putative role of counteregulator neuroactive steroids in the occurrence of seizures in patients with tuberous sclerosis. METHODS: Plasma concentrations of the enantiomers 3alpha, 5alpha- and 3alpha, 5beta-tetrahydroprogesterone (3alpha(s)-THP), which are positive modulators of GABA(A) receptors, were measured in 18 patients, along with their endogenous functional antagonists 3beta, 5alpha- and 3beta, 5beta-THP (3beta(s)-THP), to assess their possible modification compared with control subjects. Neuroactive steroids were assayed using a highly sensitive and specific gas chromatographic/mass spectrometric method. RESULTS: In the tuberous sclerosis patients with poorly controlled seizures, there was a significantly lower 3alpha(s)/3beta(s)-THP ratio than in seizure-free patients or control subjects. CONCLUSIONS: The reduced 3alpha(s)/3beta(s)-THP ratio may decrease GABAergic tone, contributing to the appearance of seizures in tuberous sclerosis patients with epilepsy.


Assuntos
Epilepsia/sangue , Epilepsia/etiologia , Pregnanolona/sangue , Receptores de GABA-A/sangue , Esclerose Tuberosa/sangue , Esclerose Tuberosa/complicações , Adolescente , Adulto , Criança , Pré-Escolar , Suscetibilidade a Doenças/sangue , Suscetibilidade a Doenças/fisiopatologia , Epilepsia/fisiopatologia , Feminino , Antagonistas GABAérgicos/sangue , Moduladores GABAérgicos/sangue , Humanos , Lactente , Isomerismo , Masculino , Pregnanolona/fisiologia , Receptores de GABA-A/fisiologia , Esclerose Tuberosa/fisiopatologia
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