Characterization of the novel GlyT1 PET tracer [18F]MK-6577 in humans.
Synapse
; 69(1): 33-40, 2015 Jan.
Article
em En
| MEDLINE
| ID: mdl-25196464
ABSTRACT
Decreased glutamatergic neurotransmission is hypothesized to be involved in the pathophysiology of schizophrenia. Inhibition of glycine transporter Type-1 (GlyT1) reuptake is expected to increase the glutamatergic neurotransmission and may serve as treatment for cognitive and negative symptoms of schizophrenia. In this article, we present human data from a novel GlyT1 PET tracer, [(18) F]MK-6577. In the process of developing a GlyT1 inhibitor therapeutic, a PET tracer can assist in determining the dose with a high probability of sufficiently testing the mechanism of action. This article reports the human PET studies with [(18) F]MK-6577 for measuring GlyT1 receptor availability at baseline in normal human subjects and occupancy with a GlyT1 inhibitor, MK-2637. Studies were also performed to measure radiation burden and the baseline test-retest (T-RT) variability of the tracer. The effective dose from sequential whole-body dosimetry scans in three male subjects was estimated to be 24.5 ± 2.9 µSV/MBq (mean ± SD). The time-activity curves from T-RT scans modeled satisfactorily using a two tissue compartmental model. The tracer uptake was highest in the pons (VT = 6.7 ± 0.9, BPND = 4.1 ± 0.43) and lowest in the cortex (VT = 2.1 ± 0.5, BPND = 0.60 ± 0.23). VT T-RT variability measured in three subjects was <12% on average. The occupancy scans performed in a cohort of 15 subjects indicated absence of a reference region. The in vivo potency (Occ50 ) of MK-2637 was determined using two methods:
A Lassen plot with a population input function (Occ50 = 106 nM, SE = 20 nM) and B pseudo reference tissue model using cortex as the pseudo reference region (Occ50 = 141 nM, SE = 21 nM).Palavras-chave
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1
Bases de dados:
MEDLINE
Assunto principal:
Sulfonamidas
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Benzamidas
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Encéfalo
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Compostos Radiofarmacêuticos
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Tomografia por Emissão de Pósitrons
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Proteínas da Membrana Plasmática de Transporte de Glicina
Tipo de estudo:
Etiology_studies
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Incidence_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Humans
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Male
Idioma:
En
Revista:
Synapse
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2015
Tipo de documento:
Article