Measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade: The genomic plot.
Neuroimage
; 130: 1-12, 2016 Apr 15.
Article
em En
| MEDLINE
| ID: mdl-26850512
ABSTRACT
PET studies allow in vivo imaging of the density of brain receptor species. The PET signal, however, is the sum of the fraction of radioligand that is specifically bound to the target receptor and the non-displaceable fraction (i.e. the non-specifically bound radioligand plus the free ligand in tissue). Therefore, measuring the non-displaceable fraction, which is generally assumed to be constant across the brain, is a necessary step to obtain regional estimates of the specific fractions. The nondisplaceable binding can be directly measured if a reference region, i.e. a region devoid of any specific binding, is available. Many receptors are however widely expressed across the brain, and a true reference region is rarely available. In these cases, the nonspecific binding can be obtained after competitive pharmacological blockade, which is often contraindicated in humans. In this work we introduce the genomic plot for estimating the nondisplaceable fraction using baseline scans only. The genomic plot is a transformation of the Lassen graphical method in which the brain maps of mRNA transcripts of the target receptor obtained from the Allen brain atlas are used as a surrogate measure of the specific binding. Thus, the genomic plot allows the calculation of the specific and nondisplaceable components of radioligand uptake without the need of pharmacological blockade. We first assessed the statistical properties of the method with computer simulations. Then we sought ground-truth validation using human PET datasets of seven different neuroreceptor radioligands, where nonspecific fractions were either obtained separately using drug displacement or available from a true reference region. The population nondisplaceable fractions estimated by the genomic plot were very close to those measured by actual human blocking studies (mean relative difference between 2% and 7%). However, these estimates were valid only when mRNA expressions were predictive of protein levels (i.e. there were no significant post-transcriptional changes). This condition can be readily established a priori by assessing the correlation between PET and mRNA expression.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Mapeamento Encefálico
/
Compostos Radiofarmacêuticos
/
Tomografia por Emissão de Pósitrons
/
Modelos Teóricos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Neuroimage
Assunto da revista:
DIAGNOSTICO POR IMAGEM
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Reino Unido