Synthesis and evaluation of 18F-FE-PEO in rodents: an 18F-labeled full agonist for opioid receptor imaging.
J Nucl Med
; 54(2): 299-305, 2013 Feb.
Article
en En
| MEDLINE
| ID: mdl-23297076
ABSTRACT
UNLABELLED We have investigated the opioid receptor (OR) agonist (20R)-4,5-α-epoxy-6-(2-(18)F-fluoroethoxy)-3-hydroxy-α,17-dimethyl-α-(2-phenyleth-1-yl)-6,14-ethenomorphinan-7-methanol ((18)F-FE-PEO) as a candidate OR PET ligand. This tracer is attractive because it combines (18)F labeling, is suited to the slow kinetics of high-affinity ligands, and has agonist binding, which has been shown to be more sensitive to changes in OR occupation than is antagonist binding. METHODS:
Agonist potency and off-target binding were investigated in vitro, and autoradiographic studies on rat brain sections were used to assess binding patterns. Quantification of the tracer in vivo was investigated using small-animal PET in rats with blood sampling.RESULTS:
(18)F-FE-PEO was obtained by direct nucleophilic radiofluorination and subsequent deprotection with a yield of 28% ± 15%, a specific activity of 52-224 MBq/nmol, and a radiochemical purity of more than 97% (90 min from end of bombardment). In vitro studies showed it to be a full agonist ligand, which selectively binds to OR with high affinity, although it is not selective to a single OR subtype (inhibition constant, 0.4-1.6 nM across OR subtypes). Autoradiography binding patterns were consistent with the known distribution of OR, although nondisplaceable signal typically constituted one third of the signal in OR-dense regions. Although metabolites were present in blood (â¼40% of plasma radioactivity was nonparent 3 h after injection), no significant metabolite fraction was found in brain tissue, aiding PET quantification. A plasma input 2-tissue-compartment model provided good fits to the PET data, and regional distribution volumes from the latter correlated well with those from Logan plot analysis (r(2) = 0.98). The cerebellum had the lowest distribution volume, but the time-activity curve data could not be adequately fitted with a 1-tissue-compartment model. Reference tissue models using the cerebellum as the reference region did not provide good fits to the data, so blood-based kinetic analysis is recommended.CONCLUSION:
As the first (18)F-labeled OR agonist ligand, (18)F-FE-PEO is a useful addition to the existing OR ligand portfolio.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Encéfalo
/
Radioisótopos de Flúor
/
Receptores Opioides
/
Morfinanos
Tipo de estudio:
Diagnostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Nucl Med
Año:
2013
Tipo del documento:
Article
País de afiliación:
Reino Unido