Abstract
[11C]Carfentanil is a potent opioid agonist currently in use as a specific PET (position emission tomography) scan radioligand for brain μ opioid receptors. In order to investigate the receptor interactions of carfentanil in detail [3H]carfentanil was used as a radioligand for labelling receptors in rat and human brain tissue homogenates. [3H]Carfentanil was found to bind saturably and with high affinity (KD = 0.08 ± 0.01 nM) to membranes prepared from human cortical (Bmax = 42 ± 3 fmol/mg) and thalamic (Bmax = 84 ± 3 fmol/mg) tissues and rat cortex (Bmax = 82 ± 4 fmol/mg) and deincephalon (Bmax = 105 ± 5 fmol/mg). Association (1.23 ± 0.19 × 1010Mol-1 × min-1 and dissociation rate (0.19 ± 0.03 min-1) constants were determined in human cortical tissues; results from studies in rat cortical, and rat diencephalon tissue homogenates produced similar kinetic rate constants. Competition studies with a variety of drugs indicated that [3H]carfentanil interacts primarily with μ opioid receptors in the four tissues studied; the affinities of a series of non-radioactive opioid ligands were essentially identical in the four tissues (correlation coefficients = 0.88-0.93). Naloxone, morphine, DAGO ([D-Ala2-MePhe4-Gly-ol5]enkephalin), DADL (D-Ala2-D- Leu5]enkaphalin) and EKC (ethylketazocine) potently displaced specific [3H]carfentanil binding with nM potency while the κ agonist U-69593, the σ agonists (+)-SKF 10047, (+)-3-PPP ((3-hydroxyphenyl)-N-propylpiperidine) and haloperidol and PCP (phencyclidine) were less potent displacing agents. The higher affinities of DAGO and morphine versus DADL for the [3H]carfentanil binding site indicates that δ opioid receptors are not being labelled. These data indicate that [3H]carfentanil is a high affinity, specific μ opioid receptor radioligand that may be of use in vitro for studying μ opioid receptors and supports the PET scanning data indicating the μ opioid receptor specificity of [11C]carfentanil. The molecular kinetic rate constants determined in vitro will be of assistance in using modelling procedures to interpret PET scanning information.
Original language | English (US) |
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Pages (from-to) | 221-228 |
Number of pages | 8 |
Journal | European Journal of Pharmacology |
Volume | 167 |
Issue number | 2 |
DOIs | |
State | Published - Aug 22 1989 |
Keywords
- PET scanning
- [H]Carfentanil
- μ Opioid receptors
ASJC Scopus subject areas
- Pharmacology