A new human (psycho)pharmacology tool: the multiple organs coincidences counter (MOCC)

Abstract

We describe a novel instrument which is capable of measuring the uptake of radioligand in human organs in vivo with the administration of very small doses of positron-emitting radioligands. This technique readily detects the displacement or reduced uptake of radioligand when a competitive agonist or antagonist is administered. This system provides no tomographic information, but the small radioactive doses involved mean that investigations can be repeated at regular intervals and that female volunteers can also participate. We administered [(11) C]flumazenil, [(11)C]diprenorphine, [(11)C]meta -hydroxyephedrine (MHED) and [(11)C]RTI 55 to healthy male volunteers and performed control, pre-loading and displacement experiments. These demonstrate the feasibility of using this technique to investigate benzodiazepine and opiate receptor occupancy, as well as occupancy at dopamine, noradrenaline and serotonin (5-HT) re-uptake sites. This method is likely to be useful in pharmacokinetic/pharmacodynamic experiments, in drug development and discovery and in the development of novel imaging radioligands.

Benzodiazepine Binding Site Occupancy by the Novel GABAA Receptor Subtype-Selective Drug 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) in Rats, Primates, and Humans

“…respectively (Malizia et al, 1996). It is interesting to note that comparable data (7 and 39% occupancy at the low and high dose) were obtained using total head counts (Malizia et al, 1996), suggesting that nontomographic methods, which require lower levels of radioactivity compared with tomographic techniques, may be used to determine levels of occupancy in humans (Malizia et al, 1995). In a […”

Restoring the Spinal Pain Gate

“…This study found of a (small) antihyperalgesic effect in several parameters including in the size of the hyperalgesic area induced by intracutaneous capsaicin injection and in several muscle painrelated read-outs. Non-selective full agonists such as diazepam, clonazepam, midazolam typically induce strong sedation or sleep already at receptor occupancies between 15% and 30% (Fujita et al, 1999;Malizia et al, 1995;Pauli, Farde, Halldin, & Sedvall, 1991;Shinotoh et al, 1989). Compounds with a better α2/α1-selectivity ratio should permit higher levels of receptor occupancy and hence higher α2-GABA A R activation before reaching dose-limiting sedation.…”

Psychopharmacology -- in vivo neurochemistry and pharmacology

“…The further application of this methodology 22 should provide unique insights of CNS drug mechanisms in vivo, relating medicinal effects to receptor occupancy. It is anticipated that this line of enquiry will be of considerable interest in psychiatry.…”

“…This novel approach uses PET radiotracers but sacrifices tomographic information in order to reduce the radiation exposure of the subject to about 100-fold less than a conventional PET study 22 . Instead of using a PET camera, a modified whole body counter, consisting of a small number of large sodium iodide scintillation counters, is configured to detect the coincident gamma radiation emitted by decaying PET radioisotopes.…”

“…Instead of using a PET camera, a modified whole body counter, consisting of a small number of large sodium iodide scintillation counters, is configured to detect the coincident gamma radiation emitted by decaying PET radioisotopes. For appropriate radioligands, such as "C-diprenorphine (opioid receptors) and "C-flumazenil (central benzodiazepine receptors), determination of a tissue receptor occupancy index, at various concentrations of exogenously administered drugs, can be achieved 22 . Because of the low radiation exposure, this method allows repeated estimations, within a subject, of receptor occupancy changes with drug treatment.…”