Drug- receptor occupation studies
Due to the breakthrough advances in imaging techniques, it is now possible noninvasively measure binding of drugs to their target receptors. For a range of drugs used in neurology and psychiatry we can now perform a form of dose-response measurement at the precise target site of drug action, a big improvement as previously we had to make estimates of brain target engagement from plasma concentration measurements. In fig 7, this is shown for a D2 receptor antagonist. Both scans use 11C-raclopride to estimate the number of dopamine D2 receptors available for the tracer to bind to. In the untreated state a high level of 11C-raclopride binding is seen in the dopamine rich striatal regions. However after treatment with a D2 receptor antagonist neuroleptic this is dramatically reduced because the drug competes with 11C-raclopride for the same binding site.
Studies such as these were instrumental in changing the dosing regimens of dopamine blocking drugs for psychosis because they revealed several important facts. First the receptor occupation needed to produce an antipsychotic effect was about 65%. But when occupation reached over 80% then adverse effects such as extra-pyramidal symptoms and elevated prolactin concentrations were seen. This means that the therapeutic window for these drugs is very narrow7. Even a small increase in dose can switch a patient from being underdosed [i.e. occupation < 65% ] to overdosed [i.e. occupation > 80%].
The second advance was that it became apparent that certain doses of D2 receptor antagonist produced saturation of the dopamine receptors. Thus there was no added clinical benefit when D2 receptor occupancy was high, and when striatial receptor occupancy was lowered, the safety and tolerability profile of drugs improved.
Imaging of the serotonin reuptake site has shown rather different results because here it is necessary to get over 70-80% occupation by a reuptake blocker to produce significant lifting of depression8. Different receptor occupation/effect relationships apply to different drugs so the full mu receptor opioid agonist produces it actions with very low [less than 8%] occupation of the receptor whereas the partial mu receptor opioid agonist requires occupation of > 50% of receptors9.
PET and MRI imaging offer important new ways to explore brain structure and function in psychiatry and neurology. At present whilst MRI is in regular clinical use for diagnosis, PET is largely just a research tool, but some tracers e.g. F-DOPA and 11C-PIB are being used to aid diagnosis of Parkinson's disease and Alzheimer's disease respectively. The future development of tracers that use 18F instead of 11C will further spread the availability of these in clinical practice. This is because the much longer half-life of 18F [110 min v 20min] allows production of the radioactive tracer at a central cyclotron site with distribution to multiple hospitals that have PET scanners. In contrast 11C tracers have to be made on the same site as the scanner, so each site needs its own cyclotron.