Quantifying drug-related 5-HT1A receptor occupancy with.
BACKGROUND
There is an increased interest in measuring the interaction of new or established drugs with their targets, in order to gain a better understanding of their mechanisms of action. PET can provide this information if an appropriate radioligand is available. [18F]MPPF (4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[18F]fluorobenzamido]ethylpiperazine) is a selective radioligand for serotonin 5-HT1A receptors. We have established that the binding potential (BP=Bmax/KD) of [18F]MPPF for cerebral 5-HT1A receptors can be assessed in human brain without arterial sampling.


OBJECTIVE
The aim of this study was to assess if 5-HT1A receptor occupancy can be measured through calculation of a drug-related decrease in BP with [18F]MPPF and PET.


METHODS
Six volunteers were scanned twice using a Siemens Exact HR+ camera following injection of 70+/-18 MBq [18F]MPPF (baseline and medicated conditions). Before the second scan, volunteers orally received either 3x10 mg pindolol at T=-15.5 h, T=-6.5 h, and T=-1.5 h (n=3) or 10 mg buspirone in a single dose at T=-1.5 h (n=3). Binding potentials were calculated using the simplified reference tissue model with the cerebellum as reference.


RESULTS
Administration of 30 mg pindolol led to a significant reduction in [18F]MPPF binding potential of 42+/-17%. In contrast, no significant reduction of [18F]MPPF binding potential was observed following administration of buspirone (5+/-17%).


CONCLUSIONS
These results show that [18F]MPPF can be used for measurement of drug-related 5-HT1A receptor occupancy and may be of particular interest in determining the 5-HT1A receptor interaction of new or established drugs in phase 1 and early phase 2 drug trials. Apparently, the 5-HT1A partial agonist buspirone is already clinically effective at low levels of 5-HT1A receptor occupancy.
Passchier
J
J
PET Center, Groningen University Hospital, The Netherlands.
van Waarde
A
A
Pieterman
R M
RM
Willemsen
A T
AT
Vaalburg
W
W
D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology; D000328:Adult; D000368:Aged; D001923:Brain Chemistry / Q000187:drug effects*; D002065:Buspirone / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D010869:Pindolol / Q000493:pharmacokinetics / Q000494:pharmacology; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics / Q000494:pharmacology; D014055:Tomography, Emission-Computed
D000319:Adrenergic beta-Antagonists; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D010869:Pindolol; C416325:4-(2'-methoxyphenyl)-1-(2'-(N-2'-pyridinyl)-p-(18F)fluorobenzamido )ethylpiperazine; D002065:Buspirone