PET studies on the mechanism of monoaminergic drugs

Positron emission tomography (PET) is a molecular imaging technique that allows for examinations of neurochemistry directly in the living human brain. In the present thesis, PET was used to assess the pharmacological effects of two drugs representing the major classes of antipsychotic and antidepressant drugs. In addition, novel methodology for studies on antidepressant mechanism of action was developed further. In study I, striatal D2 dopamine receptor occupancy was examined in healthy subjects after administration of the antipsychotic drug quetiapine in two formulations, immediate-release (IR) and extended-release (XR), respectively. The D2 occupancy at peak concentration was higher for the IR compared to the XR formulation (50±4% and 32±11% respectively). The result may explain observed pharmacodynamic differences between the two formulations, and also support the view that quetiapine may show antipsychotic effect at lower D2 receptor occupancy than the first-generation of antipsychotic drugs. In study II, changes in serotonin concentration were assessed in healthy subjects after administration of a single, clinically relevant dose of the antidepressant drug escitalopram. A competition-model with the 5-HT1B receptor selective radioligand [C]AZ10419369 was used to indirectly measure changes in extracellular endogenous serotonin concentration after drug administration. Escitalopram was found to decrease serotonin concentrations in serotonergic projection areas. This observation directly in human subjects extends previous hypotheses on the mechanism of action of antidepressant drugs, derived primarily from experimental animals. The aim of study III was primarily to evaluate the methodology of study II. The binding potential of the radioligand [C]AZ10419369 was determined in two consecutive PET measurements, performed on the same day in 8 healthy subjects. In serotonergic projection areas the mean difference in radioligand binding between PET 1 and PET 2 was minor, supporting the methodology and interpretation of the results of study II. In study IV, the effect of age on 5-HT1B receptor availability was examined. The 5-HT1B receptor availability decreased significantly with age in cortical regions. On the contrary, the 5-HT1B receptor availability in the caudate nucleus and the putamen remained stable over the investigated age range. This observation may indicate that the 5-HT1B receptors in these regions are expressed on neurons with a different sensitivity to aging. The results highlight the importance of using age-matched controls in future clinical studies on the 5-HT1B receptor. LIST OF SCIENTIFIC PAPERS I. Nord M, Nyberg S, Brogren J, Jucaite A, Halldin C, Farde L. Comparison of D2 dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects. Int J Neuropsychopharmacol, 2011, 14, 1357-66. II. Nord M, Finnema S. J, Halldin C, Farde L. Effect of a single dose of escitalopram on serotonin concentration in the non-human and human primate brain. Int J Neuropsychopharmacol, 2013, 16, 1577-86. III. Nord M, Finnema S. J, Schain M, Halldin C, Farde L. Test-retest reliability of [11C]AZ10419369 binding to 5-HT1B receptors in human brain. Eur J Nucl Med Mol Imaging, 2014, 41, 301-7 IV. Nord M, Cselenyi Z, Forsberg A, Rosenqvist G, Tiger M, Lundberg J, Varrone A, Farde L. Distinct regional age effects on [11C]AZ10419369 binding to 5HT1B receptors in the human brain. Submitted. NOT INCLUDED IN THE THESIS: Nord M, Farde L. Antipsychotic Occupancy of Dopamine Receptors in Schizophrenia. CNS Neurosci Ther 2011, 17, 97-103.