INTRODUCTION: The selective 5-hydroxytryptamine type 2a receptor (5-HT(2A)R) 
radiotracer [(18)F]altanserin is a promising ligand for in vivo brain imaging in 
rodents. However, [(18)F]altanserin is a substrate of P-glycoprotein (P-gp) in 
rats. Its applicability might therefore be constrained by both a differential 
expression of P-gp under pathological conditions, e.g. epilepsy, and its 
relatively low cerebral uptake. The aim of the present study was therefore 
twofold: (i) to investigate whether inhibition of multidrug transporters (MDT) 
is suitable to enhance the cerebral uptake of [(18)F]altanserin in vivo and (ii) 
to test different pharmacokinetic, particularly reference tissue-based models 
for exact quantification of 5-HT(2A)R densities in the rat brain.
METHODS: Eighteen Sprague-Dawley rats, either treated with the MDT inhibitor 
cyclosporine A (CsA, 50 mg/kg, n=8) or vehicle (n=10) underwent 180-min PET 
scans with arterial blood sampling. Kinetic analyses of tissue time-activity 
curves (TACs) were performed to validate invasive and non-invasive 
pharmacokinetic models.
RESULTS: CsA application lead to a two- to threefold increase of 
[(18)F]altanserin uptake in different brain regions and showed a trend toward 
higher binding potentials (BP(ND)) of the radioligand.
CONCLUSIONS: MDT inhibition led to an increased cerebral uptake of 
[(18)F]altanserin but did not improve the reliability of BP(ND) as a 
non-invasive estimate of 5-HT(2A)R. This finding is most probable caused by the 
heterogeneous distribution of P-gp in the rat brain and its incomplete blockade 
in the reference region (cerebellum). Differential MDT expressions in 
experimental animal models or pathological conditions are therefore likely to 
influence the applicability of imaging protocols and have to be carefully 
evaluated.