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BackgroundAt present, several positron emission tomography (PET) tracers are in use for imaging P-glycoprotein (P-gp) function in man. At baseline, substrate tracers such as R-[11C]verapamil display low brain concentrations with a distribution volume of around 1. [11C]phenytoin is supposed to be a weaker P-gp substrate, which may lead to higher brain concentrations at baseline. This could facilitate assessment of P-gp function when P-gp is upregulated. The purpose of this study was to synthesize [11C]phenytoin and to characterize its properties as a P-gp tracer.Methods[11C]CO was used to synthesize [11C]phenytoin by rhodium-mediated carbonylation. Metabolism and, using PET, brain pharmacokinetics of [11C]phenytoin were studied in rats. Effects of P-gp function on [11C]phenytoin uptake were assessed using predosing with tariquidar.Results[11C]phenytoin was synthesized via [11C]CO in an overall decay-corrected yield of 22 ± 4%. At 45 min after administration, 19% and 83% of radioactivity represented intact [11C]phenytoin in the plasma and brain, respectively. Compared with baseline, tariquidar predosing resulted in a 45% increase in the cerebral distribution volume of [11C]phenytoin.ConclusionsUsing [11C]CO, the radiosynthesis of [11C]phenytoin could be improved. [11C]phenytoin appeared to be a rather weak P-gp substrate.

Here we describe the design, synthesis, and pharmacological profile of 5-HT(1A) receptor ligands related to 1 (WAY-100635). The cyclohexyl moiety in 1 and its O-desmethylated analogue 3 were replaced by the bridgehead iodinated bridge-fused rings: adamantyl, cubyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.1]heptyl. All analogues displayed a (sub)nanomolar affinity for the 5-HT(1A) receptor in vitro. Compounds 6b and 7b appeared to be selective for this receptor over other relevant receptors and could easily be iodinated with radioactive iodine-123. In humane hepatocytes, [(123)I]6b showed a low propensity for amide hydrolysis and a stable carbon-iodine bond. The biodistribution of [(123)I]6b and [(123)I]7b in rats revealed that the carbon-iodine bond was also stable in vivo. Unfortunately, the brain uptake and the specificity for both radioligands were significantly lower than those of the parent molecule 1. In conclusion, the designed tracers are not suitable for SPECT imaging.

The overexpression of P-glycoprotein (Pgp) is thought to be an important mechanism of pharmacoresistance in epilepsy. Recently, 11 C-phenytoin has been evaluated preclinically as a tracer for Pgp. The aim of the present study was to assess the optimal plasma kinetic model for quantification of 11 C-phenytoin studies in humans. Methods: Dynamic 11 C-phenytoin PET scans of 6 healthy volunteers with arterial sampling were acquired twice on the same day and analyzed using single-and 2-tissue-compartment models with and without a blood volume parameter. Global and regional testretest (TRT) variability was determined for both plasma to tissue rate constant (K 1 ) and volume of distribution (V T ). Results: According to the Akaike information criterion, the reversible single-tissue-compartment model with blood volume parameter was the preferred plasma input model. Mean TRT variability ranged from 1.5% to 16.9% for K 1 and from 0.5% to 5.8% for V T . Larger volumes of interest showed better repeatabilities than smaller regions. A 45-min scan provided essentially the same K 1 and V T values as a 60-min scan. Conclusion: A reversible single-tissue-compartment model with blood volume seems to be a good candidate model for quantification of dynamic 11 C-phenytoin studies. Scan duration may be reduced to 45 min without notable loss of accuracy and precision of both K 1 and V T , although this still needs to be confirmed under pathologic conditions.

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P-glycoprotein (P-gp) is a drug efflux transporter with broad substrate specificity localized in the blood-brain barrier and in several peripheral organs. In order to understand the role of P-gp in physiological and patho-physiological conditions, several carbon-11 labelled P-gp tracers have been developed and validated. This review provides an overview of the spectrum of radiopharmaceuticals that is available for this purpose. A short overview of the physiology of the blood-brain barrier in health and disease is also provided. Tracer kinetic modelling for quantitative analysis of P-gp function and expression is highlighted, and the advantages and disadvantages of the various tracers are discussed.