Quantification of ¹¹C-Laniquidar Kinetics in the Brain

Abstract

Overexpression of the multidrug efflux transport P-glycoprotein may play an important role in pharmacoresistance. 11 C-laniquidar is a newly developed tracer of P-glycoprotein expression. The aim of this study was to develop a pharmacokinetic model for quantification of 11 C-laniquidar uptake and to assess its test-retest variability. Methods: Two (test-retest) dynamic 11 C-laniquidar PET scans were obtained in 8 healthy subjects. Plasma input functions were obtained using online arterial blood sampling with metabolite corrections derived from manual samples. Coregistered T1 MR images were used for region-of-interest definition. Timeactivity curves were analyzed using various plasma input compartmental models. Results: 11 C-laniquidar was metabolized rapidly, with a parent plasma fraction of 50% at 10 min after tracer injection. In addition, the first-pass extraction of 11 C-laniquidar was low. 11 Claniquidar time-activity curves were best fitted to an irreversible single-tissue compartment (1T1K) model using conventional models. Nevertheless, significantly better fits were obtained using 2 parallel single-tissue compartments, one for parent tracer and the other for labeled metabolites (dual-input model). Robust K 1 results were also obtained by fitting the first 5 min of PET data to the 1T1K model, at least when 60-min plasma input data were used. For both models, the test-retest variability of 11 C-laniquidar rate constant for transfer from arterial plasma to tissue (K 1 ) was approximately 19%. Conclusion: The accurate quantification of 11 C-laniquidar kinetics in the brain is hampered by its fast metabolism and the likelihood that labeled metabolites enter the brain. Best fits for the entire 60 min of data were obtained using a dual-input model, accounting for uptake of 11 C-laniquidar and its labeled metabolites. Alternatively, K 1 could be obtained from a 5-min scan using a standard 1T1K model. In both cases, the test-retest variability of K 1 was approximately 19%.

Altered GABAA receptor density and unaltered blood–brain barrier [11C]flumazenil transport in drug-resistant epilepsy patients with mesial temporal sclerosis

“…As these rate constants are related to transport of [ 11 C]flumazenil across the BBB, this finding supports the notion that [ 11 C]flumazenil is indeed a P-gp substrate, as demonstrated previously in in vivo studies in rodents using both a genetic disruption model and the same pharmacological inhibition model. 3,21 It is also in line with results from an ex vivo study in mice. 4 On the other hand, the comparison between assumed site of seizure onset and contralateral side did not show differences in K 1 /k 2 , and therefore does not provide evidence that P-gp activity is altered at the site of seizure onset in TLE patients.…”

“…22 There may be several reasons for the difference in degree of inhibition of flumazenil transport across the BBB after P-gp blockade with tariquidar in humans (23%) than in rodents ($70%). First, in the in vivo rodent studies full P-gp blockade was obtained, 3 whereas this was not possible in the present study in humans, 25 as it was considered unsafe to administer higher tariquidar doses than 2 mgÁkg À1 body weight 25 to patients who also use antiepileptic drugs. Second, species differences in BBB transport of several P-gp substrates have shown a more pronounced increase in cerebral uptake of these substrates after P-gp inhibition in rats than in higher species.…”

“…1,2 Recent ex vivo and in vivo data, however, suggest that [ 11 C]flumazenil is a P-gp substrate in rodents. [3][4][5] It has been hypothesized that P-glycoprotein (P-gp) is upregulated in areas with epileptic activity. 6 If [ 11 C]flumazenil is indeed a P-gp substrate in humans, upregulation of P-gp at the blood-brain barrier (BBB) due to epilepsy could lead to reduced cerebral uptake of [ 11 C]flumazenil, and thus to erroneous interpretation of GABA A receptor density changes.…”

The Role of P-Glycoprotein at the Blood–Brain Barrier in Neurological and Psychiatric Disease

“…This might be explained by an altered behaviour (as substrate instead of inhibitor) when laniquidar is administered in tracer concentrations. The dosimetry, kinetics and uptake of the tracer have been evaluated in healthy volunteers (Froklage et al 2015;Dörner et al 2011;Postnov et al 2013). These studies showed that [ 11 C]laniquidar generates a high amount of radioactive metabolites that cross the blood-brain barrier.…”