Permeability-glycoprotein (P-gp), an efflux transporter in several organs, acts at the blood-brain barrier to protect the brain from exogenous toxins. P-gp almost completely blocks brain entry of the PET radiotracer 11 C-N-desmethyl-loperamide ( 11 C-dLop). We examined the ability of 11 C-dLop to quantify P-gp function in humans after increasing doses of tariquidar, an inhibitor of P-gp. Methods: Seventeen healthy volunteers had a total of 23 PET scans with 11 C-dLop at baseline and after increasing doses of tariquidar (2, 4, and 6 mg/kg intravenously). A subset of subjects received PET with 15 O-H 2 O to measure cerebral blood flow. Brain uptake of 11 C-dLop was quantified in 2 ways. Without blood data, uptake was measured as area under the time-activity curve in the brain from 10 to 30 min (AUC 10-30 ). With arterial blood data, brain uptake was quantified with compartmental modeling to estimate the rates of entry into (K 1 ) and efflux from (k 2 ) the brain. Results: Brain uptake of radioactivity was negligible at baseline and increased only slightly (;30%) after 2 mg of tariquidar per kilogram. In contrast, 4 and 6 mg of tariquidar per kilogram increased brain uptake 2-and 4-fold, respectively. Greater brain uptake reflected greater brain entry (K 1 ), because efflux (k 2 ) and cerebral blood flow did not differ between tariquidartreated and untreated subjects. In the subjects who received the highest dose of tariquidar (and had the highest brain uptake), regional values of K 1 correlated linearly with absolute cerebral blood flow, consistent with high single-pass extraction of 11 C-dLop. AUC 10-30 correlated linearly with K 1 . Conclusion: P-gp function at the blood-brain barrier in humans can be quantified using PET and 11 C-dLop. A simple measure of brain uptake (AUC 10-30 ) may be used as a surrogate of the fully quantified rate constant for brain entry (K 1 ) and thereby avoid arterial sampling. However, to dissect the function of P-gp itself, both brain uptake and the influx rate constant must be corrected for radiotracer delivery (blood flow).

Few studies have demonstrated in vivo alterations of human serotonin and dopamine transporters (SERTS and DATS) during antidepressant treatment. The current study measured these transporter availabilities with [123 I]b-CIT single photon emission computed tomography (SPECT) during administration of selective serotonin reuptake inhibitors (SSRIs) or a non-SSRI, bupropion. A total of 17 healthy human subjects were randomly assigned to two different treatment protocols: (1) citalopram (40 mg/day) followed by augmentation with bupropion (100 mg/day) or (2) bupropion (100-200 mg/day) for 16 days. Citalopram significantly inhibited [123 I]b-CIT binding to SERT in brainstem (51.4%) and diencephalon (39.4%) after 8 days of administration, which was similarly observed after 16 days. In contrast, citalopram significantly increased striatal DAT binding by 15-17% after 8 and 16 days of administration. Bupropion and its augmentation to citalopram did not have a significant effect on DAT or SERT. In 10 depressed patients who were treated with paroxetine (20 mg/day), a similar increase in DAT and inhibition of SERT were observed during 6 weeks treatment. The results demonstrated the inhibition of SERT by SSRI in human in vivo during the chronic treatment and, unexpectedly, an elevation of DAT. This apparent SSRI-induced modulation of the dopamine system may be associated with the side effects of these agents, including sexual dysfunction.

PET measurements of stimulant-induced dopamine (DA) release are typically performed with antagonist radioligands that bind to both the high- and low-affinity state of the receptor. In contrast, an agonist radioligand binds preferentially to the high-affinity state and is expected to have greater sensitivity to DA, which is the endogenous agonist. [(11)C]MNPA, (R)-2-CH(3)O-N-n-propylnorapomorphine (MNPA), is a D(2) agonist radioligand with subnanomolar affinity to the D(2) receptor. The aim of the present study is to assess and compare the sensitivity of the agonist radioligand [(11)C]MNPA and antagonist radioligand [(11)C]raclopride to synaptic DA levels. Four cynomolgus monkeys were examined with [(11)C]MNPA and [(11)C]raclopride (16 PET measurements with each tracer) at baseline and after pretreatment with various doses of amphetamine. The effect of amphetamine was calculated by the change in binding potential (BP) analyzed with the multilinear reference tissue model (MRTM2). Amphetamine caused a reduction in [(11)C]MNPA BP of 4% at 0.1, 23% at 0.2, 25% at 0.5, and 46% at 1.0 mg/kg. [(11)C]Raclopride BP was reduced to a lesser extent by 2% at 0.1, 16% at 0.2, 15% at 0.5, and 23% at 1.0 mg/kg. The data were used to estimate the in vivo percentage of high-affinity state receptors to be approximately 60%. These results demonstrate that [(11)C]MNPA is more sensitive than [(11)C]raclopride to displacement by endogenous DA, and that it may provide additional information about the functional state of the D(2) receptor in illnesses such as schizophrenia and Parkinson's disease.

Abstract[ 11 C]Loperamide has been proposed for imaging P-glycoprotein (P-gp) function with positron emission tomography (PET), but its metabolism to [N-methyl-11 C]N-desmethyl-loperamide ([ 11 C] dLop; [ 11 C]3) precludes quantification. We considered that [ 11 C]3 might itself be a superior radiotracer for imaging brain P-gp function and therefore aimed to prepare [ 11 C]3 and characterize its efficacy. An amide precursor (2) was synthesized and methylated with [ 11 C]iodomethane to give [ 11 C]3. After administration of [ 11 C]3 to wild type mice, brain radioactivity uptake was very low. In P-gp (mdr-1a (−/−)) knockout mice, brain uptake of radioactivity at 30 min increased about 3.5 fold by PET measures, and over seven-fold by ex vivo measures. In knockout mice, brain radioactivity was predominantly (90%) unchanged radiotracer. In monkey PET experiments, brain radioactivity uptake was also very low, but after P-gp blockade increased more than seven-fold. [ 11 C]3 is an effective new radiotracer for imaging brain P-gp function and, in favor of future successful quantification, appears free of extensive brain-penetrant radiometabolites.