11C]-NS 4194 versus [11C]-DASB for PET imaging of serotonin transporters in living porcine brain

In vitro, the novel diazabicyclononane NS 4194 has several thousand-fold selectivity for blocking the transport into rat brain synaptosomes of [(3)H]-serotonin in comparison to [(3)H]-dopamine or [(3)H]-noradrenaline. We have prepared [(11)C]-NS 4194 in order to test its properties for PET imaging of brain serotonin transporters in comparison with the well-documented tracer [(11)C]-DASB. Both compounds had rapid clearance from blood to brain of living pigs. The apparent equilibrium distribution volumes in cerebellum were 35 ml g(-1) for [(11)C]-NS 4194 and 11 ml g(-1) for [(11)C]-DASB. Pretreatment of pigs with citalopram did not reduce the uptake of either tracer in cerebellum, validating the use of that tissue as a nonbinding reference tissue for kinetic analysis of specific binding. The binding potential (pB) calculated for [(11)C]-NS 4194 using arterial input models was close to 0.5 in the telencephalon, and was 60% displaced by citalopram. However, the reference tissue method of Lammertsma was unsuited to calculate pB for this tracer, apparently due to its excessive nonspecific binding. In contrast to the relatively homogeneous binding of [(11)C]-NS 4194, the pB of [(11)C]-DASB ranged from 0.6 in frontal cortex to 2 in the mesencephalon when calculated by the method of Lammertsma. Parametric maps of the pB of [(11)C]-DASB showed a pattern consistent with the known distribution of serotonin transporters in pig brain in vitro, and there was a uniform displacement of 80% of the specific binding after citalopram treatment in vivo. In conclusion, [(11)C]-DASB is in several respects superior to [(11)C]-NS 4194 for the detection of serotonin uptake sites by PET.     

Effects of tryptophan depletion on the serotonin transporter in healthy humans.

BACKGROUND: Lowering of brain serotonin by acute tryptophan depletion (TD) frequently leads to transient symptoms of depression in vulnerable individuals but not in euthymic healthy subjects with a negative family history of depression. The effects of TD on regional serotonin transporter binding potential (5-HTT BP), an index of 5-HTT density and affinity, were studied in healthy individuals using 3-(11)C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile ([11C]DASB) positron emission tomography (PET). Adaptive decreases in 5-HTT density and/or affinity during TD would be a possible compensatory mechanism to maintain sufficient extracellular serotonin levels during TD, thereby preventing a depressive relapse. METHODS: Regional noninvasive 5-HTT BP was found in 25 healthy subjects using [11C]DASB PET. Fourteen subjects were scanned twice, once after TD and once after sham depletion, and 11 other healthy subjects were scanned twice to measure test-retest reliability of the method. RESULTS: None of the healthy subjects experienced depressive symptoms during TD and there was no difference in regional 5-HTT BP during TD as compared with sham depletion. CONCLUSIONS: Acute changes in 5-HTT density or affinity are unlikely to play a role in protecting healthy subjects against mood symptoms during TD. Other mechanisms that may be associated with greater resilience against acute lowering of extracellular serotonin should be explored to gain further insight into the neurochemical basis of different vulnerabilities to short-term depressive relapse.     

Measurement of serotonin transporter binding with PET and [11C]MADAM: a test-retest reproducibility study

[(11)C]MADAM, or [(11)C]N,N-dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine, is a radioligand suitable for positron emission tomography (PET) studies of the serotonin transporter (5-HTT) in man. The purpose of this study was to examine the test-retest reproducibility using a design tailored for future applied studies. Nine healthy male subjects were examined with PET and [(11)C]MADAM under baseline conditions at two occasions 4-8 weeks apart. The subjects participated in a Phase 1 trial to which the present study was an addendum. Eight regions of interest were studied, including frontal cortex, hippocampal complex, and the raphe nuclei. All regions, but the raphe nuclei, were defined on MR-images to which the PET-images were coregistered using SPM2. Binding potentials were calculated using the simplified reference tissue model, with cerebellum as reference region. Test-retest data were calculated from the binding potentials, and included binding potential (BP) quotient, BP difference, and the intraclass correlation coefficient. The quotient was about one in all regions, and the mean difference varied between 0 and 11%. The intraclass correlation coefficient varied between 0.96 and 0.51 in the raphe nuclei and averaged bilateral regions. [(11)C]MADAM was shown to have good to excellent reliability in measurements of 5-HTT binding in brain regions of interest in research on psychiatric disorders.     

Elevated serotonin transporter binding in depressed patients with Parkinson's disease: A preliminary PET study with [11C]DASB

This study investigated whether abnormalities in serotonin transporter binding occur in Parkinson's disease (PD) patients with concurrent depression. We estimated serotonin transporter levels in seven clinically depressed early‐stage PD patients and in seven healthy matched‐control subjects during a single positron emission tomography (PET) scan with the serotonin transporter radioligand, [¹¹C]DASB. Depressed PD patients displayed a wide‐spread increase (8–68%) in [¹¹C]DASB specific binding outside of the striatum, which was significant in dorsolateral (37%) and prefrontal (68%) cortices. Elevated [¹¹C]DASB binding was positively correlated with depressive symptoms but not with disease severity or duration. Compatible with recent PET/[¹¹C]DASB findings in major depression, the present preliminary data suggest that increased [¹¹C]DASB binding, possibly reflecting greater serotonin transporter density (up‐regulation), might be a pathological feature of depression in Parkinson's disease—and possibly a characteristic of depressive illness in general. © 2008 Movement Disorder Society     

Serotonin transporter binding in bipolar disorder assessed using [11C]DASB and positron emission tomography.

BACKGROUND: Evidence from neuroimaging post-mortem, and genetic studies suggests that bipolar disorder (BD) is associated with abnormalities of the serotonin-transporter (5-HTT) system. Because of various limitations of these studies, however, it has remained unclear whether 5-HTT binding is abnormal in unmedicated BD-subjects. This study used PET and [(11)C]DASB, a radioligand that afforded higher sensitivity and specificity for the 5-HTT than previously available radioligands, to compare 5-HTT binding between BD and control subjects. METHODS: The 5-HTT binding-potential (BP) was assessed in 18 currently-depressed, unmedicated BD-subjects and 37 healthy controls using PET and [(11)C]DASB. RESULTS: In BD, the mean 5-HTT BP was increased in thalamus, dorsal cingulate cortex (DCC), medial prefrontal cortex and insula and decreased in the brainstem at the level of the pontine raphe-nuclei. Anxiety ratings correlated positively with 5-HTT BP in insula and DCC, and BP in these regions was higher in subjects manifesting pathological obsessions and compulsions relative to BD-subjects lacking such symptoms. Subjects with a history of suicide attempts showed reduced 5-HTT binding in the midbrain and increased binding in anterior cingulate cortex versus controls and to BD-subjects without attempts. CONCLUSIONS: This is the first study to report abnormalities in 5-HTT binding in unmedicated BD-subjects. The direction of abnormality in the brainstem was opposite to that found in the cortex, thalamus, and striatum. Elevated 5-HTT binding in the cortex may be related to anxiety symptoms and syndromes associated with BD.     

Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder.

BACKGROUND: Altered serotonergic function is thought to play a role in the pathophysiology of major depressive episodes based upon evidence from neuroimaging, pharmacological, postmortem and genetic studies. It remains unclear, however, whether depressed samples that differ with respect to having shown a unipolar versus a bipolar illness course also would show distinct patterns of abnormalities within the serotonergic system. The current study compared serotonin transporter (5-HTT) binding between unipolar-depressives (MDD), bipolar-depressives (BD) and healthy-controls (HC) to assess whether the abnormalities in 5-HTT binding recently found in depressed subjects with BD extend to depressed subjects with MDD. METHODS: The 5-HTT binding-potential (BP) measured using positron emission tomography (PET) and [(11)C]DASB was compared between unmedicated, depressed subjects with MDD (n = 18) or BD (n = 18) and HC (n = 34). RESULTS: Relative to the healthy group both MDD and BD groups showed significantly increased 5-HTT BP in the thalamus (24%, 14%, respectively), insula (15%) and striatum (12%). The unipolar-depressives had elevated 5-HTT BP relative to both BD and HC groups in the vicinity of the periaqueductal gray (PAG, 20%, 22%, respectively). The bipolar-depressives had reduced 5-HTT BP relative to both HC and MDD groups in the vicinity of the pontine raphe nuclei. Depression-severity correlated negatively with 5-HTT BP in the thalamus in MDD-subjects. CONCLUSIONS: The depressed phases of MDD and BD both were associated with elevated 5-HTT binding in the insula, thalamus and striatum, but showed distinct abnormalities in the brainstem. The latter findings conceivably could underlie differences in the patterns of illness symptoms and pharmacological sensitivity observed between MDD and BD.     

Effect of reserpine-induced depletion of synaptic dopamine on [11C]Raclopride binding to D2-dopamine receptors in the monkey brain

Positron emission tomography was used to examine the in vivo binding of [¹¹C]raclopride to D₂-dopamine (DA) receptors in the striatum of two Cynomolgus monkeys after a single dose of reserpine (1 mg/kg, i.v.). A Scatchard procedure was repeated five times to follow D₂ receptor density and apparent affinity for 7 weeks after reserpine. Reserpine-induced depletion of DA lead to a marked increase in [¹¹C]raclopride binding, which was still detectable 20 days after treatment. Scatchard analyses indicated that the measured increase in [¹¹C]raclopride binding reflected an increase in receptor affinity but no evident change in receptor density (B_max). Thus, the increase in [¹¹C]raclopride binding after reserpine should correspond to a reduced competition with endogenous DA for binding to D₂ receptors. The results were used to estimate the DA-induced D₂ occupancy to be about 40% at physiological conditions. Synapse 25:321–325, 1997. © 1997 Wiley-Liss, Inc.     

Within-subject comparison of [11C]-(+)-PHNO and [11C]raclopride sensitivity to acute amphetamine challenge in healthy humans

[¹¹C]PHNO is a D₂/D₃ agonist positron emission tomography radiotracer, with higher in vivo affinity for D₃ than for D₂ receptors. As [¹¹C]-(+)-PHNO is an agonist, its in vivo binding is expected to be more affected by acute fluctuations in synaptic dopamine than that of antagonist radiotracers such as [¹¹C]raclopride. In this study, the authors compared the effects of an oral dose of the dopamine releaser amphetamine (0.3 mg/kg) on in vivo binding of [¹¹C]-(+)-PHNO and [¹¹C]raclopride in healthy subjects, using a within-subjects, counterbalanced, open-label design. In the dorsal striatum, where the density of D₃ receptors is negligible and both tracers predominantly bind to D₂ receptors, the reduction of [¹¹C]-(+)-PHNO binding potential (BP_ND) was 1.5 times larger than that of [¹¹C]raclopride. The gain in sensitivity associated with the agonist [¹¹C]-(+)-PHNO implies that ∼65% of D₂ receptors are in the high-affinity state in vivo. In extrastriatal regions, where [¹¹C]-(+)-PHNO predominantly binds to D₃ receptors, the amphetamine effect on [¹¹C]-(+)-PHNO BP_ND was even larger, consistent with the higher affinity of dopamine for D₃. This study indicates that [¹¹C]-(+)-PHNO is superior to [¹¹C]raclopride for studying acute fluctuations in synaptic dopamine in the human striatum. [¹¹C]-(+)-PHNO also enables measurement of synaptic dopamine in D₃ regions.     

Effects of reduced endogenous 5-HT on the in vivo binding of the serotonin transporter radioligand 11C-DASB in healthy humans

Although abnormal serotonin (5-HT) function is implicated in a range of mental disorders, there is currently no method to directly assess 5-HT synaptic levels in the living human brain. The in vivo binding of some dopamine (DA) radioligands such as (11)C-raclopride is affected by fluctuations in endogenous DA, thus providing an indirect measure of DA presynaptic activity. Attempts to identify a serotonergic radiotracer with similar properties have proved unsuccessful. Here, we investigated in humans the effects of reduced synaptic 5-HT on the in vivo binding of the 5-HT transporter (SERT) radioligand (11)C-DASB, using Positron Emission Tomography (PET) and the rapid tryptophan depletion (RTD) technique. Eight (8) subjects (5M, 3F) were scanned with (11)C-DASB under control and reduced endogenous 5-HT conditions, in a within-subject, double-blind, counterbalanced, crossover design. Regional distribution volumes (V(T)) were calculated using kinetic modeling and metabolite-corrected arterial input function. (11)C-DASB specific binding was estimated as binding potential (BP) and specific to nonspecific equilibrium partition coefficient (V(")(3)), using the cerebellum as reference region. RTD caused small but significant mean reductions in (11)C-DASB V(T) (-6.1%) and BP (-4.5%) across brain regions, probably explained by a concomitant reduction in (11)C-DASB plasma free fraction (f(1)) of similar magnitude. No significant change in (11)C-DASB V(")(3) was observed between control and reduced 5-HT conditions. Nor was there a significant relationship between the magnitude of tryptophan depletion and change in BP and V(")(3) across individual subjects. These results suggest that (11)C-DASB in vivo binding is not affected by reductions in endogenous 5-HT.     

Tracer kinetic modeling of [11C]AFM,a new PET imaging agent for the serotonin transporter

[¹¹C]AFM, or [¹¹C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine, is a new positron emission tomography (PET) radioligand with high affinity and selectivity for the serotonin transporter (SERT). The purpose of this study was to determine the most appropriate kinetic model to quantify [¹¹C]AFM binding in the healthy human brain. Positron emission tomography data and arterial input functions were acquired from 10 subjects. Compartmental modeling and the multilinear analysis-1(MA1) method were tested using the arterial input functions. The one-tissue model showed a lack of fit in low-binding regions, and the two-tissue model failed to estimate parameters reliably. Regional time–activity curves were well described by MA1. The rank order of [¹¹C]AFM binding potential (BP_ND) matched well with the known regional SERT densities. For routine use of [¹¹C]AFM, several noninvasive methods for quantification of regional binding were evaluated, including simplified reference tissue models (SRTM and SRTM2), and multilinear reference tissue models (MRTM and MRTM2). The best methods for region of interest (ROI) analysis were MA1, MRTM2, and SRTM2, with fixed population kinetic values ( or b′) for the reference methods. The MA1 and MRTM2 methods were best for parametric imaging. These results showed that [¹¹C]AFM is a suitable PET radioligand to image and quantify SERT in humans.     

Unchanged striatal dopamine transporter availability in narcolepsy: a PET study with [11C]-CFT

OBJECTIVE: To investigate dopamine reuptake sites (dopamine transporter) in the caudate nucleus and putamen in narcolepsy. PATIENTS AND METHODS: Ten patients with narcolepsy and 15 controls were studied with positron emission tomography. A cocaine analogue [11C]-CFT was used as a radioligand. RESULTS: The uptake of[11C]-CFT was within normal limits (89% of age-adjusted control mean in the caudate nucleus and 91% in the putamen) in patients with narcolepsy. CONCLUSIONS: No evidence of altered striataldopamine transporter availability was found in narcolepsy.     

Dopamine modulating drugs influence striatal (+)-[11C]DTBZ binding in rats: VMAT2 binding is sensitive to changes in vesicular dopamine concentration

Binding of (+)-[11C]DTBZ (dihydrotetrabenazine) to the striatal vesicular monoamine transporter (VMAT2) is widely considered to be a stable marker of dopamine neurone integrity. However, we now find that specific binding of a tracer dose of (+)-[11C]DTBZ is modestly increased in rat striatum following dopamine depletion with alpha-methyl-p-tyrosine (alpha-MPT, +14%) or d-amphetamine (d-AMPH, 20 mg/kg, +12%) and decreased following dopamine elevation with gamma-hydroxybutyrate (GHB, -16%) or levodopa (-20%). We suggest that in vivo (+)-[11C]DTBZ binding in imaging studies is subject to competition by vesicular dopamine and, in this respect, is not a "stable" dopamine biomarker as is generally assumed.     

Positron emission tomography quantification of [(11)C]-DASB binding to the human serotonin transporter: modeling strategies.

[(11) C]-DASB, namely [(11) C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, is a new highly selective radioligand for the in vivo visualization of the serotonin transporter (SERT) using positron emission tomography (PET). The current study evaluates different kinetic modeling strategies for quantification of [(11)C]-DASB binding in five healthy humans. Kinetic analyses of tissue data were performed with a one-tissue (1CM) and a two-tissue (2CM) compartment model. Time-activity curves were well described by a 1CM for all regions. A 2CM model with four parameters failed to converge reliably. Reliable fits of the data were obtained only if no more than three parameters were allowed to vary. However, even then, the rate constants k(3) and k(4) were estimated with poor precision. Only the ratio k(3)/k(4) was stable. Goodness of fit was not improved by using a 2CM as compared with a 1CM. The minimal study duration required to obtain stable k(3)/k(4) estimates was 80 minutes. For routine use of [(11)C]-DASB, several simplified methods using the cerebellum as a reference region to estimate nonspecific binding were also evaluated. The transient equilibrium, the linear graphical analysis, the ratio of target to reference region, and the simplified reference tissue methods all gave binding potential values consistent with those obtained with the 2CM. The suitability of [(11)C]-DASB for research on the SERT using PET is thus supported by the observations that tissue data can be described using a kinetic analysis and that simplified quantitative methods, using the cerebellum as reference, provide reliable estimates of SERT binding parameters.     

Characterization of in vivo pharmacological properties and sensitivity to endogenous serotonin of [11C] P943: a positron emission tomography study in Papio anubis

[11 C] P943 is a recently developed PET radiotracer for serotonin 5-HT1B receptors. We characterized a number of its in vivo pharmacokinetic properties, including the evaluation of its two stereo-isomers, saturability of specific binding, selectivity for 5-HT1B and 5-HT1D receptors, and vulnerability to pharmacologically induced increases in endogenous 5-HT levels. Six isoflurane-anesthetized baboons were scanned with [11 C] P943 at baseline, and following various pharmacological manipulations. The interventions included the administration of pharmacological doses of P943, SB-616234-S (a 5-HT1B selective antagonist), SB-714786 (a 5-HT1D selective antagonist), as well as the administration of 5-HT releasing agents (fenfluramine, amphetamine) and 5-HT reuptake inhibitor (citalopram). [11 C] P943 was observed to bind saturably and specifically to 5-HT1B receptors and to be sensitive to all three challenges known to alter 5-HT levels in the proximity of receptors. [11 C] P943 shows promise as a tracer to image serotonin function in healthy subjects as well as subjects with psychiatric or neurologic conditions.     

Effect on [11C]DASB binding after tranylcypromine-induced increase in serotonin concentration: positron emission tomography studies in monkeys and rats

Several research groups have demonstrated that under specific conditions, in vivo neuroreceptor binding techniques can be used to measure acute changes in the concentrations of endogenous transmitters in the vicinity of neuroreceptors. The aim of this study was to investigate whether [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([(11)C]DASB) binding to the plasma membrane serotonin transporter (SERT) in the rhesus monkey and rat brain decreased after a pharmacologically-induced increase in the interstitial serotonin (5HT) concentration. Three rhesus monkeys were given repeated single boluses of [(11)C]DASB in sequential positron emission tomography (PET) experiments. Rats were given the tracer as a bolus dose plus a constant infusion. In vivo binding in both models was studied before and after presumably having increased interstitial 5HT concentrations using tranylcypromine (TCP), which inhibits the enzyme (monoamine oxidase, MAO), that degrades 5HT. The rat brain tissue was analyzed using high-performance liquid chromatography (HPLC) to determine the proportion of the PET signal comprising unchanged [(11)C]DASB. The binding of [(11)C]DASB in the thalamus decreased in both rhesus monkeys and rats after TCP administration. The possibility of using [(11)C]DASB as a tool for monitoring changes in endogenous serotonin concentrations merits further investigation.     

Influence of a low dose of amphetamine on vesicular monoamine transporter binding: A PET (+)[11C]DTBZ study in humans

We previously reported increased binding of (+)[¹¹C]DTBZ (dihydrotetrabenazine), the vesicular monoamine transporter (VMAT2) positron emission tomography (PET) radioligand, in striatum of some methamphetamine users. This finding might be explained by stimulant‐induced vesicular DA depletion resulting in decreased DA (+)[¹¹C]DTBZ competition at VMAT2. In a prospective PET study, we now find that administration of an acute oral dose of amphetamine (0.4 mg/kg) to humans does not cause increased striatal (+)[¹¹C]DTBZ binding but a slight 5% decrease. Our data suggest that a low amphetamine dose is unlikely to cause sufficient DA depletion to detect increased (+)[¹¹C]DTBZ binding and that a higher dose might be required. Synapse 64:417–420, 2010. © 2010 Wiley‐Liss, Inc.     

Quantification of aromatase binding in the female human brain using [11C]cetrozole positron emission tomography

Aromatase, the enzyme that in the brain converts testosterone and androstenedione to estradiol and estrone, respectively, is a putative key factor in psychoneuroendocrinology. In vivo assessment of aromatase was performed to evaluate tracer kinetic models and optimal scan duration, for quantitative analysis of the aromatase positron emission tomography (PET) ligand [¹¹C]cetrozole. Anatomical magnetic resonance and 90-min dynamic [¹¹C]cetrozole PET-CT scans were performed on healthy women. Volume of interest (VOI)-based analyses with a plasma-input function were performed using the single-tissue and two-tissue (2TCM) reversible compartment models and plasma-input Logan analysis. Additionally, the simplified reference tissue model (SRTM), Logan reference tissue model (LRTM), and standardized uptake volume ratio model, with cerebellum as reference region, were evaluated. Parametric images were generated and regionally averaged voxel values were compared with VOI-based analyses of the reference tissue models. The optimal reference model was used for evaluation of a decreased scan duration. Differences between the plasma-input- and reference tissue-based methods and comparisons between scan durations were assessed by linear regression. The [¹¹C]cetrozole time–activity curves were best described by the 2TCM. SRTM nondisplaceable binding potential (BP_ND), with cerebellum as reference region, can be used to estimate [¹¹C]cetrozole binding and generated robust and quantitatively accurate results for a reduced scan duration of 60 min. Receptor parametric mapping, a basis function implementation of SRTM, as well as LRTM, produced quantitatively accurate parametric images, showing BP_ND at the voxel level. As PET tracer, [¹¹C]cetrozole can be employed for relatively short brain scans to measure aromatase binding using a reference tissue-based approach.     

(11)C]MADAM, a new serotonin transporter radioligand characterized in the monkey brain by PET

The aim of this study was to explore the potential of a new selective serotonin transporter (5-HTT) inhibitor, N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine (MADAM, K(i)=1.65 nM), as a PET radioligand for examination of 5-HTT in the nonhuman primate brain. MADAM was radiolabeled by an N-methylation reaction using [(11)C]methyl triflate and the binding was characterized by PET in four cynomolgus monkeys. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography (HPLC). The radiochemical incorporation yield of [(11)C]MADAM was 75-80% and the specific radioactivity at the time of administration was 34-652 GBq/micromol (n=8). The highest uptake of radioactivity was observed in striatum, thalamus, mesencephalon, and the lower brainstem. Lower binding was detected in neocortex and the lowest radioactive uptake was found in the cerebellum. This distribution is in accordance with the known expression of 5-HTT in vitro. The fraction of the total radioactivity in monkey plasma representing unchanged [(11)C]MADAM was 20% at 45 min after injection, as measured by gradient HPLC. Pretreatment measurements, using unlabeled citalopram, GBR 12909, and maprotiline, as well as a displacement measurement, using unlabeled MADAM, confirmed that [(11)C]MADAM binds selectively and reversibly to 5-HTT, and support the use of the cerebellum as reference region. The present characterization of binding in the monkey brain suggests that [(11)C]MADAM is a potential PET radioligand for quantitative studies of 5-HTT binding in the human brain.     

Quantitative analysis of [11C]AZ10419369 binding to 5-HT1B receptors in human brain

A novel radioligand for positron emission tomography (PET) imaging of serotonin 5-HT_1B receptors, [¹¹C]AZ10419369, has been recently described. In this study, the potential for quantitative analysis of [¹¹C]AZ10419369 binding to central 5-HT_1B receptors was evaluated in human subjects. PET measurements were performed after injection of [¹¹C]AZ10419369 in 10 subjects. Data were analyzed with kinetic modeling and linear graphical analysis using the arterial plasma as input function, and with reference tissue models using cerebellar cortex as the reference region. Binding of [¹¹C]AZ10419369 was highest in pallidum, ventral striatum, and occipital cortex and lowest in cerebellum. The percentage of unchanged radioligand in plasma was 97% to 99%, indicating that no significant amounts of radioactive metabolites were formed during the time of analysis. Time–activity curves of [¹¹C]AZ10419369 could be described with both one-tissue compartment (1-TC) and two-tissue compartment (2-TC) models in the majority of subjects. The 2-TC model failed to deliver reasonable estimates of the kinetic parameters. However, stable estimates of binding potential (BP_ND) were obtained by constraining K₁/k₂ to the distribution volume obtained with the 1-TC model in the cerebellar cortex. BP_ND values estimated with reference tissue models were correlated with the corresponding values obtained with kinetic modeling. The findings support the use of reference tissue models in applied clinical studies with [¹¹C]AZ10419369.     

Brain uptake and plasma metabolism of [11C]vinpocetine: a preliminary PET study in a cynomolgus monkey.

Vinpocetine, a vinca alkaloid, is a widely used therapeutic agent in patients with acute and chronic stroke. To reveal the mechanisms of vinpocetine action in the brain, vinpocetine was labeled with 11C. Positron emission tomography (PET) was used to determine the uptake and distribution of [11C]vinpocetine in brain regions and the trunk of a cynomolgous monkey in two independent measurements. The concentration of vinpocetine and its labeled metabolites was determined in blood and plasma using high-performance liquid chromatography (HPLC). Almost identical measurements were obtained in the two independent studies. After intravenous administration, following an initial peak, the total concentration of radioactivity in blood was relatively stable with time, whereas the concentration of the unchanged compound decreased with time in an exponential manner. The uptake of [11C]vinpocetine in brain was rapid, and 5% of the radioactivity totally injected was present in the brain 2 minutes after drug administration, indicating that the compound entered the brain readily. The radioactivity uptake was heterogeneously distributed among brain regions and was highest in the thalamus, the basal ganglia, and certain neocortical regions. The high brain uptake and the heterogeneous regional distribution indicate that direct central nervous system (CNS) effects of vinpocetine must be considered as explanation for the therapeutic effects. The detailed exploration of this suggestion requires further studies.