Effect of amphetamine on dopamine D2 receptor binding in nonhuman primate brain: a comparison of the agonist radioligand [11C]MNPA and antagonist [11C]raclopride

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.     

Differential effects of stress on [11C]raclopride and [11C]MNPA binding to striatal D2/D3 dopamine receptors: A PET study in conscious monkeys

It has been reported that stress and facilitation of dopamine neuronal system are closely related. In the present study, the effects of stress on the binding of antagonist‐based [¹¹C]raclopride and agonist‐based (R)‐2‐CH3O‐N‐n‐ propylnorapomorphine ([¹¹C]MNPA) to D₂/D₃ receptors were evaluated in the striatum of conscious monkey brain. The stress state assessed from plasma cortisol level was negatively correlated with [¹¹C]raclopride binding as expected. It was noteworthy that [¹¹C]MNPA binding exhibited a positive correlation with stress state; thus, the animals with higher cortisol levels showed higher binding to D₂/D₃ receptors. Synapse 65:84–89, 2011. © 2010 Wiley‐Liss, Inc.     

Impulse control disorders are associated with lower ventral striatum dopamine D3 receptor availability in Parkinson's disease: A [11C]-PHNO PET study

IntroductionReduced postsynaptic D3 dopaminergic receptor availability has been reported in the ventral striatum of pathological gamblers without Parkinson's disease (PD) and in patients with PD and impulse control disorders (ICD). However, a direct relationship between ventral striatum D3 dopaminergic receptors and the severity of ICD in PD patients has not yet been proven using a validated tool for ICD in PD, such as the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease-Rating Scale (QUIP-RS). In this pilot study, we investigated the relationship between ventral striatum D3 dopamine receptor availability and severity of impulse control disorder (ICD) in Parkinson's disease (PD).MethodsTwelve patients were assessed with PET and the high affinity dopamine D3 receptor radioligand [¹¹C]-PHNO. Severity of ICD was assessed with the QUIP-RS.ResultsWe found that lower ventral striatum D3 receptor availability measured with [¹¹C]-PHNO PET was associated with greater severity of ICD, as measured by the QUIP-RS score (rho = −0.625, p = 0.03).ConclusionThese findings suggest that the occurrence and severity of ICD in Parkinson's disease may be linked to reductions in ventral striatum dopamine D3 receptor availability. Further studies in larger cohort of patients need to be performed in order to confirm our findings and clarify whether lower ventral striatum D3 receptor may reflect a pharmacological downregulation to higher dopamine release in ventral striatum of patients with ICD or a patients' predisposition to ICD.     

Dopamine displaces [3H]domperidone from high-affinity sites of the dopamine D2 receptor,but not [3H]raclopride or [3H]spiperone in isotonic medium: Implications for human positron emission tomography

Because the high-affinity state of the dopamine D2 receptor, D2High, is the functional state of the receptor, has a role in demarcating typical from atypical antipsychotics, and is markedly elevated in amphetamine-sensitized rats, it is important to have a method for the convenient detection of this state by a ligand. The present data show that, in contrast to [(3)H]spiperone or [(3)H]raclopride, [(3)H]domperidone labels D2High sites in the presence of isotonic NaCl in either striatum or cloned D2Long receptors, yielding a dopamine dissociation constant (1.75 nM) in agreement with that found with [(3)H]dopamine. Increased labeling of D2High sites occurred with [(3)H]domperidone after severe disruption of the cells, suggesting that [(3)H]domperidone has better access to the D2 receptor from the cytoplasmic aspect of the cell membrane. The density of the [(3)H]domperidone-labeled D2 receptors was the same as that of the [(3)H]raclopride-labeled D2 receptors, but twice the density of [(3)H]spiperone sites for human cloned D2Long receptors, compatible with the monomer-dimer concept of the D2 receptor. [(3)H]domperidone readily labels the D2High sites in postmortem human brain homogenates. Although [(3)H]spiperone or [(3)H]raclopride can occupy D2High sites, the inability of 1-10 nM dopamine to displace these ligands under isotonic conditions suggests that these ligands may not be suitable for monitoring the physiological high-affinity state of the dopamine D2 receptor by means of [(11)C]methylspiperone or [(11)C]raclopride in humans.     

Variability in D2-dopamine receptor density and affinity: A PET study with [11C]raclopride in man

The variability of D₂-dopamine receptor binding parameters in man was determined using Positron Emission Tomography (PET) and [¹¹C]raclopride. A saturation analysis based on five PET-experiments was performed in each of ten men and ten women. The mean density of D₂-dopamine receptors (B_max) was 28 ± 6.9 pmol/ml (mean ± S.D.) and the apparent affinity (K_d^app)9.1 ± 1.9 pmol/ml. The Hill coefficient was in all subjects close to unity (n_H: 0.999 ± 0.020), thereby indicating binding to a homogeneous class of receptors. No significant differences between males and females were found in B_max or K_d^app. The interindividual difference in B_maxwas statistically significant (α = 0.01). The difference in K_d^app was not significant. Upregulation of the receptor density (B_max) has been widely discussed as a mechanism for increased dopaminergic neurotransmission in schizophrenia. This study indicates that receptor density varies considerably in a group of healthy subjects. © 1995 Wiley-Liss, Inc.     

Antiparkinson concentrations of pramipexole and PHNO occupy dopamine D2(high) and D3(high) receptors

Because the high-affinity state of dopamine D2 receptors, D2(High), is the functional state of D2, and because the proportion of D2 receptors in the high-affinity state correlates with dopamine behavioral supersensitivity, the present study was designed to determine the affinities of antiparkinson dopamine agonists at the D2(High) site by means of competition with [3H]domperidone. In contrast to [125I]iodosulpride or [3H]spiperone, which are not sensitive to low concentrations of dopamine agonists, [3H]domperidone readily reveals dissociation constants (K(i)) for antiparkinson agonists at D2(High) and D3(High) receptors. The K(i) values for the human cloned D2(High) and D3(High) receptors, respectively, were 19 and 9 nM for pramipexole, 0.24 and 0.6 nM for +PHNO, 0.7 and 1.3 nM for bromocriptine, 0.5 and 2.6 nM for apomorphine, and 0.09 and 0.25 nM for (-)N-propylnorapomorphine. After correcting for the fraction of drug bound to plasma proteins, the known clinical concentrations in plasma or plasma water of these drugs, including pramipexole and +PHNO, are sufficient to occupy and activate the high-affinity state of D2, D2(High), in treating Parkinson's disease. The D3(High) receptors are less selectively occupied by +PHNO, bromocriptine, apomorphine, and -NPA.     

Characterization of in vivo pharmacokinetic properties of the dopamine D1 receptor agonist DAR-0100A in nonhuman primates using PET with [11C] NNC112 and [11C] raclopride

DAR-0100A, the active enantiomer of dihydrexidine, is a potent dopamine D1 agonist under investigation for treatment of cognitive impairment and negative symptoms of schizophrenia. We measured the dose–occupancy relationship for DAR-0100A at D1 receptors using positron emission tomography (PET) imaging in baboons with [¹¹C] NNC112 and its binding to D2 with [¹¹C] raclopride. Two baboons were scanned with [¹¹C] NNC112 at baseline and after three different doses of DAR-0100A. Two baboons were scanned with [¹¹C] raclopride at baseline and after one dose of DAR-0100A. Occupancy (ΔBP_ND) was computed in the striatum and cortex. A clear relationship was observed between plasma concentration of DAR-0100A and ΔBP_ND. ΔBP_ND was larger in the striatum than in the cortex, consistent with reports showing that 25% of [¹¹C] NNC112 BP_ND in the cortex is attributed to 5-HT_2A. Plasma EC₅₀ estimates ranged from 150 to 550 ng/mL according to the constraints on the model. There was no detectable effect of DAR-0100A on [¹¹C] raclopride BP_ND. These data suggest that at doses likely to be administered to patients, occupancy will not be detectable with [¹¹C] NNC112 PET and binding of DAR-0100A to D2 will be negligible. This is the first demonstration with PET of a significant occupancy by a full D1 agonist in vivo.     

Dopamine (D2/3) receptor agonist positron emission tomography radiotracer [11C]-(+)-PHNO is a D3 receptor preferring agonist in vivo

[11C]PHNO is a recently introduced agonist to image DA D2-like receptors with Positron Emission Tomography (PET). In cats and humans, [11C]PHNO revealed an atypical distribution compared to radiolabeled D2-like antagonists (such as [11C]raclopride) or other D2-like agonists (such as [11C]NPA), as it displayed unusual high binding in the globus pallidus (GP). The goal of this study was to assess the pharmacological nature of the binding of [11C]PHNO in the GP in nonhuman primates. As previously reported in humans, [11C]PHNO equilibrium specific to nonspecific equilibrium partition coefficients (V3') in baboons was much higher in GP (3.88 +/- 1.15) than in the dorsal striatum (DST, 2.07 +/- 0.43), whereas the reverse was true for [11C]raclopride (1.48 +/- 0.41 in GP, 2.56 +/- 0.91 in DST) and [11C]NPA (0.87 +/- 0.19 in GP, 1.02 +/- 0.13 in DST). Administration of unlabeled raclopride resulted in similar reductions of [11C] PHNO V3' and [11C]raclopride V3' in both the GP and the DST. This observation demonstrated that the [11C]PHNO binding in the GP was specific to D2-like receptors. To evaluate the respective contribution of D3 and D2 receptors to the binding potential (BP) of [11C]PHNO and [11C]raclopride, experiments were carried out with the selective D3 partial agonist 1-(4(2-Napthoylamino)butyl)-4-(2-methoxyphenyl)-1A-piperazine HCL (BP897). BP897 reduced [11C]raclopride V3' by 29% +/- 9%, 19% +/- 8%, and 10% +/- 7% in GP, VST, and DST, respectively, a result consistent with expectation from postmortem studies (D3/D2 ratio in GP > VST > DST). BP897 reduced [11C]PHNO V3' by 57% +/- 11%, 30% +/- 11%, and 13% +/- 8% in GP, VST, and DST, respectively, indicating that the D3 receptor contribution to [11C]PHNO signal is higher than that of [11C]raclopride. From these experiments we conclude that [11C]PHNO is a D3 preferring agonist, and that this property explains the high GP signal not observed with [11C]raclopride or [11C]NPA. This property might contribute to its higher vulnerability to endogenous DA compared to [11C]raclopride and [11C]NPA.     

Therapeutic effect of repetitive transcranial magnetic stimulation in Parkinson's disease: Analysis of [11C] raclopride PET study

Repetitive transcranial magnetic stimulation (rTMS) has been used as a potential therapeutic tool in Parkinson's disease (PD). However, the therapeutic value and/or the placebo effect of rTMS on PD remain to be elucidated. To investigate the therapeutic value and/or placebo effect of rTMS in PD, we compared the motor section of unified PD rating scale (UPDRS III) and the amount of extracellular dopamine concentration using [¹¹C] raclopride PET before and after two sessions of rTMS in 9 PD patients. During a consecutive 2 days while off‐medication, two series of 15 trains of 5 Hz‐frequency rTMS (intensity, 90% of the resting motor threshold) were applied to the hand area of more severely symptomatic motor cortex (MC). After unilateral rTMS of MC, mean raclopride binding potentials (BPs) were reduced not only in putaminal and caudate areas on the stimulated side (?4.9% and ?6.5%, respectively) (P > 0.05) but also in putaminal and caudate areas of nonstimulated hemispheres (?6.6%, P > 0.05 and ?12.1%, P = 0.049, respectively). UPDRS III scores were significantly decreased (35.0 ± 14.1 to 32.0 ± 13.4, P = 0.049). A reduction of raclopride BP in nonstimulated ventral striatum by unilateral rTMS supports the placebo response during rTMS. © 2007 Movement Disorder Society     

Brain uptake and distribution of the dopamine D3/D2 receptor partial agonist [11C]cariprazine: An in vivo positron emission tomography study in nonhuman primates

Cariprazine is a dopamine D₃/D₂ receptor partial agonist antipsychotic candidate, which binds with high affinity to dopamine D₃ and D₂ receptors (with ～10‐fold higher in vitro affinity to D₃ vs. D₂ receptors) and with moderate affinity to 5‐HT_1A receptors. The main objective of the present molecular imaging investigation was to evaluate the uptake and reversible binding of 11‐C labeled cariprazine in the nonhuman primate brain, in relation to the known distributions of dopamine D₂ and D₃ receptors. We examined the brains of two cynomolgus monkeys at baseline condition as well as during a pharmacological blocking condition, using unlabeled cariprazine or raclopride as blockers before injection of [¹¹C]cariprazine. Of the total injected radioactivity, ～7% entered the brain and ～3–4% remained in the brain after 90 min, indicating good blood brain barrier penetration and slow washout. It was possible to block cariprazine binding with unlabeled cariprazine and raclopride indicating that [¹¹C]cariprazine binds to dopamine D₃/D₂ receptors. Nondisplaceable binding potential (BP_ND) measurements, using a simplified reference tissue model and cerebellum as the reference region, yielded values of ～1.5 and 0.3 in the striatum and thalamus, respectively. Striatum BP_ND values were reduced by 80 and 85% following pretreatment with 0.1 mg/kg IV injection of unlabeled cariprazine and 1 mg/kg IV injection of unlabeled raclopride, respectively. The data confirm that cariprazine, a novel antipsychotic drug candidate, enters the nonhuman primate brain readily and binds to dopamine D₃/D₂ receptors. Furthermore, in PET imaging [¹¹C]cariprazine can effectively visualize dopamine D₃/D₂ receptors in the nonhuman primate brain. Synapse 67:258–264, 2013. © 2013 Wiley Periodicals, Inc.     

Antiparkinsonian effects of the novel D3/D2 dopamine receptor agonist, S32504, in MPTP-lesioned marmosets: Mediation by D2, not D3, dopamine receptors.

L-dopa remains the most common treatment for Parkinson's disease. However, there is considerable interest in D3/D2 receptor agonists such as the novel agent S32504, since they exert antiparkinsonian properties in the absence of dyskinesia. An important question concerns the roles of D2 vs. D3 receptors, an issue we addressed with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned nonhuman primate model of Parkinson's disease. In L-dopa-primed animals, S32504 (0.16-2.5 mg/kg p.o.) dose-dependently enhanced locomotor activity. This action was abolished by the D2 antagonist, L741,626 (2.5 mg/kg), but potentiated by the D3 antagonist, S33084 (0.63 mg/kg). Both antagonists were inactive alone. In drug-naive animals, a maximally effective dose of S32504 (2.5 mg/kg p.o.) displayed pronounced antiparkinsonian properties from the third day of administration, and its actions were expressed rapidly and durably. Thus, on day 33, antiparkinsonian properties of S32504 were apparent within 5 minutes and present for > 4 hours. Moreover, they were associated with neither wearing off nor significant dyskinesia. In conclusion, the novel D3/D2 agonist S32504 may offer advantages over L-dopa in the treatment of newly diagnosed parkinsonian patients. Its actions are expressed primarily by activation of D2, not D3, receptors.     

In vitro characterization of SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone, monohydrochloride): a novel partial dopamine D2 and D3 receptor agonist and serotonin 5-HT1A receptor agonist

Present Parkinson's disease treatment strategies are far from ideal for a variety of reasons; it has therefore been suggested that partial dopamine receptor agonism might be a potential therapeutic approach with potentially fewer side effects. In the present study, we describe the in vitro characterization of the nonergot ligand SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolonemonohydrochloride). SLV308 binds to dopamine D(2), D(3), and D(4) receptors and 5-HT(1) (A) receptors and is a partial agonist at dopamine D(2) and D(3) receptors and a full agonist at serotonin 5-HT(1) (A) receptors. At cloned human dopamine D(2,L) receptors, SLV308 acted as a potent but partial D(2) receptor agonist (pEC(50) = 8.0 and pA(2) = 8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D(3) receptors, SLV308 acted as a partial agonist in the induction of [(35)S]GTPgammaS binding (intrinsic activity of 67%; pEC(50) = 9.2) and antagonized the dopamine induction of [(35)S]GTPgammaS binding (pA(2) = 9.0). SLV308 acted as a full 5-HT(1) (A) receptor agonist on forskolin induced cAMP accumulation at cloned human 5-HT(1) (A) receptors but with low potency (pEC(50) = 6.3). In rat striatal slices SLV308 concentration-dependently attenuated forskolin stimulated accumulation of cAMP, as expected for a dopamine D(2) and D(3) receptor agonist. SLV308 antagonized the inhibitory effect of quinpirole on K(+)-stimulated [(3)H]-dopamine release from rat striatal slices (pA(2) = 8.5). In the same paradigm, SLV308 had antagonist properties in the presence of quinpirole (pA(2) = 8.5), but the partial D(2) agonist terguride had much stronger antagonistic properties. In conclusion, SLV308 combines high potency partial agonism at dopamine D(2) and D(3) receptors with full efficacy low potency serotonin 5-HT(1) (A) receptor agonism and is worthy of profiling in in vivo models of Parkinson's disease.     

Dopamine D2 receptor TaqIA and TaqIB polymorphisms in Parkinson's disease.

In a case control study, we examined the association of DRD2 Taq1A and Taq1B polymorphisms and risk of PD, and evaluated the strength of linkage disequilibrium of the polymorphisms. The Taq1A and Taq1B polymorphisms were in strong linkage disequilibrium. There was, however, no significant association of the two polymorphisms with PD.     

In vivo imaging of monoaminergic nerve terminals in normal and MPTP-lesioned primate brain using positron emission tomography (PET) and [11C]tetrabenazine

The first successful in vivo imaging of monoamine vesicular transporters in the living primate brain is described, using [¹¹C]tetrabenazine ([¹¹C]TBZ) and Positron Emission Tomography (PET). Radioligand uptake into brain is rapid, and at short time periods (10-30 minutes) the higher uptake and retention of the radiotracer in the more densely dopaminergic innervated striatum is clearly visualized. Specific binding in striatum can be entirely blocked with co-administration of a pharmacological dose (1 mg/kg i. v.) of tetrabenazine. In a unilaterally MPTP-lesioned monkey, specific binding of radioligand was absent in the striatum on the lesioned side, with no effect on radiotracer distribution in the cortex, cerebellum or contralateral striatum. PET imaging with [¹¹C]TBZ provides a new approach to the in vivo study of monoaminergic neurons and their loss in neurodegenerative diseases. © 1993 Wiley-Liss, Inc.     

D2 receptor occupancy in conscious rat brain is not significantly distinguished with [3H]‐MNPA, [3H]‐(+)‐PHNO,and [3H]‐raclopride

Positron emission tomography (PET) antagonist ligands such as [¹¹C]‐raclopride are commonly used to study dopamine D2 receptor (D2) binding of antipsychotics. It has been suggested that agonist radioligands bind preferentially to the high‐affinity state of D2 receptor and may provide a more relevant means of assessing D2 occupancy. The main objective of this study was to determine if D2 receptor occupancy (RO) could be differentiated with agonist and antagonist radioligands in vivo. Agonist radioligands [³H]‐MNPA and [³H]‐(+)‐PHNO were synthesized and compared to antagonist [³H]‐raclopride in the in vitro binding and in vivo occupancy studies. In vivo, unanesthetized rats were pretreated with quinpirole (full agonist), aripiprazole (partial agonist), or haloperidol (antagonist) prior to administration of the agonist or antagonist radioligand. All three pretreatment compounds showed equivalent dose‐dependent D2 receptor occupancy in the rat striatum with each radioligand. The in vivo receptor occupancy results suggested that the binding of quinpirole, aripiprazole, and haloperidol to the high or low affinity state of the D2 receptor could not be differentiated using radiolabeled agonists or antagonists, presumably due to a predominance of high affinity states of the D2 receptor in vivo. This hypothesis was supported in part by the in vitro binding results. Our in vitro results show that [³H]‐MNPA binds to D2S transfected CHO cell membranes at a single high affinity site. Displacement of [³H]‐(+)‐PHNO binding by quinpirole and elimination of most [³H]‐(+)‐PHNO binding by the guanine nucleotide GppNHp in striatal membranes suggest that the majority of D2 in striatal tissue is G‐protein coupled. Together, these findings suggest that D2 agonist radioligands produce in vivo receptor occupancy comparable to [³H]‐raclopride. Synapse, 2010. © 2010 Wiley‐Liss, Inc.     

[11C]PBR28 PET imaging is sensitive to neuroinflammation in the aged rat

Neuroinflammation in the aging rat brain was investigated using [¹¹C]PBR28 microPET (positron emission tomography) imaging. Normal rats were studied alongside LRRK2 p.G2019S transgenic rats; this mutation increases the risk of Parkinson''s disease in humans. Seventy [¹¹C]PBR28 PET scans were acquired. Arterial blood sampling enabled tracer kinetic modeling and estimation of V_T. In vitro autoradiography was also performed. PBR28 uptake increased with age, without differences between nontransgenic and transgenic rats. In 12 months of aging (4 to 16 months), standard uptake value (SUV) increased by 56% from 0.44 to 0.69 g/mL, whereas V_T increased by 91% from 30 to 57 mL/cm³. Standard uptake value and V_T were strongly correlated (r=0.52, 95% confidence interval (CI)=0.31 to 0.69, n=37). The plasma free fraction, f_p, was 0.21±0.03 (mean±standard deviation, n=53). In vitro binding increased by 19% in 16 months of aging (4 to 20 months). The SUV was less variable across rats than V_T; coefficients of variation were 13% (n=27) and 29% (n=12). The intraclass correlation coefficient for SUV was 0.53, but was effectively zero for V_T. These data show that [¹¹C]PBR28 brain uptake increases with age, implying increased microglial activation in the aged brain.     

N-0923, A novel soluble dopamine D2 agonist in the treatment of parkinsonism

N-0923, a novel aminotetralin dopamine D₂ agonist, was shown to effectively reverse parkinsonian symptoms in nine dopa/agonist-responsive Parkinson's disease patients. The drug was given up to 4.5 hours by continuous intravenous (IV) infusion using an IV pump. The onset of anti-parkinsonian effect was seen within minutes of the initiation of the infusion and was absent within 90 minutes of cessation of the infusion. The short elimination half-life of N-0923 (90 min) would allow for the rapid initiation of drug effect when necessary and at the same time permit the effect to be terminated quickly if necessary. The drug would be useful in situations where oral medication is not feasible or is associated with erratic absorption. The patients tolerated the drug well. Dose escalation load was limited by nausea and vomiting. It should be noted that the doses were increased until these symptoms occurred, but therapeutic effects were noted well before the side effects occurred. Using a modified Columbia scale, maximum improvement consisted of a 27–95% drop in score. Maximum response was obtained at infusion rates varying from 2–16 μg/kg per hour and at blood levels of 0.11–1.49 μg/mL.     

Measurement error analysis for the determination of dopamine D2 receptor occupancy using the agonist radioligand [11C]MNPA

The purpose of this study is to investigate errors in quantitative analysis for estimating dopamine D₂ receptor occupancy of antipsychotics with agonist radioligand [¹¹C]MNPA by numerical simulation, with particular attention to the validity of a quantitative approach based on the use of a reference region. Synthetic data were validated using clinical data combined with a bootstrap approach. Time–activity curves (TACs) of [¹¹C]MNPA were simulated, and the reliability of binding potential (BP_ND) and occupancy estimated by nonlinear least square (NLS) fitting and a simplified reference tissue model (SRTM) were investigated for various noise levels and scan durations. In the human positron emission tomography (PET) study with and without antipsychotic, risperidone, the uncertainty of BP_ND and occupancy estimated by SRTM was investigated using resampled TACs based on bootstrap approach with weighted residual errors of fitting. For both NLS and SRTM, it was possible to have <3% of bias in occupancy estimates of [¹¹C]MNPA by 60 mins. However, shortened scan duration degrades the quantification of very small binding potentials, especially in case of SRTM. Observations were replicated on the clinical data. Results showed that dopamine D₂ receptor occupancy by antipsychotics can be estimated precisely in region of interest analysis by SRTM with a longer than 60-min [¹¹C]MNPA PET scan duration.     

Evaluation of distribution of adenosine A2A receptors in normal human brain measured with [11C]TMSX PET

Adenosine A(2A) receptor (A2AR) is thought to interact with dopamine D(2) receptor. Selective A2AR antagonists have attracted attention as the treatment of Parkinson's disease. In this study, we investigated the distribution of the A2ARs in the living human brain using positron emission tomography (PET) and [7-methyl-(11)C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([(11)C]TMSX). We recruited five normal male subjects. A dynamic series of PET scans was performed for 60 min, and the arterial blood was sampled during the scan to measure radioactivity of the parent compound and labeled metabolites. Circular regions of interest of 10-mm diameter were placed in the PET images over the cerebellum, brainstem, thalamus, head of caudate nucleus, anterior and posterior putamen, frontal lobe, temporal lobe, parietal lobe, occipital lobe, and posterior cingulate gyrus for each subject. A two-tissue, three-compartment model was used to estimate K(1), k(2), k(3), and k(4) between metabolite-corrected plasma and tissue time activity of [(11)C]TMSX. The binding potential (BP) was the largest in the anterior (1.25) and posterior putamen (1.20), was next largest in the head of caudate nucleus (1.05) and thalamus (1.03), and was small in the cerebral cortex, especially frontal lobe (0.46). [(11)C]TMSX PET showed the largest BP in the striatum in which A2ARs were enriched as in postmortem and nonhuman studies reported, but that the binding of [(11)C]TMSX was relatively larger in the thalamus to compare with other mammals. To date, [(11)C]TMSX is the only promising PET ligand, which is available to clinical use for mapping the A2ARs in the living human brain.