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D₁ receptors are the main mediators of dopamine transmission in the cortex and subserve cognitive functions that are affected in patients with schizophrenia. Prior imaging studies have suggested abnormalities in the expression of these receptors in schizophrenia, but no conclusive picture has emerged yet. One source of discrepancy may have been prior antipsychotic exposure. We used positron emission tomography (PET) and a D1 radiotracer, [¹¹C]NNC112, in drug naïve (DN, n = 12) and drug free (DF, n = 13) patients with schizophrenia and 40 healthy control subjects (HC, n = 40 total, n = 24 per comparison group) matched for age, gender, ethnicity, parental socioeconomic status and cigarette smoking. We measured the binding potential BPP, corrected for partial volume effects. The outcome measure was obtained in cortical and striatal subregions outlined on coregistered individual MRIs. Partial volume effect corrected BPP measures were significantly higher in DN vs controls in cortical regions. No such increases were found in the DF versus controls comparison. Furthermore, in the DF group, DF interval correlated positively with cortical BPP. We conclude that upregulation of D1 receptors in schizophrenia is related to the illness itself and may be corrected and normalized by chronic antipsychotic treatment.

[(11)C]PHNO is a D(2)/D(3) agonist positron emission tomography radiotracer, with higher in vivo affinity for D(3) than for D(2) receptors. As [(11)C]-(+)-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 [(11)C]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 [(11)C]-(+)-PHNO and [(11)C]raclopride in healthy subjects, using a within-subjects, counterbalanced, open-label design. In the dorsal striatum, where the density of D(3) receptors is negligible and both tracers predominantly bind to D(2) receptors, the reduction of [(11)C]-(+)-PHNO binding potential (BP(ND)) was 1.5 times larger than that of [(11)C]raclopride. The gain in sensitivity associated with the agonist [(11)C]-(+)-PHNO implies that ∼65% of D(2) receptors are in the high-affinity state in vivo. In extrastriatal regions, where [(11)C]-(+)-PHNO predominantly binds to D(3) receptors, the amphetamine effect on [(11)C]-(+)-PHNO BP(ND) was even larger, consistent with the higher affinity of dopamine for D(3). This study indicates that [(11)C]-(+)-PHNO is superior to [(11)C]raclopride for studying acute fluctuations in synaptic dopamine in the human striatum. [(11)C]-(+)-PHNO also enables measurement of synaptic dopamine in D(3) regions.

The aim of this study was to compare 5-HT(1A) availability in vivo in individuals with schizophrenia before and during treatment with the atypical antipsychotic ziprasidone. Six individuals with schizophrenia underwent two PET scans with [(11)C]WAY 100635; the first while medication-free (baseline) and the second while taking the atypical antipsychotic ziprasidone (on-medication). Regional volumes of distribution (V(T), mL g(-1)) were derived using a two-tissue compartment kinetic model. Outcome measures included binding potential relative to the plasma (BP(P), mL g(-1)) and the binding potential relative to the nonspecific distribution volume (BP(ND), unitless). No significant differences were observed in regional BP(P) or BP(ND) with ziprasidone treatment. A significant correlation was noted between BP(P) measured in the orbitofrontal cortex during the on-medication condition and degree of improvement in negative symptoms with treatment (r = 0.96, p = 0.004). Consistent with the published literature of changes in 5-HT(1A) binding during treatment with 5-HT(1A) receptor agonists, this study did not detect a significant reduction in 5-HT(1A) binding with ziprasidone. The finding of a relationship between 5-HT(1A) binding and the degree of improvement in negative symptoms provides further support for the role of the 5-HT(1A) receptor in the pathophysiology and treatment of this symptom domain.

Positron emission tomography (PET) is used in drug development to assist dose selection and to establish the relationship between blood and tissue pharmacokinetics (PKs). We present a new biomathematical approach that allows prediction of repeat-dose (RD) brain target occupancy (TO) using occupancy data obtained after administration of a single dose (SD). A PET study incorporating a sequential adaptive design was conducted in 10 healthy male adults who underwent 4 PET scans with [(11)C]DASB ([(11)C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine): 1 at baseline, 2 after 20 mg SD of the 5-hydroxytryptamine transporter (5-HTT) inhibitor duloxetine, and 1 after 4 days daily administration of 20 mg duloxetine. An adaptive design was used to select optimal times after SD for measurement of occupancy. Both direct and indirect PK/TO models were fitted to the SD data to characterise the model parameters and then applied to a predicted RD duloxetine plasma time course to predict the 5-HTT occupancy after RD. Repeat-dose prediction from the indirect model (OC(50)=2.62±0.93 ng/mL) was significantly better (P<0.05) than that from the direct model (OC(50)=2.29±1.11 ng/mL). This approach increases the value of SD occupancy studies that are performed as part of first time in human drug development programmes by providing an estimate of the dose required to achieve the desired TO at RD.

[(11)C]NNC112 (8-chloro-7-hydroxy-3-methyl-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-IH-3-benzazepine), a selective positron-emission tomography (PET) ligand for the D(1) receptor (R) over the 5-HT(2A) R in vitro, has shown lower selectivity in vivo, hampering measurement of D(1) R in the cortex. [(11)C]NNC112 PET and intravenous (i.v) ketanserin challenge were used to (1) confirm the previous findings of [(11)C]NNC112 in vivo D(1) R selectivity, and (2) develop a feasible methodology for imaging cortical D(1) R without contamination by 5-HT(2A) R. Seven healthy volunteers underwent [(11)C]NNC112 PET scans at baseline and after a 5-HT(2A) R-blocking dose of ketanserin (0.15 mg/kg, i.v.). Percent BP(ND) change between the post-ketanserin and baseline scans was calculated. Irrespective of the quantification method used, ketanserin pretreatment led to significant decrease of BP(ND) in the cortical (approximately 30%) and limbic regions (approximately 20%) but not in the striatum, which contains a much lower amount of 5-HT(2A) R. Therefore, ketanserin allows D(1) R signal to be detected by [(11)C]NNC112 PET without significant 5-HT(2A) R contamination. These data confirm the presence of a significant 5-HT(2A) R contribution to cortical [(11)C]NNC112 signal, and call for caution in the interpretation of published [(11)C]NNC112 PET findings on cortical D(1) R in humans. In the absence of more selective ligands, [(11)C]NNC112 PET with ketanserin can be used for cortical D(1) R imaging in vivo.

Quantitative estimation of neuroreceptor occupancy by exogenous drugs using positron emission tomography is based on the reduction in the total volume of distribution (V(T)) of site-specific radioligands after drug administration. An estimate of the distribution volume of free and nonspecifically bound radioligand (V(ND)) is also required to distinguish specific from total binding. However, a true reference region, devoid of specific binding, is often not available. We present a transformation of a graphical method, originally introduced by Lassen, using regional estimates of V(T) alone to determine occupancy, together with an extension that does not require baseline data.

The dopamine D(1) receptor antagonist radioligand [(11)C]NNC 112 has previously been reported to have 100-fold selectivity for the D(1) receptor compared with the serotonin 5-HT(2A) receptor. In this study, we tested the selectivity by scanning seven healthy human research volunteers with [(11)C]NNC 112 before and after 2 mg of the antipsychotic drug risperidone, a dose that putatively blocks all 5-HT(2A) receptors with negligible effect on D(1) receptors. We found that specific binding in cortical regions was reduced by 20% to 30%, whereas the striatum showed no change. Based on the known relative densities of these receptors in humans, our results suggest 5- to 10-fold selectivity of [(11)C]NNC 112 for D(1) versus 5-HT(2A) as opposed to 100-fold selectivity. These results suggest caution in interpreting data from studies using this tracer to measure cortical D(1) receptors as well as the need for more selective radioligands to assess cortical D(1) receptors.