Ingo Vernaleken

Elevated [18F]Fluorodopamine Turnover in Brain of Patients with Schizophrenia: An [18F]Fluorodopa/Positron Emission Tomography Study

Previous positron emission tomography (PET) studies with levodopa analogs have revealed a modestly increased capacity for dopamine synthesis in the striatum of patients with schizophrenia compared with healthy age-matched control subjects. We hypothesized that not just the synthesis but also the turnover of radiolabeled dopamine is elevated in patients. To test the hypothesis, we reanalyzed 2-h-long [18F]fluorodopa (FDOPA)/PET recordings from eight unmedicated patients with schizophrenia and 15 healthy age-matched control subjects, using new methods for the quantification of [18F]fluorodopamine steady-state kinetics. The fractional rate constant for the catabolism and elimination of [18F]fluorodopamine was elevated nearly twofold in striatum, the largest biochemical difference in brain of schizophrenics yet reported. The magnitude of the intrinsic blood–brain FDOPA clearance with correction for this loss of [18F]fluorodopamine metabolites was increased by 20% in caudate and putamen and by 50% in amygdala and midbrain of the patients. However, the magnitude of the steady-state storage of FDOPA and its decarboxylated metabolites (Vd) was reduced by one-third in the caudate nucleus and amygdala of the schizophrenic group. Thus, reduced steady-state storage of [18F]fluorodopamine occurs in the midst of accelerated synthesis in brain of untreated patients. Positive scores of the positive and negative syndrome scale correlated inversely with the magnitude of Vd in amygdala, suggesting an association between positive symptoms and impaired steady-state storage of FDOPA metabolites in that structure.

Brain and Plasma Pharmacokinetics of Aripiprazole in Patients With Schizophrenia: An [ 18 F]Fallypride PET Study

OBJECTIVE Aripiprazole at clinically effective doses occupies some 90% of striatal dopamine 2 and 3 (D(2)/D(3)) receptors. In order to further characterize its extrastriatal and time-dependent binding characteristics, the authors conducted positron emission tomography (PET) studies with the D(2)/D(3) antagonist [(18)F]fallypride at varying time points after the last aripiprazole administration in patients with schizophrenia. METHOD Sixteen inpatients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder receiving treatment with aripiprazole underwent an [(18)F]fallypride PET scan. Receptor occupancy was calculated as the percentage reduction in binding potential relative to unblocked values measured in eight age-matched, medication-free patients with schizophrenia. In addition, aripiprazole serum concentrations were determined as part of a routine therapeutic drug monitoring program in a large group of patients (N=128) treated with aripiprazole. RESULTS Mean dopamine D(2)/D(3) receptor occupancy was high in all brain regions investigated, with no binding difference across brain regions. Nonlinear regression analysis revealed maximum attainable receptor occupancy (E(max)) values close to saturation. The values for serum concentration predicted to provide 50% of E(max) (EC(50)) were in the range of 5-10 ng/ml in all brain regions. The D(2)/D(3) receptors were completely saturated when serum aripiprazole concentration exceeded 100-150 ng/ml. The mean concentration in the large clinical patient sample was 228 ng/ml (SD=142). CONCLUSIONS Because of its high affinity for D(2)/D(3) receptors and its long elimination half-life, aripiprazole at clinical doses occupies a high fraction of its target receptor everywhere in the brain. Its dissociation from those receptors is very slow, such that the authors calculate from the results that in patients with serum aripiprazole concentrations in the range typical for clinical practice, D(2)/D(3) receptors must remain nearly saturated for as long as 1 week after the last dose.

Therapeutic Monitoring of New Antipsychotic Drugs

Abstract: Typical antipsychotic drugs qualify for therapeutic drug monitoring (TDM) primarily for the following reasons: control of compliance and avoidance of extrapyramidal side effects by keeping chronic exposure to minimal effective blood levels. For the atypical antipsychotic clozapine, drug safety is another reason to use TDM. With regard to the new antipsychotics risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, and aripiprazole, which have been introduced in the clinic during the last few years, the rationale to use TDM is a matter of debate. Positron emission tomography (PET), which enables measurement of the occupancy of dopamine D2 receptors, revealed that receptor occupancy correlated better with plasma concentrations than with doses of the antipsychotics. Regarding plasma levels related to therapeutic effects, optimal concentrations have been established for clozapine (350–600 ng/mL), risperidone (20–60 ng/mL), and olanzapine (20–80 ng/mL) but not for the other new antipsychotics. Studies that included analyses of drug levels in blood reported mean concentrations of 68 ng/mL for quetiapine and 317 ng/mL for amisulpride under therapeutic doses of the antipsychotic drugs. For ziprasidone or aripriprazole, data on therapeutic drug concentrations are so far lacking. In conclusion, evidence is growing that TDM may improve efficacy and safety in patients treated with the new antipsychotic drugs, especially when patients do not respond or develop side effects under therapeutic doses. The few reported investigations, however, need to be confirmed and extended.

The Striatal and Extrastriatal D2/D3 Receptor-Binding Profile of Clozapine in Patients with Schizophrenia

Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D2/D3 dopamine receptors in human striatum. Here, the occupancy of D2/D3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [18F]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D2/D3 receptor occupancy was statistically significantly higher in cortical (inferior temporal cortex 55%) than in striatal regions (putamen 36%, caudate 43%, p<0.005). While the maximum attainable receptor occupancy Emax approached 100% both in the striatum and cortex, the plasma concentration at 50% of Emax (ED50) was much higher in the putamen (950 ng/ml) than in the inferior temporal cortex (333 ng/ml). Clozapine binds preferentially to cortical D2/D3 receptors over a wide range of plasma concentrations. This selectivity is lost at extremely high plasma levels. Occupancy of cortical receptors approaches 60% with plasma clozapine in the range 350–400 ng/ml, which corresponds to the threshold for antipsychotic efficacy of clozapine. Extrastriatal binding of clozapine may be more relevant to its antipsychotic actions than striatal. However, further studies with an intraindividual comparison of untreated vs treated state are desirable to confirm this finding.

Subchronic haloperidol downregulates dopamine synthesis capacity in the brain of schizophrenic patients in vivo.

The antipsychotic effect of neuroleptics cannot be attributed entirely to acute blockade of postsynaptic D2-like dopamine (DA) receptors, but may arise in conjunction with the delayed depolarization block of the presynaptic neurons and reduced DA synthesis capacity. Whereas the phenomenon of depolarization block is well established in animals, it is unknown if a similar phenomenon occurs in humans treated with neuroleptics. We hypothesized that haloperidol treatment should result in decreased DA synthesis capacity. We used 6-[18F]fluoro-L-dopa (FDOPA) and positron emission tomography (PET) in conjunction with compartmental modeling to measure the relative activity of DOPA decarboxylase (DDC) (kD3, min−1) in the brain of nine unmedicated patients with schizophrenia, first in the untreated condition and again after treatment with haloperidol. Patients were administered psychometric rating scales at baseline and after treatment. Consistent with our hypothesis, there was a 25% decrease in the magnitude of kD3 in both caudate and putamen following 5 weeks of haloperidol therapy. In addition, the magnitudes of kD3 in cerebral cortex and thalamus were also decreased. Psychopathology as measured with standard rating scales improved significantly in all patients. The decrease of kD3 in the thalamus was highly significantly correlated with the improvement of negative symptoms. Subchronic treatment with haloperidol decreased the activity of DDC in the brain of patients with schizophrenia. This observation is consistent with the hypothesis that the antipsychotic effect of chronic neuroleptic treatment is associated with a decrease in DA synthesis, reflecting a depolarization block of presynaptic DA neurons. We link an alteration in cerebral catecholamine metabolism in human brain with the therapeutic action of neuroleptic medication.

Modulation of [18F]fluorodopa (FDOPA) kinetics in the brain of healthy volunteers after acute haloperidol challenge

In animal studies, acute antipsychotic treatment was shown to enhance striatal DOPA-decarboxylase (DDC) activity. However, this phenomenon has not been demonstrated in humans by positron emission tomography (PET). Therefore, we investigated acute haloperidol effects on DDC activity in humans using [18F]fluorodopa (FDOPA) PET. Nine healthy volunteers were scanned with FDOPA in drug-free baseline conditions and after 3 days of haloperidol treatment (5 mg/day). A continuous performance test (CPT) was administered in both conditions. The net blood-brain clearance of FDOPA (K(in)app) in striatum, mesencephalon, and medial prefrontal cortex was calculated by volume-of-interest analysis. The macroparameter K(in)app is a composite of several kinetic terms defining the distribution volume of FDOPA in brain (V(e)D) and the relative activity of DOPA decarboxylase (k3D). Therefore, compartmental kinetic analysis was used to identify the physiological basis of the observed changes in K(in)app period. The magnitude of K(in)app was significantly increased in the putamen (18%) and mesencephalon (36%). Furthermore, V(e)D in the brain was increased by 15%. Increments of k3(D) in the basal ganglia did not attain statistical significance. The significant worsening of CPT results did not correlate with changes in FDOPA utilization. The present PET results indicate potentiation of FDOPA utilization in human basal ganglia by acute haloperidol treatment, apparently due to increased availability throughout the brain. The stimulation of DDC cannot be excluded due to insufficient statistical power in the estimation of k3(D) changes.

Asymmetry in dopamine D2/3 receptors of caudate nucleus is lost with age

Molecular and functional imaging techniques reveal evidence for lateralization of human cerebral function. Based on animal data, we hypothesized that asymmetry in dopamine neurotransmission declines during normal aging. In order to test this hypothesis, we measured dopamine D2/3 receptor availability with [18F]desmethoxyfallypride-PET (DMFP) in putamen and caudate nucleus (NC) of 21 healthy, right-handed males (24-60 years; 35+/-10). For volumetric analysis, high-resolution T1-weighted MR-images were obtained in 18 of the PET-subjects in order to assess possible age-related decreases in NC and putamen volume. The calculated DMFP binding potentials (BP) showed a right-ward asymmetry in NC of young subjects that decreased with age (r = 0.577, p = 0.006; Pearson correlation; two-tailed). An age-independent analysis showed a right-ward asymmetry in NC of the whole subject group (left: 1.49+/-0.35; right: 1.65+/-0.43 [mean+/-S.D.]; p = 0.020). No such side lateralization or age-effects could be found in the putamen. Volumes tended to be asymmetric in the putamen (right: 4.85+/-0.56 cm3; left: 4.64+/-0.86 cm3 [mean+/-S.D.]; p = 0.063), but not in NC. The decline of putamen volume during aging was significant in the right putamen (r = -0.613; p = 0.007; Pearson correlation; two-tailed). There were no other significant correlations between striatal volumes and age or BP. Because ventral striatal dopamine neurotransmission is involved in cognitive processes, this loss of physiological asymmetry in NC dopamine transmission during aging might be involved in age-related declines of cognitive performance.

‘Prefrontal’ cognitive performance of healthy subjects positively correlates with cerebral FDOPA influx: An exploratory [18F]‐fluoro‐L‐DOPA‐PET investigation

Dopamine neurotransmission influences those cognitive processes, which are generally regarded as prefrontal cortical functions. In previous positron‐emission‐tomography (PET) studies, net blood‐brain clearance of [18F]‐fluoro‐l‐DOPA (FDOPA) correlated with impaired cognitive performance in patients with Parkinsons disease or schizophrenia. We hypothesized that FDOPA influx also correlates with performance of cognitive tasks associated with prefrontal functioning in healthy volunteers. The net blood‐brain clearance of FDOPA (K  inapp ) was mapped in a group of 11 healthy volunteers and calculated in striatal volumes‐of‐interest. The Wisconsin‐Card‐Sorting‐Test (WCST), Stroop‐Test, Trail‐Making‐Test (TMT‐A/B), and Continuous‐Performance‐Test (CPT‐M) had been administered previously to the same subjects. No correlation of K  inapp with perseverative errors in WCST or age could be found. However, there were significant positive correlations between the magnitude of K  inapp in caudate nucleus, putamen, and midbrain with performance of the TMT‐B, CPT‐M, and the Stroop test. Highest correlations were found between the time needed to perform the Stroop interference task and the K  inapp of striatal areas (Caudate nucleus: −0.780, P = 0.005; putamen: −0.870, P < 0. 001). Thus, the present findings reveal a strong correlation between dopamine synthesis capacity in striatum of healthy volunteers and performance of cognitive tasks linked to the prefrontal cortex. Hum Brain Mapp 2006.

PET studies of net blood-brain clearance of FDOPA to human brain: age-dependent decline of [18F]fluorodopamine storage capacity.

Conventional methods for the graphical analysis of 6-[18F]fluorodopa (FDOPA)/positron emission tomography (PET) recordings (Kappin) may be prone to negative bias because of oversubtraction of the precursor pool in the region of interest, and because of diffusion of decarboxylated FDOPA metabolites from the brain. These effects may reduce the sensitivity of FDOPA/PET for the detection of age-related changes in dopamine innervations. To test for these biasing effects, we have used a constrained compartmental analysis to calculate the brain concentrations of the plasma metabolite 3-O-methyl-FDOPA (OMFD) during 120 mins of FDOPA circulation in healthy young, healthy elderly, and Parkinsons disease subjects. Calculated brain OMFD concentrations were subtracted frame-by-frame from the dynamic PET recordings, and maps of the FDOPA net influx to brain were calculated assuming irreversible trapping (Kapp). Comparison of Kappin and Kapp maps revealed a global negative bias in the conventional estimates of FDOPA clearance. The present OMFD subtraction method revealed curvature in plots of Kapp at early times, making possible the calculation of the corrected net influx (K) and also the rate constant for diffusion of decarboxylated metabolites from the brain (kloss). The effective distribution volume (EDV2; K/kloss) for FDOPA, an index of dopamine storage capacity in brain, was reduced by 85% in putamen of patients with Parkinsons disease, and by 58% in the healthy elderly relative to the healthy young control subjects. Results of the present study support claims that storage capacity for dopamine in both caudate and putamen is more profoundly impaired in patients with Parkinsons disease than is the capacity for DOPA utilization, calculated by conventional FDOPA net influx plots. The present results furthermore constitute the first demonstration of an abnormality in the cerebral utilization of FDOPA in caudate and putamen as a function of normal aging, which we attribute to loss of vesicular storage capacity.

Positron Emission Tomography in CNS Drug Discovery and Drug Monitoring

Molecular imaging methods such as positron emission tomography (PET) are increasingly involved in the development of new drugs. Using radioactive tracers as imaging probes, PET allows the determination of the pharmacokinetic and pharmacodynamic properties of a drug candidate, via recording target engagement, the pattern of distribution, and metabolism. Because of the noninvasive nature and quantitative end point obtainable by molecular imaging, it seems inherently suited for the examination of a pharmaceuticals behavior in the brain. Molecular imaging, most especially PET, can therefore be a valuable tool in CNS drug research. In this Perspective, we present the basic principles of PET, the importance of appropriate tracer selection, the impact of improved radiopharmaceutical chemistry in radiotracer development, and the different roles that PET can fulfill in CNS drug research.