Initial evaluation of123|-5-|-R91150, a selective 5-HT2A ligand for single-photon emission tomography, in healthy human subjects

The mapping of 5-HT₂ receptors in the brain using functional imaging techniques has been limited by a relative lack of selective radioligands. Iodine-123 labelled 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide (¹²³I-5-I-R91150 or¹²³I-R93274) is a new ligand for single-photon emission tomography (SPET), with high affinity and selectivity for 5-HT_2A receptors. This study reports on preliminary¹²³I-5-I-R91150 SPET, wholebody and blood distribution findings in five healthy human volunteers. Maximal brain uptake was approximately 2% of total body counts at 180 min post injection (p.i.). Dynamic SPET sequences were acquired with the brain-dedicated, single-slice multi-detector system SEM-810 over 200 min p.i. Early peak uptake (at 5 min p.i.) was seen in the cerebellum, a region free from 5HT_2A receptors. In contrast, radioligand binding in the frontal cortex increased steadily over time, up to a peak at approximately 100–120 min p.i. Frontal cortex-cerebellum activity ratios reached values of 1.4, and remained stable from approximately 100 min p.i. onwards. Multi-slice SPET sequences showed a pattern of regional variation of binding compatible with the autoradiographic data on the distribution of 5-HT_2A receptors in (cerebral cortex>striatum>cerebellum). These findings suggest that¹²³I-5-I-R91150 may be used for the imaging of 5-HT_2A receptors in the living human brain with SPET.     

L-Dopa-responsive Parkinson's syndrome in association with phenylketonuria: In vivo dopamine transporter and D2 receptor findings.

Reports of parkinsonism in phenylketonuria are exceedingly rare. We report on a patient who had received a delayed diagnosis of phenylketonuria as an infant and subsequently developed levodopa-responsive parkinsonism at the age of 33. Single-photon emission computed tomography (SPECT) using (123)I-FP-CIT ([(123))I]-2 beta-carbomethoxy-3beta-(-4-iodophenyl)-N-(3-fluoropropyl)-nortropane) used to measure dopamine transporter levels on two occasions, 7 and 9 years after the onset of neurological symptoms, were normal. Iodine-123-iodo-lisuride SPECT (IBZM) imaging, however, showed reduced caudate over putamen binding. This combination of imaging findings indicates a possible upregulation of postsynaptic D2 receptors in the context of intact presynaptic dopamine nerve terminal density.     

SPECT imaging of the dopamine transporter in juvenile-onset dystonia

Juvenile-onset dystonia that improves after levodopa may occur in both dopa-responsive dystonia (DRD) and juvenile parkinsonism (JP), clinically similar conditions with different prognoses and management goals. The authors show normal striatal uptake of the dopamine transporter ligand FP-CIT with SPECT in a clinically atypical case of DRD, in contrast to the reduced uptake observed in JP.     

Dopamine transporter binding in Gilles de la Tourette syndrome: a [123I]FP-CIT/SPECT study

Objective: To investigate dopamine transporter binding in Gilles de la Tourette syndrome (GTS) with SPECT and [¹²³I]FP‐CIT. Method: Ten neuroleptic naïve/free patients with GTS, and 10 age‐ and gender‐matched normal volunteers were studied. Subjects were clinically evaluated. GTS severity and affective symptoms were measured and the presence of GTS‐related behaviours were recorded. Results: The GTS group showed significantly higher binding in both caudate and putamen nuclei than the controls. No associations were found between striatal binding ratios and measures of affect or GTS‐related behaviours. Conclusion: Patients with GTS show higher striatal binding of FP‐CIT to the striatum in comparison with age‐ and gender‐matched control subjects, indicating that dopamine transporter abnormalities are involved in the pathophysiology of GTS. These abnormalities appear to be distributed across both caudate and putamen.     

In vivo 5-HT2A receptor blockade by quetiapine: an R91150 single photon emission tomography study

BACKGROUND: Atypical antipsychotic drugs are thought to show a high degree of 5-HT2A receptor blockade, which may prevent the emergence of extrapyramidal symptoms. METHOD: 5-HT2A binding was estimated using 123I-5-I-R91150 and single photon emission tomography (SPET) in six schizophrenic subjects treated with quetiapine at a mean (+/-SD) daily dose of 350+/-123 mg for at least 5 weeks and a matched sample of six healthy volunteers. Clinical and side-effect ratings were performed at baseline and at the time of SPET scanning. The reference region approach was used to define a 5-HT2A binding index in the frontal and temporal cortex. Results: Quetiapine treatment resulted in a significant decline in 5-HT2A receptor availability in the frontal cortex (mean 0.98+/-0.09) relative to healthy volunteers (mean 1.33+/-0.16). All patients showed improvements in clinical symptom or side-effect ratings. The mean frontal cortex:cerebellum ratio after quetiapine treatment was significantly negatively correlated with reduction in the Abnormal Involuntary Rating scale and Simpson-Angus scores (P<0.05 Bonferroni corrected), but not with the reduction in the scores from the scale for the assessment of positive symptoms, the scale for the assessment of negative symptoms, the Montgomery-Asberg depression rating scale or patient age. CONCLUSION: Quetiapine treatment results in significant in vivo blockade of cortical 5-HT2A, similar to other atypical antipsychotic drugs. This effect may contribute to its placebo level extrapyramidal side-effect profile.     

Striatal and temporal cortical D2/D3 receptor occupancy by olanzapine and sertindole in vivo: a [123I]epidepride single photon emission tomography (SPET) study

RATIONALE: Previous work suggests clozapine preferentially targets limbic cortical dopamine systems, which could help account for its lack of extrapyramidal side effects (EPS) and superior therapeutic efficacy. OBJECTIVES: To test the hypothesis that olanzapine, a novel atypical antipsychotic drug, occupies temporal cortical D2/D3 receptors to a greater extent than striatal D2/D3 receptors in vivo. METHODS: Nine schizophrenic patients taking either olanzapine [(n=5; mean (SD) age: 32.5 (6.5) years; daily dose: 18.3 (2.6) mg] or sertindole [(n=4; mean (SD) age: 30.3 (7.4) years; daily dose: 16 (5.6) mg] were studied with [123I]epidepride ((S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxybenz amide) and single photon emission tomography (SPET). An estimate of [123I]epidepride 'specific binding' to D2/D3 receptors was obtained in patients and age-matched healthy volunteers. A summary measure was generated representing striatal and temporal cortical relative %D2/D3 receptor occupancy by antipsychotic drugs. Occupancy data were compared with previously studied groups of patients receiving typical antipsychotic drugs (n=12) and clozapine (n=10). RESULTS: Mean striatal and temporal cortical %D2/D3 receptor occupancy in olanzapine-treated patients was 41.3% (SD 17.9) and 82.8% (SD 4.2), respectively. Unexpectedly low levels of striatal relative %D2/D3 receptor occupancy were seen in two patients with typical antipsychotic-drug-induced movement disorder prior to switching to olanzapine. In the temporal cortex, mean D2/D3 dopamine receptor occupancy levels above 80% were seen for all antipsychotic drugs studied. CONCLUSIONS: The atypical antipsychotic drugs olanzapine and sertindole, in common with clozapine, demonstrate higher occupancy of temporal cortical than striatal D2/D3 dopamine receptors in vivo at clinically useful doses. This could help mediate their atypical clinical profile of therapeutic efficacy with few extrapyramidal side effects. Limbic selective blockade of D2/D3 dopamine receptors could be a common action of atypical antipsychotic drugs.     

Levels of gamma-aminobutyric acid-benzodiazepine receptors in abstinent, alcohol-dependent women: preliminary findings from an 123I-iomazenil single photon emission tomography study

BACKGROUND: Although alcohol dependence in women is an increasing problem, little is known about the effects of alcohol on the female brain. Evidence from a few structural and functional neuroimaging studies suggests that the female brain may be more susceptible than the male brain to the harmful effects of alcohol. However, no in vivo studies of the neuropharmacology of alcohol dependence in women have been carried out. The aim of this preliminary study was to test the hypothesis that alcohol dependence in women is associated with greater reduction in gamma-aminobutyric acid (GABA)-benzodiazepine receptor levels than in men with an equivalent drinking history. METHODS: We used single photon emission tomography and 123I-iomazenil to label the central GABA-benzodiazepine receptor and to compare semiquantified levels in 9 abstinent alcohol-dependent and 13 control women. These groups were further compared with equivalent male groups from a previous study. RESULTS: There was a trend toward a reduction in GABA-benzodiazepine receptor levels in alcohol-dependent women, but this did not reach significance. These lower levels were seen primarily in the cerebellum, occipital lobes, and parietal cortex (left > right). This was in marked contrast with the pattern of reduction seen in the previous study of male dependence, where significant reductions were seen primarily in the frontal cortex. CONCLUSIONS: Due to the semiquantitative analysis performed and the relatively small number of subjects in this study, which resulted in a nonsignificant trend, we can only comment on the differences in the pattern of lower levels of GABA-benzodiazepine receptors seen in alcohol dependence in men and women. Although we are not able to ascertain whether the female brain is more susceptible to the effects of alcohol, it appears that alcohol has a differential effect on the central GABA-benzodiazepine receptors in men and women. Recent animal evidence supports this hypothesis. Future studies should explore whether other neuropharmacological differences exist between men and women in alcohol dependence that could have implications for pharmacotherapy.     

Myocardial perfusion scintigraphy: patients' perception of benefit and risk

BACKGROUND AND AIM: Myocardial perfusion scintigraphy is a useful and safe investigation, which has now received approval by the National Institute of Clinical Excellence (NICE). However, there are common unpleasant side-effects to the drugs used and there is a risk from radiation. This study was performed to assess patients' perceptions of the benefits and risks of myocardial perfusion scintigraphy, and to determine whether the cardiac stress component influenced these perceptions. METHODS: Ninety patients attending our institution for thallium-201 myocardial perfusion study over a period of 2 months were interviewed with regard to their perception of the benefits of the study. Patients were interviewed prior to and following the stress study. RESULTS: On average, patients thought they had a good (three in four) chance of benefiting from myocardial perfusion imaging. Sixty per cent of patients were unaware that they were going to be exposed to ionizing radiation and over 80% were unaware of the side-effects. Two-thirds of the patients said they would undergo the test even if there was only a one in ten chance of benefiting. The majority of patients were uninfluenced by the stress component of the study. CONCLUSIONS: Many patients lack a knowledge of the risks of myocardial perfusion scintigraphy. Most patients would undergo myocardial perfusion studies even if they had a poor chance of benefit.     

Impact of combined (18)F-FDG PET/CT in head and neck tumours

To compare the interobserver agreement and degree of confidence in anatomical localisation of lesions using 2-[fluorine-18]fluoro-2-deoxy-D-glucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT) and (18)F-FDG PET alone in patients with head and neck tumours. A prospective study of 24 patients (16 male, eight female, median age 59 years) with head and neck tumours was undertaken. (18)F-FDG PET/CT was performed for staging purposes. 2D images were acquired over the head and neck area using a GE Discovery LS PET/CT scanner. (18)F-FDG PET images were interpreted by three independent observers. The observers were asked to localise abnormal (18)F-FDG activity to an anatomical territory and score the degree of confidence in localisation on a scale from 1 to 3 (1=exact region unknown; 2=probable; 3=definite). For all (18)F-FDG-avid lesions, standardised uptake values (SUVs) were also calculated. After 3 weeks, the same exercise was carried out using (18)F-FDG PET/CT images, where CT and fused volume data were made available to observers. The degree of interobserver agreement was measured in both instances. A total of six primary lesions with abnormal (18)F-FDG uptake (SUV range 7.2-22) were identified on (18)F-FDG PET alone and on (18)F-FDG PET/CT. In all, 15 nonprimary tumour sites were identified with (18)F-FDG PET only (SUV range 4.5-11.7), while 17 were identified on (18)F-FDG PET/CT. Using (18)F-FDG PET only, correct localisation was documented in three of six primary lesions, while (18)F-FDG PET/CT correctly identified all primary sites. In nonprimary tumour sites, (18)F-FDG PET/CT improved the degree of confidence in anatomical localisation by 51%. Interobserver agreement in assigning primary and nonprimary lesions to anatomical territories was moderate using (18)F-FDG PET alone (kappa coefficients of 0.45 and 0.54, respectively), but almost perfect with (18)F-FDG PET/CT (kappa coefficients of 0.90 and 0.93, respectively). We conclude that (18)F-FDG PET/CT significantly increases interobserver agreement and confidence in disease localisation of (18)F-FDG-avid lesions in patients with head and neck cancers.