On the quantification of [F-18]MPPF binding to 5-HT1A receptors in the human brain

Previous studies have shown that 4-(2 ' -methoxyphenyl)-1 [2 '-(N-2 "- pyridinyl)-p- [F-18]fluorobenzamido]ethylpiperazine ([F-18]MPPF) binds with high selectivity to serotonin (5-HT1A) receptors in man. However, in these studies, the calculation of the binding potential (BP, which equals receptor density divided by equilibrium dissociation constant) used a metabolite-corrected arterial input. The aim of this study was to determine whether metabolite correction and arterial sampling are essential for the assessment of BP. Methods: Five analytic methods using full datasets obtained from 6 healthy volunteers were compared. In addition, the clinical applicability of these methods was appraised. Three methods were based on Logan analysis of the dynamic PET data using metabolite-corrected and uncorrected arterial plasma input and cerebellar input. The other 2 methods consisted of a simplified reference tissue model and standard compartmental modeling. Results: A high correlation was found between BP calculated with Logan analysis using the metabolite-corrected plasma input (used as the reference method for this study) and Logan analysis using either the uncorrected arterial plasma input (r(2) = 0.95, slope = 0.85) or cerebellar input (r(2) = 0.98, slope = 0.91), A high correlation was also found between our reference method and the simplified reference tissue model (r(2) = 0.94, slope = 0.92). In contrast, a poor correlation was observed between our reference method and the standard compartmental model (r(2) = 0.45, slope = 1.59). Conclusion: These results indicate that neither metabolite analysis nor arterial sampling is necessary for clinical evaluation of BP in the human brain with [18F]MPPF. Both the Logan analysis method with cerebellar input and the simplified reference tissue method can be applied clinically

On the quantification of [F-18]MPPF binding to 5-HT1A receptors in the human brain

Previous studies have shown that 4-(2 ' -methoxyphenyl)-1 [2 '-(N-2 "- pyridinyl)-p- [F-18]fluorobenzamido]ethylpiperazine ([F-18]MPPF) binds with high selectivity to serotonin (5-HT1A) receptors in man. However, in these studies, the calculation of the binding potential (BP, which equals receptor density divided by equilibrium dissociation constant) used a metabolite-corrected arterial input. The aim of this study was to determine whether metabolite correction and arterial sampling are essential for the assessment of BP. Methods: Five analytic methods using full datasets obtained from 6 healthy volunteers were compared. In addition, the clinical applicability of these methods was appraised. Three methods were based on Logan analysis of the dynamic PET data using metabolite-corrected and uncorrected arterial plasma input and cerebellar input. The other 2 methods consisted of a simplified reference tissue model and standard compartmental modeling. Results: A high correlation was found between BP calculated with Logan analysis using the metabolite-corrected plasma input (used as the reference method for this study) and Logan analysis using either the uncorrected arterial plasma input (r(2) = 0.95, slope = 0.85) or cerebellar input (r(2) = 0.98, slope = 0.91), A high correlation was also found between our reference method and the simplified reference tissue model (r(2) = 0.94, slope = 0.92). In contrast, a poor correlation was observed between our reference method and the standard compartmental model (r(2) = 0.45, slope = 1.59). Conclusion: These results indicate that neither metabolite analysis nor arterial sampling is necessary for clinical evaluation of BP in the human brain with [18F]MPPF. Both the Logan analysis method with cerebellar input and the simplified reference tissue method can be applied clinically

Sex steroid hormones and brain function:PET imaging as a tool for research

Sex steroid hormones are major regulators of sexual characteristic among species. These hormones, however, are also produced in the brain. Steroidal hormone-mediated signalling via the corresponding hormone receptors can influence brain function at the cellular level and thus affect behaviour and higher brain functions. Altered steroid hormone signalling has been associated with psychiatric disorders, such as anxiety and depression. Neurosteroids are also considered to have a neuroprotective effect in neurodegenerative diseases. So far, the role of steroid hormone receptors in physiological and pathological conditions has mainly been investigated post mortem on animal or human brain tissues. To study the dynamic interplay between sex steroids, their receptors, brain function and behaviour in psychiatric and neurological disorders in a longitudinal manner, however, non-invasive techniques are needed. Positron emission tomography (PET) is a non-invasive imaging tool that is used to quantitatively investigate a variety of physiological and biochemical parameters in vivo. PET uses radiotracers aimed at a specific target (eg, receptor, enzyme, transporter) to visualise the processes of interest. In this review, we discuss the current status of the use of PET imaging for studying sex steroid hormones in the brain. So far, PET has mainly been investigated as a tool to measure (changes in) sex hormone receptor expression in the brain, to measure a key enzyme in the steroid synthesis pathway (aromatase) and to evaluate the effects of hormonal treatment by imaging specific downstream processes in the brain. Although validated radiotracers for a number of targets are still warranted, PET can already be a useful technique for steroid hormone research and facilitate the translation of interesting findings in animal studies to clinical trials in patients

SPECT and PET in Eating Disorders

Medical imaging techniques like PET and SPECT have been applied for investigation of brain function in anorexia and bulimia nervosa. Regional abnormalities have been detected in cerebral blood flow, glucose metabolism, the availability of several neurotransmitter receptors (serotonin 1A and 2A, dopamine D2/D3, histamine H1, mu-opioid, GABA(A)-benzodiazepine, and cannabinoid CB1), stimulant-induced dopamine release, presynaptic FDOPA influx, and the density of serotonin transporters. Different subtypes of eating disorders appear to be associated with specific functional changes. It is hard to judge whether such changes are a consequence of chronic dietary restrictions or are caused by a putative anorexia (or bulimia) nervosa endophenotype. Many abnormalities (particularly those of glucose metabolism) appear to be reversible after restoration of weight or normal patterns of food intake and may represent consequences of purging or starvation. However, some changes of regional flow and neurotransmitter systems persist even after successful therapy which suggests that these reflect traits that are independent of the state of the illness. Changes of the serotonergic system (altered activity of 5-HT1A and 5-HT2A receptors and 5-HT transporters) may contribute to dysregulation of appetite, mood, and impulse control in eating disorders and may represent a trait which predisposes to the development of anxiety, obsessionality, and behavioral inhibition. Assessment of functional changes in the brain with PET or SPECT may have prognostic value and predict neuropsychological status after several years of therapy

Clinical predictors of seizure threshold in electroconvulsive therapy: a prospective study

At the start and during the course of electroconvulsive therapy (ECT), estimation of the seizure threshold (ST) is useful in weighing the expected effectiveness against the risks of side effects. Therefore, this study explores clinical factors predicting initial ST (IST) and levels of ST during the ECT course. This prospective observational study included patients aged ≥18 years receiving ECT without contraindications for dose titration. At the first and every sixth consecutive ECT session, ST level was measured. Using multivariate linear regression and multilevel models, predictors for IST and change in ST levels were examined. A total of 91 patients (mean age, 59.1 ± 15.0 years; 37 % male; 97 % diagnosis of depression) were included. In multivariable analysis, higher age (β = 0.24; P = 0.03) and bifrontotemporal (BL) electrode placement (β = 0.42; P < 0.001) were independent predictors for higher IST, explaining 49 % of its variation. Also, these two variables independently predicted higher ST levels at different time points during the course. Using multilevel models, absence of a previous ECT course(s) predicted a steeper rise in ST during the course (P = 0.03 for the interaction term time*previous ECT). The age-adjusted dose-titration method is somewhat crude, resulting in some measurement error. Concomitant medication use could have influenced ST levels. Increasing age and BL electrode placement predicted higher (I)ST, which should be taken into account when selecting ECT dosage. Previous ECT course(s) may avoid an increase in ST during the course of ECT

Rapid reduction of sigma(1)-Receptor binding and F-18-FDG uptake in rat gliomas after in vivo treatment with doxorubicin

sigma-Receptors are strongly overexpressed in most rodent and human tumors and are proliferation markers. To evaluate the potential of a radiolabeled sigma(1)-ligand for therapy monitoring, we compared early changes of C-11-1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine (C-11-SA4503) binding and F-18-FDG uptake in gliomas after in vivo chemotherapy. Methods: C6 cells (2.5 x 10(6)) were subcutaneously injected into the right shoulder of male Wistar rats. After 7 cl, the tumor volume was 0.60 +/- 0.08 cm(3). Animals then received either saline or doxorubicin (8 mg/kg, intraperitoneally). One control and 1 treated rat were imaged simultaneously, 24 or 48 h after treatment, under pentobarbital anesthesia. Rodents (n = 20) were scanned first with C-11-SA4503 (25 MBq, intravenously) followed more than 100 min afterward by 18F-FDG (20 MBq, intravenously), using a dedicated small-animal PET camera (60-min protocol, tumors in the field of view). Tumor homogenates were prepared and subjected to sigma-receptor assays. The biodistribution of 18F-FDG was assessed. Results: Tumors appeared 4-5 d after inoculation and grew exponentially. No significant reduction of tumor growth was visible within 48 h after doxorubicin treatment. Both PET tracers visualized the tumors and showed reduced uptake after chemotherapy (C-11-SA4503: 26.5% +/- 6.5% at 24 h, 26.5% +/- 7.5% at 48 h; 18F-FDG: 22.6% +/- 3.2% at 24 h, 27.4% +/- 3.2% at 48 h; ex vivo F-18-FDG: 22.4% +/- 5.4% at 24 h, 31.7% +/- 12.7% at 48 h). sigma(1)-Receptor density in treated tumors was also reduced (from 172 +/- 35 to 125 +/- 28 fmol/mg of protein). Conclusion: Both C-11-SA4503 binding and 18F-FDG uptake declined in gliomas after chemotherapy. Decreased binding of C-11-SA4503 corresponded to a loss of (sigma(1)-receptors from the tumors. Changes in tracer uptake preceded the morphologic changes by at least 48 h