Progesterone level predicts serotonin-1a receptor binding in the male human brain.

BACKGROUND: Progesterone (P) is thought to influence mood and affective states. Alterations of the inhibitory serotonin-1A (5-HT(1A)) receptor distribution are associated with depression and anxiety. This study evaluates the influence of plasma P levels on the 5-HT(1A) receptor binding in healthy male subjects. METHODS: Molecular neuroimaging of the 5-HT(1A) receptor distribution using positron emission tomography and hormone assays for total plasma P and cortisol were done in a sample of 18 healthy men. RESULTS: Plasma P levels explained up to 65% of the variability in 5-HT(1A) receptor binding in limbic regions including the amygdala, orbitofrontal cortex and retrosplenial cortex. When controlling for cortisol in the model, there was an expected decline in explained variances of 5-HT(1A) binding attributed to P. CONCLUSIONS: The results of this study provide further support for the effect of P on 5-HT(1A) receptor expression and raise the possibility that P mediates the vulnerability to mood disorders by affecting the serotonergic system.

Plasma pharmacokinetics and gastrointestinal transit of a new propionyl-L-carnitine controlled release formulation.

Propionyl-L-carnitine is a naturally occurring analogue of L-carnitine (LC) produced in the body. PLC administration has shown beneficial effects in cardiovascular pathologies. In ulcerative colitis (UC), oral PLC treatment increased clinical presentation and positively influenced colon histology. In the present study, the MMX Multi Matrix System® (MMX™) was used as drug delivery strategy for targeted PLC colon delivery. A pharmacoscintigraphic study (n = 6 healthy volunteers) described release characteristics of two MMX-PLC-HCl controlled release 500 mg tablets. A pharmacokinetic (PK) parallel group study (n = 24) determined safety, plasma PLC concentrations and PK parameters after single and multiple doses. Gastrointestinal transit was slow and variable. The colon was the main site of PLC release and absorption. After single 500 or 1000 mg PLC doses plasma PLC and LC increased up to 2.6 and 1.2-1.3-fold compared to baseline. Multiple doses of 500 and 1000 mg twice a day over 7 days did not significantly increase maximum plasma concentrations of PLC or LC with respect to concentrations achieved after single dose administration. The colon is the main site of PLC release and absorption from MMX-PLC tablets. A daily dose of 500 mg to 1000 mg PLC twice a day was well tolerated, justifying further studies in patients with pathologies of the distal gastrointestinal tract to evaluate the efficacy of the MMX-PLC formulation.

Cortisol plasma levels in social anxiety disorder patients correlate with serotonin-1A receptor binding in limbic brain regions.

Dysregulation of the hypothalamic-pituitary-adrenocortical axis with deficient glucocorticoid feedback and alterations in the serotonergic system have been identified as biological correlates of mood disorders. Close examination of the interaction between these systems may offer insights into the pathophysiology of anxiety disorders and depression to understand how stress and these disorders are related. In this study, we investigated the relationship between plasma levels of cortisol and the dominant inhibitory serotonergic receptor, serotonin-1A (5-HT1A). Using positron emission tomography (PET) and the radioligand [carbonyl-11C]WAY-100635, we quantified the 5-HT1A receptor binding. Data from 12 male patients with social phobia and 18 matched control subjects were analysed. Seven brain regions were investigated: the anterior and posterior cingulate cortices, hippocampus, amygdala, medial orbitofrontal and retrosplenial cortices, and dorsal raphe nucleus. Partial correlation analysis, controlled for age and radiochemical variables, was performed to demonstrate the association between cortisol plasma levels and 5-HT1A receptor binding. Cortisol plasma levels were significantly lower in patients with social phobia compared to healthy controls. Moreover, we found strong negative correlations between cortisol plasma levels and 5-HT1A binding in the amygdala (r=-0.93, p=0.0004), hippocampus (r=-0.80, p=0.009), and retrosplenial cortex (r=-0.48, p=0.04) in patients with social phobia. Within the former two regions, these associations were significantly higher in patients than in healthy controls. This PET study confirms a negative association between plasma cortisol levels and the 5-HT1A receptor distribution consistent with studies in rodents and non-human primates. Dysregulation of the cortisol level might increase the vulnerability for mood disorders by altering limbic 5-HT1A receptors.

Evaluating repetitive 18F-fluoroazomycin-arabinoside (18FAZA) PET in the setting of MRI guided adaptive radiotherapy in cervical cancer.

BACKGROUND: The aim of this pilot study was to assess tumour hypoxia in patients with cervical cancer before, during and after combined radio-chemotherapy and Magnetic Resonance Imaging (MRI) guided brachytherapy (BT) by use of the hypoxia Positron Emission Tomography (PET) tracer (18)F-fluoroazomycin-arabinoside ((18)FAZA ). MATERIAL AND METHODS: Fifteen consecutive patients with locally advanced cervical cancer referred for definitive radiotherapy (RT) were included in an approved clinical protocol. Stage distribution was 3 IB1, 1 IB2, 10 IIB, 1 IIIB, tumour volume was 55 cm(3) (+/- 67, SD). Dynamic and static (18)FAZA -PET scans were performed before, during and after external beam therapy (EBRT) and image guided BT +/- concomitant cisplatin. Dose was prescribed to the individual High Risk Clinical Target Volume (HR CTV) taking into account the dose volume constraints for adjacent organs at risk. RESULTS: Five patients had visually identifiable tumours on (18)FAZA -PET scans performed prior to radio-chemotherapy and four patients before brachytherapy. One of five (18)FAZA PET positive patients had incomplete remission three months after RT, one had regional recurrence. Four of ten (18)FAZA-PET negative patients developed distant metastases. The one patient with incomplete remission received 69 Gy (D90) in the HR CTV, whereas all other patients received mean 99 Gy (+/-12, SD). CONCLUSION: PET imaging with (18)FAZA is feasible in patients with cancer of the uterine cervix. However, its predictive and prognostic value remains to be clarified. This applies in particular for the additional value of (18)FAZA-PET compared to morphologic repetitive MRI within the setting of image guided high dose radiotherapy which may contribute to overcome hypoxia related radioresistance.

Central serotonin 1A receptor binding in temporal lobe epilepsy: a [carbonyl-(11)C]WAY-100635 PET study.

We performed positron emission tomography using [carbonyl-(11)C]WAY-100635, a serotonin 1A (5-HT(1A)) receptor antagonist, in 13 patients with temporal lobe epilepsy (TLE) and in 13 controls. 5-HT(1A) receptor distribution mapping allowed correct lateralization of the epileptogenic temporal lobe in all patients. 5-HT(1A) receptor binding potential (BP(ND)) was significantly reduced in almost all temporal regions of the epileptogenic lobe. Compared with controls, the patients had significantly decreased BP(ND) values in the hippocampus, parahippocampal gyrus, and amygdala. The asymmetry index (AI), which characterizes the interhemispheric asymmetry in BP(ND), was significantly higher in patients than in controls in most regions. Depression scores were not significantly correlated with BP(ND) or AI values. Our data provide further evidence of functional changes in the serotonergic system in TLE. Molecular imaging of the 5-HT(1A) receptor may help to define the in vivo neurochemistry of TLE, and may provide a valuable tool in the noninvasive presurgical assessment of patients with medically refractory TLE.

Lateralization of the serotonin-1A receptor distribution in language areas revealed by PET.

Lateralization is a well described aspect of the human brain. A plethora of morphological, cytological and functional studies describes hemispheric asymmetry in auditory and language areas. However, no study has reported cortical lateralization in the healthy human brain in vivo on the level of neurotransmitter receptors and in relation to functional organization so far. In this study, we assessed the distribution of the main inhibitory serotonergic receptor (the 5-HT1A receptor) and analyzed its regional binding with regard to hemisphere, sex and plasma levels of sex steroid hormones (testosterone, estradiol, progesterone). We quantified the 5-HT1A receptor binding potential by positron emission tomography (PET) using the highly selective and specific radioligand [carbonyl-11C]WAY-100635 and measured hormone levels in thirty-four (16 females, 18 males) healthy right-handed subjects. The obtained data were analyzed in an automated region of interest (ROI) based approach investigating 14 auditory, language and limbic areas. We found significantly higher 5-HT1A receptor binding in the superior and middle frontal gyri of the right hemisphere, the triangular and orbital parts of the inferior frontal gyrus, the supramarginal gyrus, the superior gyrus of the temporal pole and the middle temporal gyrus. Regions of the primary and secondary auditory cortex (Heschl's gyrus and superior temporal gyrus) and the Rolandic operculum displayed significantly higher receptor binding in the left hemisphere. 5-HT1A receptor binding was 1.8-2.9% higher in right frontal ROIs and 2-3.6% higher in left primary and secondary auditory regions. There was no hemispheric difference in 5-HT(1A) receptor binding in the hippocampus, amygdala, and insula. Post-hoc testing suggested that lateralization of 5-HT1A receptor binding differed between the sexes in the triangular part of the inferior frontal gyrus. For the first time, this PET study shows lateralization of the main inhibitory receptor of the serotonergic system in functionally asymmetric organized regions of the healthy human brain in vivo.

Aggression is related to frontal serotonin-1A receptor distribution as revealed by PET in healthy subjects.

OBJECTIVES: Various studies indicate that serotonin regulates impulsivity and the inhibitory control of aggression. Aggression is also known to be modified by sex hormones, which exert influence on serotonergic neurotransmission. The present study aimed to elucidate potential interactions between human aggression, the inhibitory serotonergic 5-HT(1A) receptor, and sex hormones. EXPERIMENTAL DESIGN: Thirty-three healthy volunteers (16 women, aged 26.24 +/- 5.5 yr) completed a validated questionnaire incorporating five dimensions of aggression. Subsequently, all subjects underwent positron emission tomography with the radioligand [carbonyl-(11)C]WAY-100635 to quantify 5-HT(1A) binding potentials (BP(ND)s) in the prefrontal cortex, limbic areas, and midbrain. Also, plasma levels of testosterone, 17beta-estradiol and sex hormone-binding globulin (SHBG) were measured. Relations between aggression scores, regional 5-HT(1A) BP(ND)s, and hormone levels were analyzed using correlations, multivariate analyses of variance, and linear regressions. PRINCIPAL OBSERVATIONS: Statistical analyses revealed higher 5-HT(1A) receptor BP(ND)s in subjects exhibiting higher aggression scores in prefrontal (all P < 0.041) and anterior cingulate cortices (P = 0.016). More aggressive subjects were also characterized by lower SHBG levels (P = 0.015). Moreover, higher SHBG levels were associated with lower 5-HT(1A) BP(ND)s in frontal (P = 0.048) and cingulate cortices (all P < 0.013) and in the amygdala (P = 0.03). CONCLUSIONS: The present study provides first-time evidence for a specific interrelation between the 5-HT(1A) receptor distribution, sex hormones, and aggression in humans. Our findings point to a reduced down-stream control due to higher amounts or activities of frontal 5-HT(1A) receptors in more aggressive subjects, which is presumably modulated by sex hormones.

Age dependency of cerebral P-gp function measured with (R)-[11C]verapamil and PET.

PURPOSE: The aim of this study was to assess the influence of age on the functional activity of the multidrug efflux transporter P-glycoprotein (P-gp) at the human blood-brain barrier. METHODS: Seven young (mean age: 27 +/- 4 years) and six elderly (mean age: 69 +/- 9 years) healthy volunteers underwent dynamic (R)-[(11)C]verapamil (VPM) positron emission tomography (PET) scans and arterial blood sampling. Parametric distribution volume (DV) images were generated using Logan linearisation, and age groups were compared with statistical parametric mapping (SPM). Brain regions that SPM analysis had shown to be most affected by age were analysed by a region of interest (ROI)-based approach using a maximum probability brain atlas, before and after partial volume correction (PVC). RESULTS: SPM analysis revealed significant clusters of DV increases in cerebellum, temporal and frontal lobe of elderly compared to younger subjects. In the ROI-based analysis, elderly subjects showed significant DV increases in amygdala (+30%), insula (+26%) and cerebellum (+25%) before PVC, and in insula (+33%) after PVC. CONCLUSIONS: Increased VPM DV values in the brains of elderly subjects suggest a decrease in cerebral P-gp function with increasing age.

Chronic heart failure leads to an expanded plasma volume and pseudoanaemia, but does not lead to a reduction in the body's red cell volume.

Aims Chronic heart failure (CHF) is frequently associated with a decreased haemoglobin level, whereas the mechanism remains largely unknown. Methods and results One hundred consecutive CHF patients without anaemia or renal dysfunction based on non-cardiac reasons were enrolled. We explored determinants of anaemia (as iron parameters, erythropoietin, hepcidin and kidney function) including red cell volume (RCV) (by a 51 Cr assay) as well as related markers and plasma volume. The influence of each factor on haemoglobin concentrations was determined in a multiple regression model. Mean haemoglobin concentrations were 11.7 +/- 0.8 mg/dL in anaemic CHF patients and 14.4 +/- 1.2 mg/dL in non-anaemic patients. Corrected reticulocytes were lower in anaemic patients (35.1 +/- 15.7 vs. 50.3 +/- 19.2 G/L, P = 0.001), but the RCV was not reduced (1659.3 +/- 517.6 vs. 1826.4 +/- 641.3 mL, P = 0.194). We found that plasma volumes were significantly higher in anaemic CHF patients (70.0 +/- 2.4 vs. 65.0 +/- 4.0%, P < 0.001). Plasma volume was the best predictor of haemoglobin concentrations in the regression model applied (B = -0.651, P < 0.001, R(2) = 0.769). Conclusion Haemodilution appears to be the most potent factor for the development of low haemoglobin levels in patients with CHF. Our data support an additional independent, but minor influence of iron deficiency on haemoglobin concentrations in CHF patients.

Tariquidar-induced P-glycoprotein inhibition at the rat blood-brain barrier studied with (R)-11C-verapamil and PET.

UNLABELLED: The multidrug efflux transporter P-glycoprotein (P-gp) is expressed in high concentrations at the blood-brain barrier (BBB) and is believed to be implicated in resistance to central nervous system drugs. We used small-animal PET and (R)-11C-verapamil together with tariquidar, a new-generation P-gp modulator, to study the functional activity of P-gp at the BBB of rats. To enable a comparison with human PET data, we performed kinetic modeling to estimate the rate constants of radiotracer transport across the rat BBB. METHODS: A group of 7 Wistar Unilever rats underwent paired (R)-11C-verapamil PET scans at an interval of 3 h: 1 baseline scan and 1 scan after intravenous injection of tariquidar (15 mg/kg, n = 5) or vehicle (n = 2). RESULTS: After tariquidar administration, the distribution volume (DV) of (R)-11C-verapamil was 12-fold higher than baseline (3.68 +/- 0.81 vs. 0.30 +/- 0.08; P = 0.0007, paired t test), whereas the DVs were essentially the same when only vehicle was administered. The increase in DV could be attributed mainly to an increased influx rate constant (K1) of (R)-11C-verapamil into the brain, which was about 8-fold higher after tariquidar. A dose-response assessment with tariquidar provided an estimated half-maximum effect dose of 8.4 +/- 9.5 mg/kg. CONCLUSION: Our data demonstrate that (R)-11C-verapamil PET combined with tariquidar administration is a promising approach to measure P-gp function at the BBB.

Peripheral metabolism of (R)-[11C]verapamil in epilepsy patients.

PURPOSE: (R)-[(11)C]verapamil is a new PET tracer for P-glycoprotein-mediated transport at the blood-brain barrier. For kinetic analysis of (R)-[(11)C]verapamil PET data the measurement of a metabolite-corrected arterial input function is required. The aim of this study was to assess peripheral (R)-[(11)C]verapamil metabolism in patients with temporal lobe epilepsy and compare these data with previously reported data from healthy volunteers. METHODS: Arterial blood samples were collected from eight patients undergoing (R)-[(11)C]verapamil PET and selected samples were analysed for radiolabelled metabolites of (R)-[(11)C]verapamil by using an assay that measures polar N-demethylation metabolites by solid-phase extraction and lipophilic N-dealkylation metabolites by HPLC. RESULTS: Peripheral metabolism of (R)-[(11)C]verapamil was significantly faster in patients compared to healthy volunteers (AUC of (R)-[(11)C]verapamil fraction in plasma: 29.4 +/- 3.9 min for patients versus 40.8 +/- 5.0 min for healthy volunteers; p < 0.0005, Student's t-test), which resulted in lower (R)-[(11)C]verapamil plasma concentrations (AUC of (R)-[(11)C]verapamil concentration, normalised to injected dose per body weight: 25.5 +/- 2.1 min for patients and 30.5 +/- 5.9 min for healthy volunteers; p = 0.038). Faster metabolism appeared to be mainly due to increased N-demethylation as the polar [(11)C]metabolite fraction was up to two-fold greater in patients. CONCLUSIONS: Faster metabolism of (R)-[(11)C]verapamil in epilepsy patients may be caused by hepatic cytochrome P450 enzyme induction by antiepileptic drugs. Based on these data caution is warranted when using an averaged arterial input function derived from healthy volunteers for the analysis of patient data. Moreover, our data illustrate how antiepileptic drugs may decrease serum levels of concomitant medication, which may eventually lead to a loss of therapeutic efficacy.

The serotonin-1A receptor distribution in healthy men and women measured by PET and [carbonyl-11C]WAY-100635.

PURPOSE: The higher prevalence rates of depression and anxiety disorders in women compared to men have been associated with sexual dimorphisms in the serotonergic system. The present positron emission tomography (PET) study investigated the influence of sex on the major inhibitory serotonergic receptor subtype, the serotonin-1A (5-HT(1A)) receptor. METHODS: Sixteen healthy women and 16 healthy men were measured using PET and the highly specific radioligand [carbonyl-(11)C]WAY-100635. Effects of age or gonadal hormones were excluded by restricting the inclusion criteria to young adults and by controlling for menstrual cycle phase. The 5-HT(1A) receptor BP(ND) was quantified using (1) the 'gold standard' manual delineation approach with ten regions of interest (ROIs) and (2) a newly developed delineation method using a PET template normalized to the Montreal Neurologic Institute space with 45 ROIs based on automated anatomical labeling. RESULTS: The 5-HT(1A) receptor BP(ND) was found equally distributed in men and women applying both the manual delineation method and the automated delineation approach. Women had lower mean BP(ND) values in every region investigated, with a borderline significant sex difference in the hypothalamus (p = 0.012, uncorrected). There was a high intersubject variability of the 5-HT(1A) receptor BP(ND) within both sexes compared to the small mean differences between men and women. CONCLUSIONS: To conclude, when measured in the follicular phase, women do not differ from men in the 5-HT(1A) receptor binding. To explain the higher prevalence of affective disorders in women, further studies are needed to evaluate the relationship between hormonal status and the 5-HT(1A) receptor expression.

Preparation and first evaluation of [(18)F]FE@SUPPY: a new PET tracer for the adenosine A(3) receptor.

INTRODUCTION: Changes of the adenosine A(3) receptor subtype (A3AR) expression have been shown in a variety of pathologies, especially neurological and affective disorders, cardiac diseases and oncological and inflammation processes. Recently, 5-(2-fluoroethyl) 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (FE@SUPPY) was presented as a high-affinity ligand for the A3AR with good selectivity. Our aims were the development of a suitable labeling precursor, the establishment of a reliable radiosynthesis for the fluorine-18-labeled analogue [(18)F]FE@SUPPY and a first evaluation of [(18)F]FE@SUPPY in rats. METHODS: [(18)F]FE@SUPPY was prepared in a feasible and reliable manner by radiofluorination of the corresponding tosylated precursor. Biodistribution was carried out in rats, and organs were removed and counted. Autoradiography was performed on rat brain slices in the presence or absence of 2-Cl-IB-MECA. RESULTS: Overall yields and radiochemical purity were sufficient for further preclinical and clinical applications. The uptake pattern of [(18)F]FE@SUPPY found in rats mainly followed the described mRNA distribution pattern of the A3AR. Specific uptake in brain was demonstrated by blocking with a selective A3AR agonist. CONCLUSION: We conclude that [(18)F]FE@SUPPY has the potential to serve as the first positron emission tomography tracer for the A3AR.

Metabolism and autoradiographic evaluation of [(18)F]FE@CIT: a Comparison with [(123)I]beta-CIT and [(123)I]FP-CIT.

PURPOSE: Since the late 1980s, cocaine analogues based on the phenyltropane structure, such as [(11)C]CFT and [(123)I]beta-CIT have been used for the imaging of the dopamine transporter. FE@CIT (fluoropropyl ester) and FP-CIT (N-fluoropropyl derivative) are further analogues. The aim of this study was to (1) evaluate and compare the metabolic stability of beta-CIT, FP-CIT and FE@CIT against carboxyl esterases and (2) evaluate selectivity of [(18)F]FE@CIT compared to [(123)I]beta-CIT and [(123)I]FP-CIT using autoradiography. METHODS: In vitro enzymatic hydrolysis assays were performed using different concentrations of beta-CIT, FE@CIT and FP-CIT with constant concentrations of carboxyl esterase. Autoradiography was performed on coronal 20-microm rat brain sections incubated with different radioactivity concentrations of [(123)I]beta-CIT, [(123)I]FP-CIT or [(18)F]FE@CIT and, additionally, with 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile [serotonin transporter (SERT)] and nisoxetine [norepinephrine transporter (NET)] for blocking experiments. RESULTS: In vitro assays showed Michaelis-Menten constants of 175 micromol (beta-CIT), 183 micromol (FE@CIT) and 521 micromol (FP-CIT). Limiting velocities were 0.1005 micromol/min (beta-CIT), 0.1418 micromol/min (FE@CIT) and 0.1308 micromol/min (FP-CIT). This indicates a significantly increased stability of FP-CIT, whereas carboxyl esterase stability of beta-CIT and FE@CIT showed no significant difference. Autoradiographic analyses revealed a good correlation between dopamine transporter (DAT)-rich regions and the uptake pattern of FE@CIT. Blocking experiments showed a higher DAT selectivity for [(18)F]FE@CIT than for the other two tracers. CONCLUSION: We found that (1) the metabolic stability of FE@CIT was comparable to that of beta-CIT, whereas FP-CIT showed higher resistance to enzymatic hydrolysis; and (2) the overall uptake pattern of [(18)F]FE@CIT on brain slices was comparable to that of [(123)I]beta-CIT and [(123)I]FPCIT. After blocking of NET and SERT binding, a significantly higher DAT selectivity was observed for [(18)F]FE@CIT. Hence, [(18)F]FE@CIT may be of interest for further clinical application.

No immunological benefit of selenium in consecutive patients with autoimmune thyroiditis.

BACKGROUND: Recently it has been demonstrated that after selenium (Se) supplementation in autoimmune thyroiditis (AIT) patients, there was a significant decrease of thyroid peroxidase (TPO) autoantibody (TPOAb) levels. The aim of our study was to evaluate the immunological benefit of Se administration in unselected AIT patients and thus address the question whether Se administration should generally be recommended for AIT patients. METHODS: Thirty-six consecutive AIT patients (aged 19-85 years) were included in the present study. In addition to their levothyroxine (LT(4)) treatment, 18 patients received 200 microg (2.53 micromol) sodium selenite per day orally for the time span of 3 months, whereas 18 patients received placebo. All patients had measurement of thyroid hormones, thyrotropin (TSH), autoantibodies (thyroglobulin antibodies [TgAb] and TPOAb), Se levels, and intracellular cytokine detection in CD4(+) and CD8(+) T cells of peripheral blood mononuclear cells (PBMC) by flow cytometry before and after Se or placebo administration. RESULTS: No significant difference in the TPOAb levels was found after Se administration (524 +/- 452 vs. 505 +/- 464 IU/mL; p > 0.05). Furthermore, we found no significant differences in the CD4(+) or CD8(+) cytokine pattern (IFN-gamma, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, TNF-alpha, TNF-beta) in patients before and after Se administration, in patients before and after placebo administration and between Se group and placebo group before and after Se vs. placebo administration. CONCLUSION: We demonstrate that Se administration in our AIT patient's cohort does not induce significant immunological changes, either in terms of cytokine production patterns of peripheral T lymphocytes or of TPOAb levels. Our data suggest that AIT patients with moderate disease activity (in terms of TPOAb and cytokine production patterns) may not (equally) benefit as patients with high disease activity.

Preparation and pre-vivo evaluation of no-carrier-added, carrier-added and cross-complexed [(68)Ga]-EDTMP formulations.

PURPOSE: The present study aimed to develop convenient preparation and quality control protocols for [(68)Ga]-EDTMP, a potential radiotracer for skeletal PET imaging. Furthermore, bone binding characteristics with special focus on the influence of carrier addition were evaluated. METHODS: No-carrier-added (nca), carrier-added and novel cross-complexed [(68)Ga]-EDTMP formulations were prepared using [(68)Ga]-gallium chloride and a commercial EDTMP kit. Respective bone binding characteristics were determined on the basis of an established in-vitro method using hydroxyapatite and human bone powders as binding matrices. RESULTS: Pre-vivo evaluation of nca [(68)Ga]-EDTMP yielded irreversible binding on the mineral bone phase characterised by fast binding kinetics. Generally, nca [(68)Ga]-EDTMP showed low uptake values comparable to nca [(99m)Tc]-EDTMP. Interestingly, the bone binding affinity of [(68)Ga]-EDTMP could be increased by the addition of carriers, presumably by changing the complex structure. CONCLUSIONS: This fast and reliable preparation protocol could enable small PET facilities without onsite cyclotron to perform PET bone scans. A comparison of all cross-complexed [(68)Ga]-EDTMP preparations further strengthens the recently presented "foreign carrier theory", which highlights carrier addition as a factor strongly affecting bone uptake of radiolabelled polyphosphonates. The clinical applicability of [(68)Ga]-EDTMP - particularly with respect to lesion specificity and sensitivity - should be clarified in forthcoming in-vivo studies.

Reduced serotonin-1A receptor binding in social anxiety disorder.

BACKGROUND: Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT1A receptor binding potential (BP) in social anxiety disorder (SAD). METHODS: Using PET and [carbonyl-11C]WAY-100635, we compared a homogeneous group of 12 unmedicated, male SAD patients with 18 healthy control subjects (HC). A multivariate ANOVA with all regional BP values as dependent variables, age and four radiochemical variables as covariates was performed. RESULTS: We found a significantly lower 5-HT1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT1A binding was most significant in the amygdala (-21.4%; p = .003). There was also a more than 20% lower 5-HT(1A) BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030). CONCLUSIONS: The lower 5-HT1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT1A binding, thus corroborating the potential validity of 5-HT1A receptors as targets in the treatment of human anxiety disorders.

Typical chest pain and normal coronary angiogram: cardiac risk factor analysis versus PET for detection of microvascular disease.

UNLABELLED: Angiography of patients with typical chest pain reveals normal epicardial coronary arteries in about 20%. Coronary flow reserve (CFR) determination is an elaborate, but helpful, task, as only the evidence of microvascular disease enables appropriate therapy. We prospectively evaluated the incidence of a dysfunctional microcirculation and searched for predictive parameters of a reduced CFR. METHODS: In 79 consecutive patients (52 females, 27 males) with typical angina and a normal angiogram and 10 control subjects (6 females, 4 males), CFR was measured by 13N-ammonia rest/dipyridamole PET and correlated with clinical parameters individually and summarized as the number of risk factors (NRF) using an elaborated cardiac risk factor score. RESULTS: Sixty-five percent of patients had a reduced CFR (CFR < 2.5). CFR correlated with NRF (r = 0.55, P < 0.001), systolic blood pressure (r = 0.46, P < 0.001), interventricular septal thickness (r = 0.33, P < 0.01), and age (r = 0.25, P = 0.02). Eighty-five percent of patients with a high risk factor score (NRF > or = 5) had a reduced CFR. In contrast, 100% of our patients with a low risk factor score (NRF < 2) presented a normal CFR. In total, 55% of our patients could be allocated to either one of these groups. CONCLUSION: In about two thirds of patients, anginal pain can be explained by a reduced CFR. Risk factors have a cumulative negative effect on CFR. A clinical cardiac risk factor analysis enables estimation of individual probability of microvascular dysfunction in a significant proportion of these patients. However, CFR measurements are recommended for those with an intermediate NRF.

18F fluoroethylations: different strategies for the rapid translation of 11C-methylated radiotracers.

INTRODUCTION: The translation of 11C-labeled compounds into their respective 18F-labeled derivatives is an important tool in the rapid development of positron emission tomography (PET) tracers. Thus, our aim was the development of a general method for the preparation of 18F-fluoroethylated compounds that (a) is applicable to a variety of precursors, (b) can be performed in a fully automated commercially available synthesizer and (c) enables this rapid translation of 11C-methylated tracers into their 18F-fluoroethylated analogs sharing the same precursor molecules. METHODS: Ten methods for the preparation and purification of different 18F-fluoroethylating agents were compared. Subsequently, five 18F-labeled PET tracers were synthesized under fully automated conditions. RESULTS: Radiochemical yields ranged from 34.4% to 60.8%, and time consumption ranged from 20 to 55 min for all methods. Use of 1-bromo-2-[18F]fluoroethane and distillation evinced as the method of choice. CONCLUSIONS: We were able to develop a general method for the preparation of a variety of 18F-fluoroethylated molecules. The provided tool is solely based on commercially available resources and has the potential to simplify and accelerate innovative PET tracer development in the future.

Pre vivo, ex vivo and in vivo evaluations of [68Ga]-EDTMP.

INTRODUCTION: The objectives of this study were to develop a simple preparation method for [68Ga]-EDTMP and to evaluate the applicability of [68Ga]-EDTMP as a potential positron emission tomography (PET) bone imaging agent using pre vivo, ex vivo and in vivo models. METHODS: [68Ga]-EDTMP was prepared using 68Ga]-gallium chloride eluted from the 68Ge/68Ga generator and commercially available Multibone kits. Binding affinity to bone compartments was evaluated using a recently established pre vivo model. In vivo (microPET) and ex vivo experiments were performed in mice, and the results of which were compared with those obtained with [18F]-fluoride. RESULTS: [68Ga]-EDTMP was accessible via simple kit preparation and predominantly accumulated in bone tissue in vivo, ex vivo and pre vivo. Binding to mineral bone was irreversible, and low binding was observed in organic bone. In vivo microPET evaluation revealed predominant uptake in bone with renal excretion. Compared with [18F]-fluoride, the uptake was lower and the PET image quality was reduced. CONCLUSIONS: From the present evaluation, apart from the autonomy for PET centers without an onsite cyclotron, the advantage of [68Ga]-EDTMP over [18F]-fluoride is not apparent and the future clinical prospect of [68Ga]-EDTMP remains speculative.