Prevalence of Physical Frailty: Results from the DO-HEALTH Study.

BACKGROUND: Frailty is a geriatric syndrome associated with multiple negative health outcomes. However, its prevalence varies by population and instrument used. We investigated frailty and pre-frailty prevalence by 5 instruments in community-dwelling older adults enrolled to a randomized-controlled trial in 5 European countries. METHODS: Cross-sectional baseline analysis in 2,144 DO-HEALTH participants recruited from Switzerland, Austria, France, Germany, and Portugal with complete data for frailty. Frailty status was assessed by the Physical Frailty Phenotype [PFP], SOF-Frailty Index [SOF-FI], FRAIL-Scale, SHARE-Frailty Instrument [SHARE-FI], and a modified SHARE-FI, and compared by country, age, and gender. Logistic regression was used to determine relevant factors associated with frailty and pre-frailty. RESULTS: Mean age was 74.9 (±4.4) years, 61.6% were women. Based on the PFP, overall frailty and pre-frailty prevalence was 3.0% and 43.0%. By country, frailty prevalence was highest in Portugal (13.7%) and lowest in Austria (0%), and pre-frailty prevalence was highest in Portugal (57.3%) and lowest in Germany (37.1%). By instrument and overall, frailty and pre-frailty prevalence was highest based on SHARE-FI (7.0% / 43.7%) and lowest based on SOF-FI (1.0% / 25.9%). Frailty associated factors were residing in Coimbra (Portugal) [OR 12.0, CI 5.30-27.21], age above 75 years [OR 2.0, CI 1.17-3.45], and female gender [OR 2.8, CI 1.48-5.44]. The same three factors predicted pre-frailty. CONCLUSIONS: Among relatively healthy adults age 70 and older enroled to DO-HEALTH, prevalence of frailty and pre-frailty differed significantly by instrument, country, gender, and age. Among instruments, the highest prevalence of frailty and pre-frailty was documented by the SHARE-FI and the lowest by the SOF-FI.

Increase in the Magnetic Ordering Temperature (Tc) as a Function of the Applied Pressure for A2Mn[Mn(CN)6] (A = K, Rb, Cs) Prussian Blue Analogues.

Magnetization measurements under pressure reveal that the external hydrostatic pressure significantly increases in the ferrimagnetic transition temperature, Tc, for A2Mn[Mn(CN)6] (A = K, Rb, Cs). In the case of monoclinic A = K and Rb, dTc/dp values are 21.2 and 14.6 K GPa-1, respectively, and Tc increases by 53 and 39%, respectively, from ambient pressure to 1.0 GPa. The cubic A = Cs compound also shows a monotonous increase with an initial rate of 4.22 K GPa-1 and about 11.4 K GPa-1 above 0.6 GPa, and an overall Tc increase by 26% at 1.0 GPa. The increase in Tc is attributed to deformation of the structure such that the MnII-N≡C angle decreases with increasing pressure. The smaller the alkali cation, the greater the decrease in the MnII-N≡C angle induced by pressure and the larger the increase of dTc/dp. This is in accordance with the ambient-pressure structures for A2Mn[Mn(CN)6] (A = K, Rb, Cs), which have decreasing MnII-N≡C angles that correlate to the observed increasing Tcs as K > Rb > Cs. The large increase in Tc for the A = K compound is the highest class among several cyano-bridged metal complexes. The tuning of the transition temperature by such a weak pressure may lead to additional applications such as switching devices.

A Multi-Center, Randomized, Controlled, Pivotal Study to Assess the Safety and Efficacy of a Selective Cytopheretic Device in Patients with Acute Kidney Injury.

OBJECTIVE: Acute kidney injury (AKI) is a highly morbid condition in critically ill patients that is associated with high mortality. Previous clinical studies have demonstrated the safety and efficacy of the Selective Cytopheretic Device (SCD) in the treatment of AKI requiring continuous renal replacement therapy in the intensive care unit (ICU). DESIGN, SETTING, PATIENTS: A randomized, controlled trial of 134 ICU patients with AKI, 69 received continuous renal replacement therapy (CRRT) alone and 65 received SCD therapy. RESULTS: No significant difference in 60-day mortality was observed between the treated (27/69; 39%) and control patients (21/59; 36%, with six patients lost to follow up) in the intention to treat (ITT) analysis. Of the 19 SCD subjects (CRRT+SCD) and 31 control subjects (CRRT alone) who maintained a post-filter ionized calcium (iCa) level in the protocol's recommended range (≤ 0.4 mmol/L) for greater or equal to 90% of the therapy time, 60-day mortality was 16% (3/19) in the SCD group compared to 41% (11/27) in the CRRT alone group (p = 0.11). Dialysis dependency showed a borderline statistically significant difference between the SCD treated versus control CRRT alone patients maintained for ≥ 90% of the treatment in the protocol's recommended (r) iCa target range of ≤ 0.4 mmol/L with values of, 0% (0/16) and 25% (4/16), respectively (P = 0.10). When the riCa treated and control subgroups were compared for a composite index of 60 day mortality and dialysis dependency, the percentage of SCD treated subjects was 16% versus 58% in the control subjects (p<0.01). The incidence of serious adverse events did not differ between the treated (45/69; 65%) and control groups (40/65; 63%; p = 0·86). CONCLUSION: SCD therapy may improve mortality and reduce dialysis dependency in a tightly controlled regional hypocalcaemic environment in the perfusion circuit. TRIAL REGISTRATION: ClinicalTrials.gov NCT01400893 http://clinicaltrials.gov/ct2/show/NCT01400893.

The role of F(18)-fluorodeoxyglucose positron emission tomography in guiding diagnosis and management in patients with known or suspected cardiac sarcoidosis.

Cardiac sarcoidosis (CS) has gained significant interest in recent years with the emergence of advanced imaging modalities such as MRI and F(18)-fluorodeoxyglucose-positron emission tomography (FDG-PET) as modalities to aid in the diagnosis of this condition. CS remains a difficult condition to diagnose, particularly in cases of isolated cardiac involvement and it can present with a broad spectrum of clinical syndromes. Furthermore, the appropriate management of these patients remains controversial. FDG-PET has a potential role not only in diagnosis of CS but also in directing further therapies, facilitating the decision to start immunosuppression and monitoring the response to it. In this article, we discuss when to consider FDG-PET, outline the current optimal patient preparation and scanning protocols and then, using case examples, discuss the use of FDG-PET in follow-up of patients with known or suspected CS. We also outline how PET can influence management decisions in these patients.

The effect of the selective cytopheretic device on acute kidney injury outcomes in the intensive care unit: a multicenter pilot study.

Acute kidney injury (AKI) is characterized by deterioration in kidney function resulting in multisystem abnormalities. Much of the morbidity and mortality associated with AKI result from a systemic inflammatory response syndrome (SIRS). This study described herein is a prospective, single-arm, multicenter US study designed to evaluate the safety and efficacy of the Selective Cytopheretic Device (SCD) treatment on AKI requiring continuous renal replacement therapy (CRRT) in the ICU. The study enrolled 35 subjects. The mean age was 56.3±15. With regard to race, 71.4% of the subjects were Caucasian, 22.9% were Black, and 5.7% were Hispanic. Average SOFA score was 11.3±3.6. Death from any cause at Day 60 was 31.4%. Renal recovery, defined as dialysis independence, was observed in all of the surviving subjects at Day 60. The results of this pilot study indicate the potential for a substantial improvement in patient outcomes over standard of care therapy, which is associated with a greater than 50% 60-day mortality in the literature. The SCD warrants further study in scientifically sound, pivotal trial to demonstrate reasonable assurance of safety and effectiveness.

Social partnering significantly reduced rapid eye movement sleep fragmentation in fear-conditioned, stress-sensitive Wistar-Kyoto rats.

Negative emotionality affects sleep-wake behavior in humans and rodents, and the Wistar-Kyoto (WKY) rat strain is known for its stress-sensitive phenotype. Analyzing rapid eye movement sleep (REMS) microarchitecture by separating REMS into single (siREMS; inter-REM episode interval>3 min) and sequential (seqREMS; interval≤3 min) episodes, we previously reported that cued fear conditioning (CFC) increased REMS fragmentation in WKY compared to Wistar rats by increasing the number of seqREMS episodes. Since social support affects fear responsiveness in humans, we hypothesized that social interaction with a naive partner would affect the sleep-wake response to CFC in WKY rats. Thus, male WKY rats were assigned to either the social support or the social isolation group. Animals were fear-conditioned to 10 tones (800 Hz, 90 dB, 5 s), each co-terminating with a mild foot shock (1.0 mA, 0.5 s), at 30-s intervals. All subjects underwent a tone-only test both 24 h (Day 1) and again two weeks (Day 14) later. Social partnering was achieved by providing the fear-conditioned rat with 30 min of interaction with its naive partner immediately after CFC and during the tone presentations on Day 1 and Day 14. The results indicate that while CFC increased freezing behavior in socially isolated WKY rats, it increased grooming behavior in socially partnered rats. Socially partnered rats had increased sleep efficiency during the light phase and spent less time in NREMS during the dark phase. The number of siREMS episodes increased during both the light and dark phases in partnered rats, and the number of seqREMS episodes increased in socially isolated rats. Our findings suggest that social partnering may protect WKY rats from the REMS fragmentation that is observed following CFC in isolation.

The effects of a novel therapeutic device on acute kidney injury outcomes in the intensive care unit: a pilot study.

Despite decades of improvements in the provision of renal replacement therapy, the morbidity and mortality associated with acute kidney injury (AKI) in the intensive care unit (ICU) setting remains extremely high. Much of the morbidity and mortality of this disorder is the consequence of systemic cellular damage that results from immune dysregulation. This is a prospective, single-arm, single-center study designed to evaluate the safety and efficacy of treatment with a selective cytopheretic device (SCD) on clinical outcomes in AKI requiring renal replacement therapy in the ICU. The patients enrolled in the trial were compared with historical case-matched controls with respect to age and Sequential Organ Failure Assessment (SOFA) score. The mortality for the case-matched controls was 77.78%, whereas the mortality in the SCD treatment group was 22.22% (p = 0.027). Multiple regression analysis identified treatment with SCD as the only significant variable affecting mortality among age, SOFA score, average change in urine output over the first 7 days during or after treatment. Mean total urine output in the 10 subjects receiving SCD treatment increased from a baseline of approximately 500 ml/d to more than 2,000 ml/d by day 7 of treatment. The SCD represents a novel therapeutic approach to alter the acute inflammatory response seen in AKI, and further evaluation of the safety and efficacy of the device is being evaluated in a multicenter investigation in the United States under an Food and Drug Administration (FDA) approved investigational device exemption (IDE).

Kinetic model-based factor analysis of dynamic sequences for 82-rubidium cardiac positron emission tomography.

PURPOSE: Factor analysis has been pursued as a means to decompose dynamic cardiac PET images into different tissue types based on their unique temporal signatures to improve quantification of physiological function. In this work, the authors present a novel kinetic model-based (MB) method that includes physiological models of factor relationships within the decomposition process. The physiological accuracy of MB decomposed (82)Rb cardiac PET images is evaluated using simulated and experimental data. Precision of myocardial blood flow (MBF) measurement is also evaluated. METHODS: A gamma-variate model was used to describe the transport of (82)Rb in arterial blood from the right to left ventricle, and a one-compartment model to describe the exchange between blood and myocardium. Simulations of canine and rat heart imaging were performed to evaluate parameter estimation errors. Arterial blood sampling in rats and (11)CO blood pool imaging in dogs were used to evaluate factor and structure accuracy. Variable infusion duration studies in canine were used to evaluate MB structure and global MBF reproducibility. All results were compared to a previously published minimal structure overlap (MSO) method. RESULTS: Canine heart simulations demonstrated that MB has lower root-mean-square error (RMSE) than MSO for both factor (0.2% vs 0.5%, p < 0.001 MB vs MSO, respectively) and structure (3.0% vs 4.7%, p < 0.001) estimations, as with rat heart simulations (factors: 0.2% vs 0.9%, p < 0.001 and structures: 3.0% vs 6.7%, p < 0.001). MB blood factors compared to arterial blood samples in rats had lower RMSE than MSO (1.6% vs 2.2%, p =0.025). There was no difference in the RMSE of blood structures compared to a (11)CO blood pool image in dogs (8.5% vs 8.8%, p =0.23). Myocardial structures were more reproducible with MB than with MSO (RMSE=3.9% vs 6.2%, p < 0.001), as were blood structures (RMSE=4.9% vs 5.6%, p =0.006). Finally, MBF values tended to be more reproducible with MB compared to MSO (CV= 10% vs 18%, p =0.16). The execution time of MB was, on average, 2.4 times shorter than MSO (p < 0.001) due to fewer free parameters. CONCLUSIONS: Kinetic model-based factor analysis can be used to provide physiologically accurate decomposition of (82)Rb dynamic PET images, and may improve the precision of MBF quantification.

Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)gamma(3) results in increased oxidative capacity and glucose uptake in human primary myotubes.

AIMS/HYPOTHESIS: AMP-activated protein kinase (AMPK) has a broad role in the regulation of glucose and lipid metabolism making it a promising target in the treatment of type 2 diabetes mellitus. We therefore sought to characterise for the first time the effects of chronic AMPK activation on skeletal muscle carbohydrate metabolism in carriers of the rare gain-of-function mutation of the gene encoding AMPKgamma(3) subunit, PRKAG3 R225W. METHODS: Aspects of fuel metabolism were studied in vitro in myocytes isolated from vastus lateralis of PRKAG3 R225W carriers and matched control participants. In vivo, muscular strength and fatigue were evaluated by isokinetic dynamometer and surface electromyography, respectively. Glucose uptake in exercising quadriceps was determined using [(18)F]fluorodeoxyglucose and positron emission tomography. RESULTS: Myotubes from PRKAG3 R225W carriers had threefold higher mitochondrial content (p < 0.01) and oxidative capacity, higher leak-dependent respiration (1.6-fold, p < 0.05), higher basal glucose uptake (twofold, p < 0.01) and higher glycogen synthesis rates (twofold, p < 0.05) than control myotubes. They also had higher levels of intracellular glycogen (p < 0.01) and a trend for lower intramuscular triacylglycerol stores. R225W carriers showed remarkable resistance to muscular fatigue and a trend for increased glucose uptake in exercising muscle in vivo. CONCLUSIONS/INTERPRETATION: Through the enhancement of skeletal muscle glucose uptake and increased mitochondrial content, the R225W mutation may significantly enhance exercise performance. These findings are also consistent with the hypothesis that the gamma(3) subunit of AMPK is a promising tissue-specific target for the treatment of type 2 diabetes mellitus, a condition in which glucose uptake and mitochondrial function are impaired.

Myocardial blood flow in patients with low-flow, low-gradient aortic stenosis: differences between true and pseudo-severe aortic stenosis. Results from the multicentre TOPAS (Truly or Pseudo-Severe Aortic Stenosis) study.

BACKGROUND: Impairment of myocardial flow reserve (MFR) in aortic stenosis (AS) with normal left ventricular function relates to the haemodynamic severity. OBJECTIVES: To investigate whether myocardial blood flow (MBF) and MFR differ in low-flow, low-gradient AS depending on whether there is underlying true-severe AS (TSAS) or pseudo-severe AS (PSAS). METHODS: In 36 patients with low-flow, low-gradient AS, dynamic [13N]ammonia PET perfusion imaging was performed at rest (n = 36) and during dipyridamole stress (n = 20) to quantify MBF and MFR. Dobutamine echocardiography was used to classify patients as TSAS (n = 18) or PSAS (n = 18) based on the indexed projected effective orifice area (EOA) at a normal flow rate of 250 ml/s (EOAI(proj )0.55 cm(2)/m(2)). RESULTS: Compared with healthy controls (n = 14), patients with low-flow, low-gradient AS had higher resting mean (SD) MBF (0.83 (0.21) vs 0.69 (0.09) ml/min/g, p = 0.001), reduced hyperaemic MBF (1.16 (0.31) vs 2.71 (0.50) ml/min/g, p<0.001) and impaired MFR (1.44 (0.44) vs 4.00 (0.91), p<0.001). Resting MBF and MFR correlated with indices of AS severity in low-flow, low-gradient AS with the strongest relationship observed for EOAI(proj) (r(s) = -0.50, p = 0.002 and r(s) = 0.61, p = 0.004, respectively). Compared with PSAS, TSAS had a trend to a higher resting MBF (0.90 (0.19) vs 0.77 (0.21) ml/min/g, p = 0.06), similar hyperaemic MBF (1.16 (0.31) vs 1.17 (0.32) ml/min/g, p = NS), but a significantly smaller MFR (1.19 (0.26) vs 1.76 (0.41), p = 0.003). An MFR <1.8 had an accuracy of 85% for distinguishing TSAS from PSAS. CONCLUSIONS: Low-flow, low-gradient AS is characterised by higher resting MBF and reduced MFR that relates to the AS severity. The degree of MFR impairment differs between TSAS and PSAS and may be of value for distinguishing these entities.

A hollow-bulb interim obturator for maxillary resection. A case report.

The treatment of hemimaxillectomy patients include the construction of an interim obturator in the wound healing period. With the aim of simplifying this process, we describe construction of an obturator in a short single visit, in the dental chair with no need for impressions or for laboratory services. The obturator comprises: (i) the surgical obturator and (ii) a hollow light-cured resin bulb built onto the base, and providing a large surface for bonding of the soft reline material. The advantages of this approach are rapid construction and ease of ongoing adjustment during the healing process.

Intracytoplasmic gene delivery for in vitro transfection with cytoskeleton-specific immunoliposomes.

A novel and highly efficient method of in vitro gene transfection has been developed. This method employs direct intracytoplasmic gene delivery into embryonic cardiocytes using neutral cytoskeletal-antigen specific immunoliposomes (CSIL). These immunoliposomes target cardiocytes specifically under reversible hypoxic conditions. Two independent reporter genes, pGL2 and pSV-beta-galactosidase, were used to verify CSIL-transfection (CSIL-fection). The efficiency of CSIL-fection with firefly luciferase pGL2 vector was 30+ times greater than controls consisting of hypoxic cardiocytes treated with plain liposomes (PL) or normoxic cardiocytes treated with CSIL, PL or naked DNA. CSIL-fection was also compared to cationic liposome transfection. Net cationic liposome transfection appeared to be more efficient than CSIL-fection for pGL2 vectors. However, a smaller number of viable cells was observed in the cationic liposome treated cultures than in the CSIL treated cultures. Therefore, to determine whether more cells were transfected with cationic liposomes or CSIL, pSV-beta-galactosidase vector was used. CSIL-fection with pSV-beta-galactosidase vector produced at least 40 times more transfected cells than those transfected with cationic liposomes. No transfection with pSV-beta-galactosidase vectors was obtained with IgG-liposome, PL or naked DNA treatments. Targeted enhanced efficiency of transfection by this novel method could have practical therapeutic applications in the genetic modification of cells ex vivo that could then be reimplanted into patients for gene therapy.

Characterization of r-[11C]rolipram for PET imaging of phosphodieterase-4: in vivo binding, metabolism, and dosimetry studies in rats.

The high-affinity phosphodiesterase-4 (PDE4) inhibitor R-rolipram and the less potent S-enantiomer, both labeled with (11)C, were evaluated in vivo in rats. Regional brain uptake of R-[(11)C]rolipram was higher than R/S-[(11)C]rolipram, whereas S-[(11)C]rolipram retention subsided rapidly to levels below blood. Binding of R-[(11)C]rolipram was selective for PDE4 over PDE1, since treatment with PDE4 competitors Ro 20-1724, or R-, S- or R/S-rolipram, but not with the PDE1 inhibitor vinpocetine, significantly reduced radioactivity uptake to non-specific levels. R-Rolipram (ED(50) congruent with 0.04 mg/Kg) was approximately 13 fold more potent than S-rolipram at inhibiting R-[(11)C]rolipram binding in all brain regions. Nevertheless, S-[(11)C]rolipram appears to be unsuitable for measuring the non-specific binding of R-[(11)C]rolipram. Only unchanged R-[(11)C]rolipram was detected in rat brain homogenates. Additionally, the estimated absorbed radiation dose extrapolated to humans was low. These results support further investigation of R-[(11)C]rolipram in studying PDE4 in vivo by positron emission tomography imaging.

Carbon-11 labelled cholecystokininB antagonists: radiosynthesis and evaluation in rats.

Three cholecystokinin type B (CCKB) receptor antagonists were labelled with 11C and evaluated ex vivo in rat biodistribution studies. The CCKB antagonists were YF 476 and two other compounds of the basic 3-ureido-1,4-benzodiazepine class. Following tail-vein administration of [11C]-YF 476 exceedingly low levels of radioactivity were found in all brain regions from 5 to 60 min post-injection. Similar results were obtained using the other two 11C-labelled CCKB antagonists. In light of the very poor brain penetration of these compounds, reports on the central nervous system activity of this class of CCKB antagonists should be viewed with caution.

An admonition when measuring the lipophilicity of radiotracers using counting techniques.

Log P measurements are a fundamental physico-chemical parameter and one of the cornerstones of structure activity relationships in medicinal chemistry. Despite the attractiveness of the method, the use of counting techniques to measure the log P of lipophilic radiotracers is fraught with pitfalls due to the amplifying effects of small quantities of radioactive impurities. For example, a radiotracer with a log P of 4 containing only 0.1% of a radioactive impurity with a log P of -1 will have an apparent log P of 3 if measured using conventional shake-flask partition techniques, counting the radioactivity in each phase. However, pre-washing the radiotracer-containing organic phase with aqueous phase can, in many cases, allay doubts about the validity of such measurements.

The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study.

OBJECTIVE: In the cortex of animals, serotonin (5-HT) levels increase after several weeks of treatment with selective serotonin reuptake inhibitors (SSRIs). Studies using an intrasubject design to examine the effects of SSRI treatment on 5-HT(2A) receptors in the cortex of drug-free depressed patients are needed. In theory, agonist stimulation of 5-HT(2A) receptors could be relevant to SSRI treatment by promoting neuronal growth and survival as well as direct elevation of mood. The objective of this study was to evaluate the effect of 6 weeks of paroxetine treatment on 5-HT(2A) receptors in depressed patients. METHOD: After a medication-free period of at least 3 months, 19 depressed patients were treated for 6 weeks with paroxetine, 20 mg/day. The authors used [(18)F]setoperone and positron emission tomography to assess 5-HT(2A) receptor binding potential in the patients before and after treatment and in 19 age-matched healthy subjects. RESULTS: 5-HT(2A) binding potential declined with age in all cortical regions in the depressed and healthy subjects. There was a significant interaction between age and treatment effect on 5-HT(2A) binding potential in all cortical regions. Subjects aged 20 to 30 years had a 10% decrease in 5-HT(2A) binding potential after treatment, whereas subjects aged 30 to 40 had no change. No regional differences in 5-HT(2A) binding potential between depressed and healthy subjects were found. CONCLUSIONS: 5-HT(2A) receptors down-regulate in young depressed subjects after treatment with paroxetine, but this down-regulation attenuates with age. This suggests that over 6 weeks paroxetine treatment increases 5-HT agonism on 5-HT(2A) receptors in the cortex of young patients with depression.

Imaging the 5-HT(1A) receptors with PET: WAY-100635 and analogues.

This paper summarizes our work on WAY-100635 and analogues, labeled either with carbon-11 or fluorine-18, as potential radioligands for the 5-hydroxytryptamine(1A) (5-HT(1A)) neuroreceptors. Other facets of our work include: (1) human studies with [O-methyl-(11)C]WAY-100634, the major radioactive metabolite of [O-methyl-(11)C]WAY-100635, and with [(11)C]CPC 222; (2) use of a human liver metabolism model to screen in vitro potential metabolic problems in humans; (3) modification of the "dry method" to prepare [carbonyl-(11)C]WAY-100635; and (4) validation studies in humans with [carbonyl-(11)C]WAY-100635.

Mannosylphosphodolichol synthase activity is associated with a 32 kDa phosphoprotein.

Failure of actinomycin D to block the activation of Dol-P-Man synthase in isoproterenol-treated capillary endothelial cells, supported that isoproterenol effect was not mediated by active transcription of the Dol-P-Man synthase gene during a short-term beta-adrenoreceptor stimulation. Instead, it was a net effect of protein phosphorylation by cAMP-dependent protein kinase. Using antibody as a probe we have now demonstrated that Dol-P-Man synthase activity is associated with a 32 kDa ER phosphoprotein.

Dopamine D1 agonist R-[11C]SKF 82957: synthesis and in vivo characterization in rats.

The active enantiomer R-SKF 82957 was labeled with 11C by N-[11C]methylation of the full dopamine (D1) agonist R-SKF 81297, using [11C]methyl iodide in the presence of N-ethyldiisopropylamine, in high specific activity, radiochemical purity and yields. Compared with the D1 agonist R/S-[11C]SKF 82957, R-[11C]SKF 82957 showed higher binding in the D1 rich regions, such as striatum and olfactory tubercles (approximately 1.7 times), thereby improving the tissue contrast. R-[11C]SKF 82957 exhibited high in vivo binding selectivity for D1 receptors in rats, because only high doses of D1 competitors, but not D2 or serotonin (5-HT2) blockers, significantly reduced the radioactivity levels in all brain areas. No labeled metabolites were detected in rat brain. These results indicate that R-[11C]SKF 82957 will provide more sensitive measurements of D1 receptors in in vivo studies than the racemic mixture.

Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging study.

OBJECTIVE: Widespread disturbances of serotonin (5-HT) are implicated in the pathophysiology of depression. Of 5-HT receptor abnormalities reported, the most replicated finding is increased 5-HT2 receptor binding in the postmortem prefrontal cortex of depressed suicide victims. The extent to which these findings exist in depressed persons without recent suicide attempts is uncertain. The objective of this study was to evaluate 5-HT2 receptors in depressed patients who were medication-free and who had not made recent suicide attempts. METHOD: With the use of [18F]setoperone and positron emission tomography (PET), 5-HT2 receptor binding potential was assessed in 14 depressed and 19 healthy subjects. Exclusion criteria for depressed patients included use of antidepressant medication within the past 6 months, a history of suicide attempts within the past 5 years, other current axis I disorders including bipolar disorder, and the presence of psychotic symptoms. The 5-HT2 (setoperone) binding potential in the two groups of subjects was compared by analysis of covariance with age as the covariate. RESULTS: Age had a significant effect on 5-HT2 binding potential, but depression did not. The interaction of age and depression was not significant. CONCLUSIONS: The 5-HT2 binding potential is not increased in untreated depressed subjects who have not made recent suicide attempts. This negative finding does not rule out the possibility that there is a role for 5-HT2 receptors in treatment or that 5-HT2 receptors are increased in highly suicidal states.