Positron emission tomography (PET) studies have revealed significant interindividual variation in dopamine D 2 receptor density in vivo in human striatum. 1 Low D 2 receptor binding in vivo has been found to associate with alcohol/substance dependence. [2][3][4][5][6] It has been suggested that the A1 allele of human D 2 receptor gene might be associated to a specific type of alcoholism 7 and possibly to a reduced D 2 receptor density in vitro. 8 We have determined D 2 dopamine receptor-binding density (B max ), affinity (K d ) and availability (B max /K d ) in 54 healthy Finnish volunteers using PET and [ 11 C]raclopride in order to determine whether the A1 allele is associated with a 'baseline' difference in D 2 receptor characteristics in vivo. A statistically significant reduction in D 2 receptor availability reflecting an alteration in receptor density was observed in the A1/A2 genotype group compared to the A2/A2 group. There was no difference in apparent K d between the two groups. In conclusion, the association between the A1 allele and low D 2 receptor availability in healthy subjects indicates that the A1 allele of the TaqIA polymorphism might be in linkage disequilibrium with a mutation in the promoter/regulatory gene element that affects dopamine D 2 receptor expression. This study provides an in vivo neurobiological correlate to the A1 allele in healthy volunteers.The dopaminergic system plays a major role in the regulation of movement, hormone secretion, mood and various motivational behaviors related to reward and reinforcement. While the contribution of the dopaminergic system has frequently been implicated in the etiology of alcohol/drug dependence, the mechanisms underlying this have remained unclear. It has been suggested that genetic factors might contribute individual differences in the regulation of D 2 receptor density and liability for predisposition to alcohol/drug dependence. This is supported by recent positron emission tomography (PET) studies which have consistently demonstrated that alcohol, 2,3 cocaine 4,5 and opiate 6 abusers have lower striatal D 2 receptor availability in vivo compared to healthy volunteers. The molecular basis of the possible hereditary factors in the dopaminergic system affecting predisposition to alcohol/drug dependence have remained unknown. The three nucleotide substitutions causing alteration in amino acid sequence found in the coding region of the D 2 dopamine receptor gene have been revealed to be relatively rare 9 and without clear effect on the D 2 receptor function in vivo. 10 While some regulatory sequences and promoter regions have been identified for human D 1 , 11 D 5 12 and rat D 2 13-15 receptors within the 5′ flanking region, little is known about the molecular events that regulate the transcription of the human D 2 receptor. From the several polymorphic gene markers, the A1 allele of TaqIA RFLP within the D 2 receptor gene suggests association with a specific type of alcoholism. 7 Despite numerous case-control studies, 16 the role of the A1 al...

Levosimendan has an energetically favorable short-term profile in the treatment of congestive heart failure. It enhances cardiac output without oxygen wasting, particularly by improving efficiency in the right ventricle.

Carbon-11 choline has recently been introduced as a potential tracer for tumour imaging with positron emission tomography (PET). We evaluated the kinetics of the uptake of [(11)C]choline in prostate cancer and benign prostatic hyperplasia. We also evaluated the association between the uptake of [(11)C]choline and the histological grade of malignancy, Gleason score, volume of the prostate and prostate-specific antigen (PSA). Fourteen patients with histologically confirmed prostate cancer and five patients with benign prostatic hyperplasia were studied with [(11)C]choline PET. A mean dose of 430+/-31 MBq of [(11)C]choline was injected intravenously and a dynamic emission acquisition of prostate was performed for 30 min. The uptake of [(11)C]choline was measured as a standardised uptake value (SUV) and as a kinetic influx constant ( K(i)) obtained from graphical analysis. Both cancerous and hyperplastic prostate were well visualised with [(11)C]choline against low or moderate tracer accumulation in the bladder and rectal wall. The measured radioactivity in urine was invariably low. In the graphical analysis, linear plots were achieved. The mean K(i) of the untreated tumour was 0.205+/-0.089 min(-1) (range 0.128-0.351; n=7) and the mean SUV was 5.6+/-3.2 (range 1.9-15.5; n=15). K(i) values and SUVs correlated closely ( r=0.964, P=0.0005), whereas no correlation could be demonstrated between the tumour uptake of [(11)C]choline and the histological grade, Gleason score, volume of the prostate or PSA. The mean SUV and the mean K(i) of benign hyperplastic prostate were 3.5+/-1.0 (range 2.0-4.5; n=4) and 0.119+/-0.076 min(-1) (range 0.065-0.173; n=2). In conclusion, a high uptake of [(11)C]choline characterises not only carcinomatous but also hyperplastic prostatic tissue. Dynamic imaging of the uptake of [(11)C]choline in the prostate shows a good applicability of the graphical analysis model with an irreversible compartment. A close correlation between the K(i) values and semiquantitative SUVs of tumours supports the use of the simpler SUV in the clinical setting.

Striatal D2 dopamine receptor characteristics of nine male patients with alcohol dependence abstinent for 1-68 weeks and eight healthy male volunteers were studied in vivo with positron emission tomography. The selective D2 receptor ligand [11C]raclopride and equilibrium model was used for D2 receptor density (Bmax) and affinity (Kd) measurements. A trend for a decreased striatal D2 receptor density and for reduced D2 receptor affinity was observed in patients with alcohol dependence. These parameters were not statistically significantly different between alcoholics and controls, but the ratio between D2 receptor density and affinity (Bmax/Kd or the striatum/cerebellum ratio from the high specific activity scan) was highly significantly lower in alcoholics than that of controls. In conclusion, the low D2 dopamine receptor Bmax/Kd ratio (striatum/cerebellum ratio) indicates that specific aspects of striatal [11C]raclopride binding in vivo are deviant in alcoholics compared to controls. The result is compatible with a reduced avidity of striatal dopamine D2 receptors in alcoholics, which is in line with the idea that D2 dopaminergic mechanisms are involved in the biology of alcohol dependence in man.

[methyl-11C]choline (11C-choline) is a radioligand potentially useful for oncological positron emission tomography (PET). As a first step towards the development of a kinetic model for quantification of 11C-choline uptake, blood metabolism of 11C-choline during PET imaging was studied in humans. High-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) were used for the analysis of 11C-choline and its radioactive metabolites. Prior to human PET imaging we studied ex vivo the biodistribution and metabolism of intravenously administered 11C-choline in rats. Our results revealed that the radioactivity accumulated particularly in kidney, lung, adrenal gland and liver. Chromatographic analysis showed that the level of unmetabolized 11C-choline in rat plasma decreased from 42% +/- 20% (mean +/- SD) at 5 min to 21% +/- 10% at 15 min after injection. In accordance with these findings, in humans the unmetabolized 11C-choline represents 62% +/- 19% of the total radioactivity in arterial plasma at 5 min after injection and 27% +/- 12% at 15 min. In human venous plasma the corresponding values were 85% +/- 12% and 48% +/- 12% at 5 and 10 min, respectively. The major metabolite observed in both human and rat plasma was identified as 11C-betaine. In human arterial plasma this maximally represented 82% +/- 9% of the total radioactivity at 25 min after radiotracer injection. By 20 min after injection, the 11C-choline and 11C-betaine in human arterial plasma reached a plateau, and their fractional activities remained nearly constant thereafter. Although most of the circulating 11C-choline in blood is transported to tissues, it does not disappear totally from blood within the first 40 min after tracer injection.