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The membrane-based purinergic 7 receptor (P2X7R) is expressed on activated microglia and the target of the radioligand [11C]SMW139 for in vivo assessment of neuroinflammation. This study investigated the contribution of radiolabelled metabolites which potentially affect its quantification. Ex vivo high-performance liquid chromatography with a radio detector (radioHPLC) was used to evaluate the parent and radiometabolite fractions of [11C]SMW139 in the brain and plasma of eleven mice. Twelve healthy humans underwent 90-min [11C]SMW139 brain PET with arterial blood sampling and radiometabolite analysis. The volume of distribution was estimated by using one- and two- tissue compartment (TCM) modeling with single (V T) and dual (V Tp) input functions. RadioHPLC showed three major groups of radiometabolite peaks with increasing concentrations in the plasma of all mice and humans. Two radiometabolite peaks were also visible in mice brain homogenates and therefore considered for dual input modeling in humans. 2TCM with single input function provided V T estimates with a wide range (0.10–10.74) and high coefficient of variation (COV: 159.9%), whereas dual input function model showed a narrow range of V Tp estimates (0.04–0.24; COV: 33.3%). In conclusion, compartment modeling with correction for brain-penetrant radiometabolites improves the in vivo quantification of [11C]SMW139 binding to P2X7R in the human brain. [ABSTRACT FROM AUTHOR]

Abstract Background Prostate tumours are commonly poorly oxygenated which is associated with tumour progression and development of resistance to chemotherapeutic drugs and radiotherapy. Fibroblast growth factor 8b (FGF8b) is a mitogenic and angiogenic factor, which is expressed at an increased level in human prostate tumours and is associated with a poor prognosis. We studied the effect of FGF8b on tumour oxygenation and growth parameters in xenografts in comparison with vascular endothelial growth factor (VEGF)-expressing xenografts, representing another fast growing and angiogenic tumour model. Methods Subcutaneous tumours of PC-3 cells transfected with FGF8b, VEGF or empty (mock) vectors were produced and studied for vascularity, cell proliferation, glucose metabolism and oxygenation. Tumours were evaluated by immunohistochemistry (IHC), flow cytometry, use of radiolabelled markers of energy metabolism ([18F]FDG) and hypoxia ([18F]EF5), and intratumoral polarographic measurements of pO2. Results Both FGF8b and VEGF tumours grew rapidly in nude mice and showed highly vascularised morphology. Perfusion studies, pO2 measurements, [18F]EF5 and [18F]FDG uptake as well as IHC staining for glucose transport protein (GLUT1) and hypoxia inducible factor (HIF) 1 showed that VEGF xenografts were well-perfused and oxygenised, as expected, whereas FGF8b tumours were as hypoxic as mock tumours. These results suggest that FGF8b-induced tumour capillaries are defective. Nevertheless, the growth rate of hypoxic FGF8b tumours was highly increased, as that of well-oxygenised VEGF tumours, when compared with hypoxic mock tumour controls. Conclusion FGF8b is able to induce fast growth in strongly hypoxic tumour microenvironment whereas VEGF-stimulated growth advantage is associated with improved perfusion and oxygenation of prostate tumour xenografts.

Cryptochrome 2 (Cry2) is a core clock gene important for circadian regulation. It has also been associated with anxiety and depressive‐like behaviors in mice, but the previous findings have been conflicting in terms of the direction of the effect. To begin to elucidate the molecular mechanisms of this association, we carried out behavioral testing, PET imaging, and gene expression analysis of Cry2−/− and Cry2+/+ mice. Compared to Cry2+/+ mice, we found that Cry2−/− mice spent less time immobile in the forced swim test, suggesting reduced despair‐like behavior. Moreover, Cry2−/− mice had lower saccharin preference, indicative of increased anhedonia. In contrast, we observed no group differences in anxiety‐like behavior. The behavioral changes were accompanied by lower metabolic activity of the ventro‐medial hypothalamus, suprachiasmatic nuclei, ventral tegmental area, anterior and medial striatum, substantia nigra, and habenula after cold stress as measured by PET imaging with a glucose analog. Although the expression of many depression‐associated and metabolic genes was upregulated or downregulated by cold stress, we observed no differences between Cry2−/− and Cry2+/+ mice. These findings are consistent with other studies showing that Cry2 is required for normal emotional behavior. Our findings confirm previous roles of Cry2 in behavior and extend them by showing that the effects on behavior may be mediated by changes in brain metabolism. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [11C]PBR28. Methods: [11C]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19–80 years; BMI range 17.6–36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (VT) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. Results: There were significant positive correlations between age and VT in the frontal and temporal cortex. BMI showed a significant negative correlation with VT in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher VT. A subgroup analysis revealed a positive correlation between VT and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. Conclusion: These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies. [ABSTRACT FROM AUTHOR]

Background: The relationship between myocardial metabolic changes and the severity of left ventricular (LV) hypertrophy in patients with hypertrophic cardiomyopathy (HCM) is largely unknown. We characterized metabolic abnormalities in patients with a genetically identical cause for HCM but with variable LV hypertrophy. Methods and Results: Eight patients with HCM attributable to the Asp175Asn mutation in the α-tropomyosin gene underwent myocardial perfusion, oxidative, and free fatty acid (FFA) metabolism measurements via positron emission tomography and oxygen 15–labeled water, carbon 11 acetate, and fluorine 14(R,S)-[18F] Fluoro-6-thia-heptadecanoic acid (18 FTHA). LV mass, work, and efficiency were assessed by echocardiography. Thirty-six healthy volunteers served as control subjects. Compared with control subjects, HCM patients had increased myocardial oxidative metabolism and FFA uptake (P < .05). However, in patients, LV mass was inversely related to global myocardial perfusion, oxidative metabolism, and FFA uptake (all P < .03), and regional wall thickness was inversely related to regional perfusion (P < .01), oxidative metabolism (P < .001), and FFA uptake (P < .01). Therefore patients with mild (LV mass less than median of 177 g) but not advanced LV hypertrophy were characterized by increased perfusion, oxidative metabolism, and LV efficiency as compared with control subjects (P < .05). Conclusions: In HCM attributable to the Asp175Asn mutation in the α-tropomyosin gene, myocardial oxidative metabolism and FFA metabolism are increased and inversely related to LV hypertrophy at both the whole heart and regional level. Increased metabolism and efficiency characterize patients with mild myocardial hypertrophy. These hypermetabolic alterations regress with advanced hypertrophy. [Copyright &y& Elsevier]