Publications by authors named "Tove J Grönroos"

34 Publications

Intravenous transplantation of olfactory ensheathing cells reduces neuroinflammation after spinal cord injury interleukin-1 receptor antagonist.

Theranostics 2021 1;11(3):1147-1161. Epub 2021 Jan 1.

Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.

Olfactory ensheathing cell (OEC) transplantation has emerged as a promising therapy for spinal cord injury (SCI) repair. In the present study, we explored the possible mechanisms of OECs transplantation underlying neuroinflammation modulation. Spinal cord inflammation after intravenous OEC transplantation was detected and by translocator protein PET tracer [F]F-DPA. To track transplanted cells, OECs were transduced with enhanced green fluorescent protein (eGFP) and HSV1-39tk using lentiviral vector and were monitored by fluorescence imaging and [F]FHBG study. Protein microarray analysis and ELISA studies were employed to analyze differential proteins in the injured spinal cord after OEC transplantation. The anti-inflammation function of the upregulated protein was also proved by gene knocking down experiments and OECs/microglia co-culture experiment. The inflammation in the spinal cord was decreased after OEC intravenous transplantation. The HSV1-39tk-eGFP-transduced OECs showed no accumulation in major organs and were found at the injury site. After OEC transplantation, in the spinal cord tissues, the interleukin-1 receptor antagonist (IL-1Ra) was highly upregulated while many chemokines, including pro-inflammatory chemokines IL-1α, IL-1β were downregulated. studies confirmed that lipopolysaccharide (LPS) stimulus triggered OECs to secrete IL-1Ra. OECs significantly suppressed LPS-stimulated microglial activity, whereas IL-1Ra gene knockdown significantly reduced their ability to modulate microglial activity. The OECs that reached the lesion site were activated by the release of pro-inflammatory cytokines from activated microglia in the lesion site and secreted IL-1Ra to reduce neuroinflammation. Intravenous transplantation of OECs has high therapeutic effectiveness for the treatment of SCI the secretion of IL-1Ra to reduce neuroinflammation.
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http://dx.doi.org/10.7150/thno.52197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738890PMC
January 2021

Evaluation of [F]F-DPA as a target for TSPO in head and neck cancer under normal conditions and after radiotherapy.

Eur J Nucl Med Mol Imaging 2020 Dec 19. Epub 2020 Dec 19.

Preclinical Imaging Laboratory, Turku PET Centre, University of Turku, Tykistökatu 6A, FI-20520, Turku, Finland.

Background: Many malignant tumours have increased TSPO expression, which has been related to a poor prognosis. TSPO-PET tracers have not comprehensively been evaluated in peripherally located tumours. This study aimed to evaluate whether N,N-diethyl-2-(2-(4-([F]fluoro)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ([F]F-DPA) can reflect radiotherapy (RT)-induced changes in TSPO activity in head and neck squamous cell carcinoma (HNSCC).

Methods: RT was used to induce inflammatory responses in HNSCC xenografts and cells. [F]F-DPA uptake was measured in vivo in non-irradiated and irradiated tumours, followed by ex vivo biodistribution, autoradiography, and radiometabolite analysis. In vitro studies were performed in parental and TSPO-silenced (TSPO siRNA) cells. TSPO protein and mRNA expression, as well as tumour-associated macrophages (TAMs), were also assessed.

Results: In vivo imaging and ex vivo measurement revealed significantly higher [F]F-DPA uptake in irradiated, compared to non-irradiated tumours. In vitro labelling studies with cells confirmed this finding, whereas no effect of RT on [F]F-DPA uptake was detected in TSPO siRNA cells. Radiometabolite analysis showed that the amount of unchanged [F]F-DPA in tumours was 95%, also after irradiation. PK11195 pre-treatment reduced the tumour-to-blood ratio of [F]F-DPA by 73% in xenografts and by 88% in cells. TSPO protein and mRNA levels increased after RT, but were highly variable. The proportion of M1/M2 TAMs decreased after RT, whereas the proportion of monocytes and migratory monocytes/macrophages increased.

Conclusions: [F]F-DPA can detect changes in TSPO expression levels after RT in HNSCC, which does not seem to reflect inflammation. Further studies are however needed to clarify the physiological mechanisms regulated by TSPO after RT.
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http://dx.doi.org/10.1007/s00259-020-05115-zDOI Listing
December 2020

Effects of Different Exercise Training Protocols on Gene Expression of Rac1 and PAK1 in Healthy Rat Fast- and Slow-Type Muscles.

Front Physiol 2020 19;11:584661. Epub 2020 Nov 19.

Turku PET Centre, Turku University Hospital, University of Turku, Turku, Finland.

Purpose: Rac1 and its downstream target PAK1 are novel regulators of insulin and exercise-induced glucose uptake in skeletal muscle. However, it is not yet understood how different training intensities affect the expression of these proteins. Therefore, we studied the effects of (HIIT) and (MICT) on Rac1 and PAK1 expression in fast-type (, GC) and slow-type (, SOL) muscles in rats after HIIT and MICT swimming exercises.

Methods: The mRNA expression was determined using qPCR and protein expression levels with reverse-phase protein microarray (RPPA).

Results: HIIT significantly mRNA expression in GC compared to MICT ( = 0.003) and to the control group (CON) ( = 0.001). At the protein level Rac1 was in GC in both training groups, but only the difference between HIIT and CON was significant ( = 0.02). HIIT caused significant of mRNA expression in GC compared to MICT ( = 0.007) and to CON ( = 0.001). At the protein level, HIIT increased PAK1 expression in GC compared to MICT and CON (by ∼17%), but the difference was not statistically significant ( = 0.3, = 0.2, respectively). There were no significant differences in the Rac1 or PAK1 expression in SOL between the groups.

Conclusion: Our results indicate that HIIT, but not MICT, Rac1 and PAK1 mRNA expression and the protein expression of especially Rac1 but only in fast-type muscle. These exercise training findings may reveal new therapeutic targets to treat patients with metabolic diseases.
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http://dx.doi.org/10.3389/fphys.2020.584661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711069PMC
November 2020

Evaluation of image quality with four positron emitters and three preclinical PET/CT systems.

EJNMMI Res 2020 Dec 10;10(1):155. Epub 2020 Dec 10.

Turku PET Centre, University of Turku, Turku, Finland.

Background: We investigated the image quality of C, Ga, F and Zr, which have different positron fractions, physical half-lifes and positron ranges. Three small animal positron emission tomography/computed tomography (PET/CT) systems were used in the evaluation, including the Siemens Inveon, RAYCAN X5 and Molecubes β-cube. The evaluation was performed on a single scanner level using the national electrical manufacturers association (NEMA) image quality phantom and analysis protocol. Acquisitions were performed with the standard NEMA protocol for F and using a radionuclide-specific acquisition time for C, Ga and Zr. Images were assessed using percent recovery coefficient (%RC), percentage standard deviation (%STD), image uniformity (%SD), spill-over ratio (SOR) and evaluation of image quantification.

Results: Ga had the lowest %RC (< 62%) across all systems. F had the highest maximum %RC (> 85%) and lowest %STD for the 5 mm rod across all systems. For C and Zr, the maximum %RC was close (> 76%) to the %RC with F. A larger SOR were measured in water with C and Ga compared to F on all systems. SOR in air reflected image reconstruction and data correction performance. Large variation in image quantification was observed, with maximal errors of 22.73% (Zr, Inveon), 17.54% (Zr, RAYCAN) and - 14.87% (Ga, Molecubes).

Conclusions: The systems performed most optimal in terms of NEMA image quality parameters when using F, where C and Zr performed slightly worse than F. The performance was least optimal when using Ga, due to large positron range. The large quantification differences prompt optimization not only by terms of image quality but also quantification. Further investigation should be performed to find an appropriate calibration and harmonization protocol and the evaluation should be conducted on a multi-scanner and multi-center level.
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http://dx.doi.org/10.1186/s13550-020-00724-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728905PMC
December 2020

[F]SPA-RQ/PET Study of NK1 receptors in the Whole Body of Guinea Pig and Rat.

Sci Rep 2019 12 31;9(1):20412. Epub 2019 Dec 31.

Turku PET Centre, University of Turku, Turku, Finland.

There is a substantial interest in the development of NK1 substance P antagonists as potential treatments for various neuropsychiatric and somatic disorders. The aim of this study was to determine whether [F]SPA-RQ can be utilized as a tool for studying the whole body distribution and function of NK1 receptors in preclinical settings. The compound was injected into guinea pigs with or without premedication with a NK1 receptor antagonist (NK1A-2). For comparison, we included two rats in the study, as the affinity of antagonists for NK1 receptors is known to vary between species. The whole body biodistribution of the tracer was determined at several time points. The tracer showed specific binding in organs compatible with the known location of NK1-receptors. Premedication with a NK1 antagonist led to an inhibited uptake of [F]SPA-RQ in several organs of guinea pigs, notably intestine, pancreas, urinary bladder, uterus, skin and lung. Specific binding was also seen in both cortex and striatum. In contrast, negligible specific binding was observed in the rat brain with [F]SPA-RQ, whereas the tracer uptake in peripheral tissues was similar to that seen in guinea pigs. We conclude that [F]SPA-RQ/PET is a useful tool to study the distribution and function of peripherally located NK1 receptors e.g. in different disease models.
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http://dx.doi.org/10.1038/s41598-019-56848-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938475PMC
December 2019

Preperitoneal Fat Grafting Inhibits the Formation of Intra-abdominal Adhesions in Mice.

J Gastrointest Surg 2020 Dec 10;24(12):2838-2848. Epub 2019 Dec 10.

Department of Plastic and General Surgery, Turku University Hospital, Turku, Finland.

Background: Adhesion formation contributes to postoperative complications in abdominal and gynaecological surgery. Thus far, the prevention and treatment strategies have focused on mechanical barriers in solid and liquid form, but these methods are not in routine use. As autologous fat grafting has become popular in treatment of hypertrophic scars because of its immunomodulatory effects, we postulated that fat grafting could also prevent peritoneal adhesion through similar mechanisms.

Methods: This was a control versus intervention study to evaluate the effect of fat grafting in the prevention on peritoneal adhesion formation. An experimental mouse model for moderate and extensive peritoneal adhesions was used (n = 4-6 mice/group). Adhesions were induced mechanically, and a free epididymal fat graft from wild type or CAG-DsRed mice was injected preperitoneally immediately after adhesion induction. PET/CT imaging and scaling of the adhesions were performed, and samples were taken for further analysis at 7 and 30 days postoperation. Macrophage phenotyping was further performed from peritoneal lavage samples, and the expression of inflammatory cytokines and mesothelial layer recovery were analysed from peritoneal tissue samples.

Results: Fat grafting significantly inhibited the formation of adhesions. PET/CT results did not show prolonged inflammation in any of the groups. While the expression of anti-inflammatory and anti-fibrotic IL-10 was significantly increased in the peritoneum of the fat graft-treated group at 7 days, tissue-resident and repairing M2 macrophages could no longer be detected in the fat graft at this time point. The percentage of the continuous, healed peritoneum as shown by Keratin 8 staining was greater in the fat graft-treated group after 7 days.

Conclusions: Fat grafting can inhibit the formation of peritoneal adhesions in mice. Our results suggest that fat grafting promotes the peritoneal healing process in a paracrine manner thereby enabling rapid regeneration of the peritoneal mesothelial cell layer.
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http://dx.doi.org/10.1007/s11605-019-04425-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674570PMC
December 2020

Dovitinib dilactic acid reduces tumor growth and tumor-induced bone changes in an experimental breast cancer bone growth model.

J Bone Oncol 2019 Jun 19;16:100232. Epub 2019 Mar 19.

University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland.

Advanced breast cancer has a high incidence of bone metastases. In bone, breast cancer cells induce osteolytic or mixed bone lesions by inducing an imbalance in bone formation and resorption. Activated fibroblast growth factor receptors (FGFRs) are important in regulation of tumor growth and bone remodeling. In this study we used FGFR1 and FGFR2 gene amplifications containing human MFM223 breast cancer cells in an experimental xenograft model of breast cancer bone growth using intratibial inoculation technique. This model mimics bone metastases in breast cancer patients. The effects of an FGFR inhibitor, dovitinib dilactic acid (TKI258) on tumor growth and tumor-induced bone changes were evaluated. Cancer-induced bone lesions were smaller in dovitinib-treated mice as evaluated by X-ray imaging. Peripheral quantitative computed tomography imaging showed higher total and cortical bone mineral content and cortical bone mineral density in dovitinib-treated mice, suggesting better preserved bone mass. CatWalk gait analysis indicated that dovitinib-treated mice experienced less cancer-induced bone pain in the tumor-bearing leg. A trend towards decreased tumor growth and metabolic activity was observed in dovitinib-treated mice quantified by positron emission tomography imaging with 2-[F]fluoro-2-deoxy-D-glucose at the endpoint. We conclude that dovitinib treatment decreased tumor burden, cancer-induced changes in bone, and bone pain. The results suggest that targeting FGFRs could be beneficial in breast cancer patients with bone metastases.
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http://dx.doi.org/10.1016/j.jbo.2019.100232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434100PMC
June 2019

Fat Grafting Can Induce Browning of White Adipose Tissue.

Plast Reconstr Surg Glob Open 2018 Jun 19;6(6):e1804. Epub 2018 Jun 19.

Department of Plastic and General Surgery, Turku University Hospital, Turku, Finland.

Background: Fat grafting is commonly used when treating soft-tissue defects. However, much of the basic biology behind fat transfer is still uncovered. Adipocytes can be divided into energy storing white and energy burning brown adipose cells. It is now well known, that also adult humans have metabolically active brown adipose tissue (BAT) within white adipose tissue (WAT). Previously our group showed that transfer of metabolically inactive WAT into a new environment increased the metabolic activity of the fat grafts to resemble the activity in the recipient site and that different WAT depots have variation in the metabolic activity. This led us to speculate, whether the metabolic increase of the graft is a result of "browning" of the transferred WAT toward beige adipose tissue.

Methods: We investigated the metabolic and histological characteristics and BAT marker gene expression in different types of WAT grafts placed either in subcutaneous or muscle tissue in mice. Metabolic activity of the grafts was investigated by FDG-PET/CT at 4- and 12-week time-points.

Results: The glucose uptake of all transferred fat types was increased when compared with respective control WAT regardless of transfer location. gene and protein expression was increased in 4 of 15 intramuscularly placed fat graft samples and showed histological resemblance to BAT with multilocular cells.

Conclusions: Grafting of metabolically inactive fat intramuscularly may induce browning of fat grafts toward more active beige adipose tissue. This opens up new research areas in exploiting fat grafting in metabolic diseases.
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http://dx.doi.org/10.1097/GOX.0000000000001804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157953PMC
June 2018

Molecular design of radiocopper-labelled Affibody molecules.

Sci Rep 2018 04 25;8(1):6542. Epub 2018 Apr 25.

Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.

The use of long-lived positron emitters Cu or Cu for labelling of Affibody molecules may improve breast cancer patients' stratification for HER-targeted therapy. Previous animal studies have shown that the use of triaza chelators for Cu labelling of synthetic Affibody molecules is suboptimal. In this study, we tested a hypothesis that the use of cross-bridged chelator, CB-TE2A, in combination with Gly-Glu-Glu-Glu spacer for labelling of Affibody molecules with radiocopper would improve imaging contrast. CB-TE2A was coupled to the N-terminus of synthetic Affibody molecules extended either with a glycine (designation CB-TE2A-G-ZHER2:342) or Gly-Glu-Glu-Glu spacer (CB-TE2A-GEEE-ZHER2:342). Biodistribution and targeting properties of Cu-CB-TE2A-G-ZHER2:342 and Cu-CB-TE2A-GEEE-ZHER2:342 were compared in tumor-bearing mice with the properties of Cu-NODAGA-ZHER2:S1, which had the best targeting properties in the previous study. Cu-CB-TE2A-GEEE-ZHER2:342 provided appreciably lower uptake in normal tissues and higher tumor-to-organ ratios than Cu-CB-TE2A-G-ZHER2:342 and Cu-NODAGA-ZHER2:S1. The most pronounced was a several-fold difference in the hepatic uptake. At the optimal time point, 6 h after injection, the tumor uptake of Cu-CB-TE2A-GEEE-ZHER2:342 was 16 ± 6%ID/g and tumor-to-blood ratio was 181 ± 52. In conclusion, a combination of the cross-bridged CB-TE2A chelator and Gly-Glu-Glu-Glu spacer is preferable for radiocopper labelling of Affibody molecules and, possibly, other scaffold proteins having high renal re-absorption.
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http://dx.doi.org/10.1038/s41598-018-24785-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916907PMC
April 2018

Comparative Evaluation of Anti-HER2 Affibody Molecules Labeled with Cu Using NOTA and NODAGA.

Contrast Media Mol Imaging 2017 28;2017:8565802. Epub 2017 Feb 28.

Division of Molecular Imaging, Department of Medicinal Chemistry, Uppsala University, 751 05 Uppsala, Sweden.

Imaging using affibody molecules enables discrimination between breast cancer metastases with high and low expression of HER2, making appropriate therapy selection possible. This study aimed to evaluate if the longer half-life of Cu ( = 12.7 h) would make Cu a superior nuclide compared to Ga for PET imaging of HER2 expression using affibody molecules. The synthetic ZHER2:S1 affibody molecule was conjugated with the chelators NOTA or NODAGA and labeled with Cu. The tumor-targeting properties of Cu-NOTA-ZHER2:S1 and Cu-NODAGA-ZHER2:S1 were evaluated and compared with the targeting properties of Ga-NODAGA-ZHER2:S1 in mice. Both Cu-NOTA-ZHER2:S1 and Cu-NODAGA-ZHER2:S1 demonstrated specific targeting of HER2-expressing xenografts. At 2 h after injection of Cu-NOTA-ZHER2:S1, Cu-NODAGA-ZHER2:S1, and Ga-NODAGA-ZHER2:S1, tumor uptakes did not differ significantly. Renal uptake of Cu-labeled conjugates was dramatically reduced at 6 and 24 h after injection. Notably, radioactivity uptake concomitantly increased in blood, lung, liver, spleen, and intestines, which resulted in decreased tumor-to-organ ratios compared to 2 h postinjection. Organ uptake was lower for Cu-NODAGA-ZHER2:S1. The most probable explanation for this biodistribution pattern was the release and redistribution of renal radiometabolites. In conclusion, monoamide derivatives of NOTA and NODAGA may be suboptimal chelators for radiocopper labeling of anti-HER2 affibody molecules and, possibly, other scaffold proteins with high renal uptake.
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http://dx.doi.org/10.1155/2017/8565802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612711PMC
August 2018

Repeatability of tumour hypoxia imaging using [F]EF5 PET/CT in head and neck cancer.

Eur J Nucl Med Mol Imaging 2018 Feb 26;45(2):161-169. Epub 2017 Oct 26.

Turku PET Centre, University of Turku, P.O. BOX 52, FI-20521, Turku, Finland.

Purpose: Hypoxia contributes to radiotherapy resistance and more aggressive behaviour of several types of cancer. This study was designed to evaluate the repeatability of intratumour uptake of the hypoxia tracer [F]EF5 in paired PET/CT scans.

Methods: Ten patients with newly diagnosed head and neck cancer (HNC) received three static PET/CT scans before chemoradiotherapy: two with [F]EF5 a median of 7 days apart and one with [F]FDG. Metabolically active primary tumour volumes were defined in [F]FDG images and transferred to co-registered [F]EF5 images for repeatability analysis. A tumour-to-muscle uptake ratio (TMR) of 1.5 at 3 h from injection of [F]EF5 was used as a threshold representing hypoxic tissue.

Results: In 10 paired [F]EF5 PET/CT image sets, SUVmean, SUVmax, and TMR showed a good correlation with the intraclass correlation coefficients of 0.81, 0.85, and 0.87, respectively. The relative coefficients of repeatability for these parameters were 15%, 17%, and 10%, respectively. Fractional hypoxic volumes of the tumours in the repeated scans had a high correlation using the Spearman rank correlation test (r = 0.94). In a voxel-by-voxel TMR analysis between the repeated scans, the mean of Pearson correlation coefficients of individual patients was 0.65. The mean (± SD) difference of TMR in the pooled data set was 0.03 ± 0.20.

Conclusion: Pretreatment [F]EF5 PET/CT within one week shows high repeatability and is feasible for the guiding of hypoxia-targeted treatment interventions in HNC.
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http://dx.doi.org/10.1007/s00259-017-3857-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745570PMC
February 2018

HPLC and TLC methods for analysis of [F]FDG and its metabolites from biological samples.

J Chromatogr B Analyt Technol Biomed Life Sci 2017 Mar 9;1048:140-149. Epub 2017 Feb 9.

Turku PET Centre, Preclinical Imaging, University of Turku, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland.

The most used positron emission tomography (PET) tracer, 2-[F]fluoro-2-deoxy-d-glucose ([F]FDG), is a glucose analogue that is used to measure tissue glucose consumption. Traditionally, the Sokoloff model is the basis for [F]FDG modeling. According to this model, [F]FDG is expected to be trapped in a cell in the form of [F]FDG-6-phosphate ([F]FDG-6-P). However, several studies have shown that in tissues, [F]FDG metabolism goes beyond [F]FDG-6-P. Our aim was to develop radioHPLC and radioTLC methods for analysis of [F]FDG metabolites from tissue samples. The radioHPLC method uses a sensitive on-line scintillation detector to detect radioactivity, and the radioTLC method employs digital autoradiography to detect the radioactivity distribution on a TLC plate. The HPLC and TLC methods were developed using enzymatically in vitro-produced metabolites of [F]FDG as reference standards. For this purpose, three [F]FDG metabolites were synthesized: [F]FDG-6-P, [F]FD-PGL, and [F]FDG-1,6-P2. The two methods were evaluated by analyzing the [F]FDG metabolic profile from rodent ex vivo tissue homogenates. The HPLC method with an on-line scintillation detector had a wide linearity in a range of 5Bq-5kBq (LOD 46Bq, LOQ 139Bq) and a good resolution (Rs ≥1.9), and separated [F]FDG and its metabolites clearly. The TLC method combined with digital autoradiography had a high sensitivity in a wide range of radioactivity (0.1Bq-2kBq, LOD 0.24Bq, LOQ 0.31Bq), and multiple samples could be analyzed simultaneously. As our test and the method validation with ex vivo samples showed, both methods are useful, and at best they complement each other in analysis of [F]FDG and its radioactive metabolites from biological samples.
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http://dx.doi.org/10.1016/j.jchromb.2017.01.042DOI Listing
March 2017

Two weeks of moderate-intensity continuous training, but not high-intensity interval training, increases insulin-stimulated intestinal glucose uptake.

J Appl Physiol (1985) 2017 May 9;122(5):1188-1197. Epub 2017 Feb 9.

Turku PET Centre, University of Turku, Turku, Finland;

Similar to muscles, the intestine is also insulin resistant in obese subjects and subjects with impaired glucose tolerance. Exercise training improves muscle insulin sensitivity, but its effects on intestinal metabolism are not known. We studied the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on intestinal glucose and free fatty acid uptake from circulation in humans. Twenty-eight healthy, middle-aged, sedentary men were randomized for 2 wk of HIIT or MICT. Intestinal insulin-stimulated glucose uptake and fasting free fatty acid uptake from circulation were measured using positron emission tomography and [F]FDG and [F]FTHA. In addition, effects of HIIT and MICT on intestinal GLUT2 and CD36 protein expression were studied in rats. Training improved aerobic capacity ( = 0.001) and whole body insulin sensitivity ( = 0.04), but not differently between HIIT and MICT. Insulin-stimulated glucose uptake increased only after the MICT in the colon (HIIT = 0%; MICT = 37%) ( = 0.02 for time × training) and tended to increase in the jejunum (HIIT = -4%; MICT = 13%) ( = 0.08 for time × training). Fasting free fatty acid uptake decreased in the duodenum in both groups (HIIT = -6%; MICT = -48%) ( = 0.001 time) and tended to decrease in the colon in the MICT group (HIIT = 0%; MICT = -38%) ( = 0.08 for time × training). In rats, both training groups had higher GLUT2 and CD36 expression compared with control animals. This study shows that already 2 wk of MICT enhances insulin-stimulated glucose uptake, while both training modes reduce fasting free fatty acid uptake in the intestine in healthy, middle-aged men, providing an additional mechanism by which exercise training can improve whole body metabolism. This is the first study where the effects of exercise training on the intestinal substrate uptake have been investigated using the most advanced techniques available. We also show the importance of exercise intensity in inducing these changes.
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http://dx.doi.org/10.1152/japplphysiol.00431.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451533PMC
May 2017

Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using 18F-GE-179 and 18F-GE-194 Autoradiography.

J Nucl Med 2016 09 19;57(9):1442-7. Epub 2016 May 19.

PET Preclinical Laboratory, Turku PET Centre, University of Turku, Turku, Finland Medicity Research Laboratory, University of Turku, Turku, Finland

Unlabelled: In vivo imaging of N-methyl-d-aspartate (NMDA) glutamate receptor and γ-aminobutyric acid (GABA)-A receptor during progression of brain pathology is challenging because of the lack of imaging tracers with high affinity and specificity.

Methods: We monitored changes in NMDA receptor and GABA-A receptor in a clinically relevant model of traumatic brain injury (TBI) induced by lateral fluid percussion in adult rats, using 2 new ligands for PET: (18)F-GE-179 for the open/active state of the NMDA receptor ion channel and (18)F-GE-194 for GABA-A receptor. Ex vivo brain autoradiography of radioligands was performed at subacute (5-6 d) and chronic (40-42 d) time points after TBI.

Results: At 5-6 d after TBI, (18)F-GE-179 binding was higher in the cortical lesion area, in the lesion core, and in the hippocampus than in the corresponding contralateral regions; this increase was probably related to increased permeability of the blood-brain barrier. At 40-42 d after TBI, (18)F-GE-179 binding was significantly higher in the medial cortex, in the corpus callosum, and in the thalamus than in the corresponding contralateral regions. Five to 6 days after TBI, (18)F-GE-194 binding was significantly higher in the lesion core and significantly lower in the ipsilateral thalamus. By 40-42 d after TBI, the reduction in (18)F-GE-194 binding extended to the cortical lesion, including the perilesional cortex around the lesion core. The reduction in thalamic binding was more extensive at 40-42 d than at 5-6 d after TBI, suggesting a progressive decrease in thalamic GABA-A receptor density. Immunohistochemistry against GABA-A α1 subunit revealed a similar decrease to (18)F-GE-194 binding, particularly during the chronic phase.

Conclusion: Our data support the validity of novel (18)F-GE-179 and (18)F-GE-194 radioligands for the detection of changes in active NMDA receptor and GABA-A receptor in the injured brain. These tools are useful for follow-up evaluation of secondary postinjury pathologies.
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http://dx.doi.org/10.2967/jnumed.115.167403DOI Listing
September 2016

Solid-Supported Porphyrins Useful for the Synthesis of Conjugates with Oligomeric Biomolecules.

Bioconjug Chem 2016 Apr 9;27(4):1023-9. Epub 2016 Mar 9.

Department of Chemistry, University of Turku , FI-20014 Turku, Finland.

meso-Tris(pyridin-4-yl)(4-carboxyphenyl)porphyrin and 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (Photochlor, HPPH) were amide-coupled to 1R,2S,3R,4R-2,3-dihydroxy-4-(hydromethyl)-1-aminocyclopentane and immobilized via an ester linkage to long chain alkyl amine-derivatized controlled pore glass (LCAA-CPG). The applicability of these supports (5 and 6) for the synthesis of porphyrin conjugates with oligomeric biomolecules was demonstrated using an automated phosphoramidite coupling chemistry. Cleavage from the support with concentrated ammonia gave the products, viz., porphyrin conjugates of oligonucleotides (7-9) and dendritic glycoclusters (10-13) and a cyclooctyne derivative (14) in 23-58% yield. In addition, the synthesized cyclooctyne derivative of meso-tris(pyridin-4-yl)(4-carboxyphenyl)porphyrin (14) was conjugated with an azidopropyl-modified hyaluronic acid (19). The hyaluronic acid-porphyrin conjugate (15) was radiolabeled with (64)Cu and its (15[(64)Cu]) receptor binding affinity to CD44-expressing tumor cells was evaluated.
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http://dx.doi.org/10.1021/acs.bioconjchem.6b00051DOI Listing
April 2016

PET of EGFR with (64) Cu-cetuximab-F(ab')2 in mice with head and neck squamous cell carcinoma xenografts.

Contrast Media Mol Imaging 2016 Jan-Feb;11(1):65-70. Epub 2015 Aug 4.

Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.

Overexpression of the epidermal growth factor receptor (EGFR) is linked to an adverse outcome in various solid tumors. Cetuximab is an EGFR inhibitor, which in combination with radiotherapy improves locoregional control and survival in a subgroup of patients with head and neck squamous cell carcinomas (HNSCCs). The aim of this study was to develop and characterize an EGFR-directed PET tracer, (64) Cu-cetuximab-F(ab')2, to determine the systemic accessibility of EGFR. Mice with HNSCC xenografts, UT-SCC-8 (n = 6) or UT-SCC-45 (n = 6), were imaged 24 h post injection with (64) Cu-NODAGA-cetuximab-F(ab')2 using PET/CT. One mouse for each tumor model was co-injected with excess unlabeled cetuximab 3 days before radiotracer injection to determine non-EGFR-mediated uptake. Ex vivo biodistribution of the tracer was determined and tumors were analyzed by autoradiography and immunohistochemistry. The SUVmax of UT-SCC-8 tumors was higher than that of UT-SCC-45: 1.5 ± 1.0 and 0.8 ± 0.2 (p < 0.05), respectively. SUVmax after in vivo blocking of EGFR with cetuximab was 0.4. Immunohistochemistry showed that UT-SCC-8 had a significantly higher EGFR expression than UT-SCC-45: 0.50 ± 0.19 versus 0.12 ± 0.08 (p < 0.005), respectively. Autoradiography indicated that (64) Cu-cetuximab-F(ab')2 uptake correlated with EGFR expression in both tumors: r = 0.86 ± 0.06 (UT-SCC-8) and 0.90 ± 0.06 (UT-SCC-45). (64) Cu-cetuximab-F(ab')2 is a promising PET tracer to determine expression of EGFR in vivo. Clinically, this tracer has the potential to be used to determine cetuximab targeting of tumors and possibly to non-invasively monitor the response to EGFR-inhibitor treatment.
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http://dx.doi.org/10.1002/cmmi.1659DOI Listing
October 2016

Hypoxia, blood flow and metabolism in squamous-cell carcinoma of the head and neck: correlations between multiple immunohistochemical parameters and PET.

BMC Cancer 2014 Nov 24;14:876. Epub 2014 Nov 24.

Turku PET Centre, Medicity Research Laboratory, University of Turku, Tykistökatu 6 A, FI-20520 Turku, Finland.

Background: The relationship between the uptake of [18F]fluoroerythronitroimidazole ([18F]FETNIM), blood flow ([15O]H2O) and 2-[18F]fluoro-2-deoxyglucose ([18F]FDG) and immunohistochemically determined biomarkers was evaluated in squamous-cell carcinomas of the head and neck (HNSCC).

Methods: [18F]FETNIM and [18F]FDG PET were performed on separate days on 15 untreated patients with HNSCC. Hypoxia imaging with [18F]FETNIM was coupled with measurement of tumor blood flow using [15O]H2O. Uptake of [18F]FETNIM was measured as tumor-to-plasma ratio (T/P) and fractional hypoxic volume (FHV), and that of [18F]FDG as standardized uptake value (SUV) and the metabolically active tumor volume (TV). Tumor biopsies were cut and stained for GLUT-1, Ki-67, p53, CD68, HIF-1α, VEGFsc-152, CD31 and apoptosis. The expression of biomarkers was correlated to PET findings and patient outcome.

Results: None of the PET parameters depicting hypoxia and metabolism correlated with the expression of the biomarkers on a continuous scale. When PET parameters were divided into two groups according to median values, a significant association was detected between [18F]FDG SUV and p53 expression (p =0.029) using median SUV as the cut-off. There was a significant association between tumor volume and the amount of apoptotic cells (p =0.029). The intensity of VEGF stained cells was associated with [18F]FDG SUV (p =0.036). Patient outcome was associated with tumor macrophage content (p =0.050), but not with the other biomarkers. HIF-1α correlated with GLUT-1 (rs =0.553, p =0.040) and Ki-67 with HIF-1α (rs =506, p =0.065). p53 correlated inversely with GLUT-1 (rs = -618, p =0.019) and apoptosis with Ki-67 (rs = -638, p =0.014).

Conclusions: A high uptake of [18F]FDG expressed as SUV is linked to an aggressive HNSCC phenotype: the rate of apoptosis is low and the expressions of p53 and VEGF are high. None of the studied biomarkers correlated with perfusion and hypoxia as evaluated with [15O]H2O-PET and [18F]FETNIM-PET. Increased tumor metabolism evaluated with PET may thus signify an aggressive phenotype, which should be taken into account in the management of HNSCC.
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http://dx.doi.org/10.1186/1471-2407-14-876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251851PMC
November 2014

In vivo imaging of reactive oxygen and nitrogen species in murine colitis.

Inflamm Bowel Dis 2014 Aug;20(8):1435-47

*Department of Biosciences, Cell Biology, Åbo Akademi University, Biocity, Turku, Finland; †Department of Medical Microbiology and Immunology, and ‡Turku PET Center, Medicity Research Laboratory, University of Turku, Turku, Finland; §Medical Inflammation Research, MBB, Karolinska Institutet, Stockholm, Sweden; ‖Medicity Research Laboratory, University of Turku, Turku, Finland; and ¶Turku Center for Disease modeling, Turku, Finland.

Background: Traditional techniques analyzing mouse colitis are invasive, laborious, or indirect. Development of in vivo imaging techniques for specific colitis processes would be useful for monitoring disease progression and/or treatment effectiveness. The aim was to evaluate the applicability of the chemiluminescent probe L-012, which detects reactive oxygen and nitrogen species, for in vivo colitis imaging.

Methods: Two genetic colitis mouse models were used; K8 knockout (K8(-/-)) mice, which develop early colitis and the nonobese diabetic mice, which develop a transient subclinical colitis. Dextran sulphate sodium was used as a chemical colitis model. Mice were anesthetized, injected intraperitoneally with L-012, imaged, and quantified for chemiluminescent signal in the abdominal region using an IVIS camera system.

Results: K8(-/-) and nonobese diabetic mice showed increased L-012-mediated chemiluminescence from the abdominal region compared with control mice. L-012 signals correlated with the colitis phenotype assessed by histology and myeloperoxidase staining. Although L-012 chemiluminescence enabled detection of dextran sulphate sodium-induced colitis at an earlier time point compared with traditional methods, large mouse-to-mouse variations were noted. In situ and ex vivo L-012 imaging as well as [18F]FDG-PET imaging of K8(-/-) mice confirmed that the in vivo signals originated from the distal colon. L-012 in vivo imaging showed a wide variation in reactive oxygen and nitrogen species in young mice, irrespective of K8 genotype. In aging mice L-012 signals were consistently higher in K8(-/-) as compared to K8(+/+) mice.

Conclusions: In vivo imaging using L-012 is a useful, simple, and cost-effective tool to study the level and longitudinal progression of genetic and possibly chemical murine colitis.
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http://dx.doi.org/10.1097/MIB.0000000000000118DOI Listing
August 2014

Uptake of [F]EF5 as a Tracer for Hypoxic and Aggressive Phenotype in Experimental Head and Neck Squamous Cell Carcinoma.

Transl Oncol 2014 May 23. Epub 2014 May 23.

MediCity Research Laboratory, Turku PET Centre, University of Turku, Turku, Finland; Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland. Electronic address:

Purpose: This study aims to investigate whether the uptake of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide ([F]EF5) and 2-deoxy-2-[F]fluoro-d-glucose ([F]FDG) is associated with a hypoxia-driven adverse phenotype in head and neck squamous cell carcinoma cell lines and tumor xenografts.

Methods: Xenografts were imaged in vivo, and tumor sections were stained for hypoxia-inducible factor 1α (Hif-1α), carbonic anhydrase IX (CA IX), and glucose transporter 1 (Glut-1). Tracer uptakes and the expression of Hif-1α were determined in cell lines under 1% hypoxia.

Results: High [F]EF5 uptake was seen in xenografts expressing high levels of CA IX, Glut-1, and Hif-1α, whereas low [F]EF5 uptake was detected in xenografts expressing low amounts of CA IX and Hif-1α. The uptake of [F]EF5 between cell lines varied extensively under normoxic conditions. A clear correlation was found between the expression of Hif-1α and the uptake of [F]FDG during hypoxia.

Conclusions: The UT-SCC cell lines studied differed with respect to their hypoxic phenotypes, and these variations were detectable with [F]EF5. Acute hypoxia increases [F]FDG uptake in vitro, whereas a high [F]EF5 uptake reflects a more complex phenotype associated with hypoxia and an aggressive growth pattern.
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http://dx.doi.org/10.1016/j.tranon.2014.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4145394PMC
May 2014

Evaluation of repeated [(18)F]EF5 PET/CT scans and tumor growth rate in experimental head and neck carcinomas.

EJNMMI Res 2014 16;4:65. Epub 2014 Dec 16.

Turku PET Centre, Medicity Research Laboratory, University of Turku, Tykistökatu 6A, Turku, FI-20520, Finland ; Department of Oncology and Radiotherapy, Turku University Hospital, Turku, FI-20521, Finland.

Background: Tumor hypoxia is linked to invasion and metastasis but whether this associates with tumor growth rate is not well understood. We aimed to study the relationship between hypoxia evaluated with the positron emission tomography (PET) tracer [(18)F]EF5 and tumor growth. Our second goal was to assess the variability in the uptake of [(18)F]EF5 in tumor between two scans.

Methods: Four human head and neck squamous cell carcinoma (UT-SCC) cell lines were xenografted in flank or neck of nude mice, and tumor size was closely monitored over the study period. The tumors were clearly visible when the first [(18)F]EF5 scan was acquired. After an exponential growth phase, the tumors were imaged again with [(18)F]EF5 and also with (18)F-fluorodeoxyglucose ([(18)F]FDG).

Results: There was a clear correlation between the percentage of tumor growth rate per day and the [(18)F]EF5 uptake in the latter scan (r = 0.766, p = 0.01). The uptake of [(18)F]EF5 in the first scan and the uptake of [(18)F]FDG did not significantly correlate with the tumor growth rate. We also observed considerable variations in the uptake of [(18)F]EF5 between the two scans.

Conclusions: The uptake of [(18)F]EF5 in the late phase of exponential tumor growth is associated with the tumor growth rate in mice bearing HNC xenografts.
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http://dx.doi.org/10.1186/s13550-014-0065-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412195PMC
May 2015

FDG-PET in healthy and epileptic Lagotto Romagnolo dogs and changes in brain glucose uptake with age.

Vet Radiol Ultrasound 2014 May-Jun;55(3):331-41. Epub 2013 Dec 20.

Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.

Regional cerebral metabolism and blood flow can be measured noninvasively with positron emission tomography (PET). 2-[(18) F]fluoro-2-deoxy-D-glucose (FDG) widely serves as a PET tracer in human patients with epilepsy to identify the seizure focus. The goal of this prospective study was to determine whether juvenile or adult dogs with focal-onset epilepsy exhibit abnormal cerebral glucose uptake interictally and whether glucose uptake changes with age. We used FDG-PET to examine six Lagotto Romagnolo dogs with juvenile epilepsy, two dogs with adult-onset epilepsy, and five control dogs of the same breed at different ages. Three researchers unaware of dog clinical status visually analyzed co-registered PET and magnetic resonance imaging (MRI) images. Results of the visual PET analyses were compared with electroencephalography (EEG) results. In semiquantitative analysis, relative standard uptake values (SUV) of regions of interest (ROI) drawn to different brain regions were compared between epileptic and control dogs. Visual analysis revealed areas of hypometabolism interictally in five out of six dogs with juvenile epilepsy in the occipital, temporal, and parietal cortex. Changes in EEG occurred in three of these dogs in the same areas where PET showed cortical hypometabolism. Visual analysis showed no abnormalities in cerebral glucose uptake in dogs with adult-onset epilepsy. Semiquantitative analysis detected no differences between epileptic and control dogs. This result emphasizes the importance of visual analysis in FDG-PET studies of epileptic dogs. A change in glucose uptake was also detected with age. Glucose uptake values increased between dog ages of 8 and 28 weeks and then remained constant.
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http://dx.doi.org/10.1111/vru.12129DOI Listing
January 2015

6-[18F]fluoro-L-DOPA uptake in the rat pancreas is dependent on the tracer metabolism.

Mol Imaging Biol 2014 Jun 12;16(3):403-11. Epub 2013 Nov 12.

Department of Pediatrics, Central Hospital of Seinäjoki, Hanneksenrinne 7, 60220, Seinäjoki, Finland,

Purpose: 6-[(18)F]fluoro-L-3,4-dihydroxyphenyl alanine ([(18)F]FDOPA) positron emission tomography (PET) is a diagnostic tool which can detect malignancies of the pancreas. We aimed to study whether the manipulation of the [(18)F]FDOPA metabolic pathway would change the (18)F-behavior to provide a biochemical foundation for PET imaging of rat pancreas with [(18)F]FDOPA.

Procedures: Inhibitors of aromatic amino acid decarboxylase, catechol-O-methyltransferase, monoamine oxidases A and B, or their combinations on [(18)F]FDOPA uptake, metabolism, and the regional distribution in the rat pancreas was evaluated using in vivo PET/computed tomography imaging, chromatographic metabolite analyses, and autoradiography.

Results: Enzyme inhibition generally increased the uptake of [(18)F]FDOPA derived (18)F-radioactivity in rat pancreas. Dependent on which enzymatic pathway is blocked (or a combination of pathways), different radiolabeled metabolites in pancreas are responsible for this increase in uptake.

Conclusions: Altering the metabolism of [(18)F]FDOPA by using various enzymatic inhibitors increased the radioactivity uptake and changed the radiometabolic profile in the pancreas allowing better discrimination between pancreas and surrounding tissues of rat. However, these manipulations did not separate islets from the exocrine pancreas. Elucidating the metabolic behavior of [(18)F]FDOPA provides a biochemical foundation of PET imaging of the rat pancreas.
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http://dx.doi.org/10.1007/s11307-013-0701-4DOI Listing
June 2014

Analysis of fat graft metabolic adaptation and vascularization using positron emission tomography-computed tomographic imaging.

Plast Reconstr Surg 2014 Feb;133(2):291-299

Turku, Kuopio, and Helsinki, Finland From the Departments of Plastic and General Surgery and Pathology, Turku University Central Hospital; Turku PET Centre, University of Turku; the Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio; and the Cleft Unit, Department of Plastic Surgery, Helsinki University Hospital.

Background: Fat tissue transfer is commonly used for different soft-tissue defects in surgery. The immediate result of these operations is often good, but the long-term result is unfortunately unpredictable. The authors used an experimental model to evaluate the vascularization, survival, and metabolic changes after free fat transfer and the impact of proangiogenic therapy on these processes.

Methods: Fat was collected from the mouse epididymal region and placed into the subcutaneous tissue of the forehead. Fat grafts were treated with proangiogenic vascular endothelial growth factor (VEGF)-A (n = 9) or the control vector (n = 9). Metabolic activity and fat graft volume were investigated by positron emission tomography-computed tomography at 4 weeks and at 12 weeks. Histologic analysis was performed at 12 weeks.

Results: The glucose metabolism (fluorodeoxyglucose uptake) of the transferred epididymal fat was higher than in the epididymal fat before transplantation in both study groups (VEGF-A and control) and resembled that of normal subcutaneous fat. VEGF-A therapy enhanced the survival and capillary density of the transferred fat after surgery.

Conclusions: Transfer of the metabolically inactive (epididymal) fat into a new environment modulated the metabolic activity of the fat grafts to resemble the situation in the recipient site. These novel findings support the clinical use of free fat grafts in various anatomical regions and tissue types. Proangiogenic VEGF-A therapy enhanced the vascularization and survival of the free fat grafts.
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http://dx.doi.org/10.1097/01.prs.0000436839.62128.3bDOI Listing
February 2014

In vivo imaging of prostate cancer using [68Ga]-labeled bombesin analog BAY86-7548.

Clin Cancer Res 2013 Oct 9;19(19):5434-43. Epub 2013 Aug 9.

Authors' Affiliations: Department of Surgery, Division of Urology, Departments of Clinical Physiology and Nuclear Medicine, Oncology and Radiotherapy, and Pathology, Turku University Hospital; Turku PET Centre; Department of Diagnostic Radiology, University of Turku, Turku, Finland; Departments of Medical Oncology and Nuclear Medicine, University Hospital of Zurich; Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland; Bayer Pharma AG, Berlin, Germany.

Purpose: A novel [(68)Ga]-labeled DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 peptide (BAY86-7548) having high affinity to bombesin receptor subtype II to detect primary and metastatic prostate carcinoma using positron emission tomography/computed tomography (PET/CT) was synthesized and evaluated for prostate cancer.

Experimental Design: In this first human study with BAY86-7548, 14 men scheduled for radical prostatectomy (n = 11) or with biochemical recurrence after surgery or hormonal therapy (n = 3) were enrolled. The patients received an intravenous injection of BAY86-7548 followed by over 60-minute dynamic imaging of prostate gland (n = 10) and/or subsequent whole-body imaging (n = 14). The visual assessment of PET/CT images included evaluation of intraprostatic (12 subsextants) and pelvic nodal uptake of BAY86-7548 in 11 surgical patients and detection of potential metastatic foci in all patients. In patients with biochemical recurrence, results were compared with those of either [(11)C]-acetate (n = 2) or [(18)F]-fluoromethylcholine (n = 1) PET/CT.

Results: We found a sensitivity, specificity, and accuracy of 88%, 81% and 83%, respectively, for detection of primary PCa and sensitivity of 70% for metastatic lymph nodes using histology as gold standard. BAY86-7548 correctly detected local recurrence in prostate bed and showed nodal relapse in accordance with [(11)C]-acetate PET/CT in 2 patients with biochemical relapse. In the third hormone refractory patient, BAY86-7548 failed to show multiple bone metastases evident on [(18)F]-fluoromethylcholine PET/CT.

Conclusion: BAY86-7548 PET/CT is a promising molecular imaging technique for detecting intraprostatic prostate cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-3490DOI Listing
October 2013

Measurement of brown adipose tissue mass using a novel dual-echo magnetic resonance imaging approach: a validation study.

Metabolism 2013 Aug 13;62(8):1189-98. Epub 2013 Apr 13.

Medical Imaging Centre of Southwest Finland, Turku University Hospital, Turku, Finland.

Objective: The aim of this study was to evaluate and validate magnetic resonance imaging (MRI) for the visualization and quantification of brown adipose tissue (BAT) in vivo in a rat model. We hypothesized that, based on differences in tissue water and lipid content, MRI could reliably differentiate between BAT and white adipose tissue (WAT) and could therefore be a possible alternative for (18)F-Fluorodeoxyglucose Positron Emission Tomography ((18)FDG-PET), the current gold standard for non-invasive BAT quantification.

Materials/methods: Eleven rats were studied using both (18)FDG-PET/CT and MRI (1.5 T). A dual echo (in-and-out-of-phase) sequence was used, both with and without spectral presaturation inversion recovery (SPIR) fat suppression (DUAL-SPIR) to visualize BAT, after which all BAT was surgically excised. The BAT volume measurements obtained via (18)FDG-PET/CT and DUAL-SPIR MR were quantitatively compared with the histological findings. All study protocols were reviewed and approved by the local ethics committee.

Results: The BAT mass measurements that were obtained using DUAL-SPIR MR subtraction images correlated better with the histological findings (P=0.017, R=0.89) than did the measurements obtained using (18)FDG-PET/CT (P=0.78, R=0.15), regardless of the BAT metabolic activation state. Additionally, the basic feasibility of the DUAL-SPIR method was demonstrated in three human pilot subjects.

Conclusions: This study demonstrates the potential for MRI to reliably detect and quantify BAT in vivo. MRI can provide information beyond that provided by (18)FDG-PET imaging, and its ability to detect BAT is independent of its metabolic activation state. Additionally, MRI is a low-cost alternative that does not require radiation.
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http://dx.doi.org/10.1016/j.metabol.2013.03.002DOI Listing
August 2013

Enzyme inhibition of dopamine metabolism alters 6-[18F]FDOPA uptake in orthotopic pancreatic adenocarcinoma.

EJNMMI Res 2013 Mar 14;3(1):18. Epub 2013 Mar 14.

MediCity/PET Preclinical Imaging, Turku PET Centre, University of Turku, Turku, 20520, Finland.

Background: An unknown location hampers removal of pancreatic tumours. We studied the effects of enzyme inhibitors on the uptake of 6-[18F]fluoro-l-3,4-dihydroxyphenylalanine ([18F]FDOPA) in the pancreas, aiming at improved imaging of pancreatic adenocarcinoma.

Methods: Mice bearing orthotopic BxPC3 pancreatic adenocarcinoma were injected with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) and scanned with positron emission tomography/computed tomography (PET/CT). For [18F]FDOPA studies, tumour-bearing mice and sham-operated controls were pretreated with enzyme inhibitors of aromatic amino acid decarboxylase (AADC), catechol-O-methyl transferase (COMT), monoamine oxidase A (MAO-A) or a combination of COMT and MAO-A. Mice were injected with [18F]FDOPA and scanned with PET/CT. The absolute [18F]FDOPA uptake was determined from selected tissues using a gamma counter. The intratumoural biodistribution of [18F]FDOPA was recorded by autoradiography. The main [18F]FDOPA metabolites present in the pancreata were determined with radio-high-performance liquid chromatography.

Results: [18F]FDG uptake was high in pancreatic tumours, while [18F]FDOPA uptake was highest in the healthy pancreas and significantly lower in tumours. [18F]FDOPA uptake in the pancreas was lowest with vehicle pretreatment and highest with pretreatment with the inhibitor of AADC. When mice received COMT + MAO-A inhibitors, the uptake was high in the healthy pancreas but low in the tumour-bearing pancreas.

Conclusions: Combined use of [18F]FDG and [18F]FDOPA is suitable for imaging pancreatic tumours. Unequal pancreatic uptake after the employed enzyme inhibitors is due to the blockade of metabolism and therefore increased availability of [18F]FDOPA metabolites, in which uptake differs from that of [18F]FDOPA. Pretreatment with COMT + MAO-A inhibitors improved the differentiation of pancreas from the surrounding tissue and healthy pancreas from tumour. Similar advantage was not achieved using AADC enzyme inhibitor, carbidopa.
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http://dx.doi.org/10.1186/2191-219X-3-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618317PMC
March 2013

Radiation dosimetry and biodistribution of the hypoxia tracer (18)F-EF5 in oncologic patients.

Cancer Biother Radiopharm 2012 Sep 16;27(7):412-9. Epub 2012 Aug 16.

Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Unlabelled: The primary goals of this study were to determine the biodistribution and excretion of (18)F-EF5 in oncologic patients, to estimate the radiation-absorbed dose and to determine the safety of this drug.

Methods: Sixteen patients with histologically confirmed malignancy received a mean intravenous infusion of 217  MBq (range 107-364  MBq) of (18)F-EF5. Over a 4-6-hour period, four to five serial positron emission tomography (PET) or PET/computed tomography (CT) scans were obtained. To calculate the radiation dosimetry estimates, volumes of interest were drawn over the source organs for each PET scan or on the CT for each PET/CT scan. Serial blood samples were obtained to measure (18)F-EF5 blood clearance. Bladder-wall dose was calculated based on urine activity measurements.

Results: The urinary bladder received the largest radiation-absorbed dose, 0.12 ± 0.034 mSv/MBq (mean ± SD). The average effective dose equivalent and the effective dose of (18)F-EF5 were 0.021 ± 0.003 mSv/MBq and 0.018 ± 0.002 mSv/MBq, respectively. (18)F-EF5 was well tolerated in all subjects.

Conclusions: (18)F-EF5 was demonstrated to be safe for patients, and the radiation exposure is clinically acceptable. As with any radiotracer with primary excretion in the urine, the bladder-wall dose can be minimized by active hydration and frequent voiding.
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http://dx.doi.org/10.1089/cbr.2011.1130DOI Listing
September 2012

Electrophilic addition of chlorine monofluoride for PET tracers.

Mol Imaging Biol 2013 Apr;15(2):131-5

Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Turku, Finland.

Purpose: We have studied the utility of [(18)F]ClF electrophilic addition to the carbon-carbon double bond of analogues of a model positron emission tomography (PET) tracer, [(18)F]EF5. The consequence of simultaneous chlorine/fluorine addition on lipophilicity and biological activity of the molecule is evaluated.

Procedures: Post-target produced [(18)F]F2 was reacted with Cl2 to produce [(18)F]ClF, which was used in electrophilic addition.

Results: [(18)F]ClF was produced and used to label chlorinated analogues of [(18)F]EF5. The chlorinated analogues, [(18)F]EF4Cla and [(18)F]EF4Clb, were synthesized simultaneously. The in vivo uptake of the analogues compared well with [(18)F]EF5 uptake in tumor-bearing mice.

Conclusion: [(18)F]ClF is a suitable labeling reagent for electrophilic addition to double bonds of PET tracers. The results show that the modification of the pentafluoro group of [(18)F]EF5 by monofluorine-for-chlorine exchange affected the lipophilicity, but the hypoxia avidity of these molecules was not apparently altered.
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http://dx.doi.org/10.1007/s11307-012-0584-9DOI Listing
April 2013

Novel electrophilic synthesis of 6-[¹⁸F]fluorodopamine and comprehensive biological evaluation.

Eur J Nucl Med Mol Imaging 2012 May 10;39(5):800-10. Epub 2012 Jan 10.

Turku PET Centre, University of Turku, Radiopharmaceutical Chemistry Laboratory, Kiinamyllynkatu 4-8, 20520, Turku, Finland.

Purpose: 6-[(18)F]Fluorodopamine (4-(2-aminoethyl)-5-[(18)F]fluorobenzene-1,2-diol, 6-[(18)F]FDA) is a tracer for imaging sympathetically innervated tissues. Previous electrophilic labelling methods produced 6-[(18)F]FDA with low specific radioactivity (SA) which has limited its wider use. Our aim was to employ electrophilic labelling and increase the SA to around 15 GBq/μmol. We also sought to determine an extensive biodistribution pattern for 6-[(18)F]FDA in rats in order to thoroughly identify tissues with dense sympathetic innervation that were specifically labelled with 6-[(18)F]FDA. In addition, to investigate the safety profile of 6-[(18)F]FDA in larger animals, we performed in vivo studies in pigs.

Methods: 6-[(18)F]FDA was synthesised using high SA electrophilic [(18)F]F(2) as the labelling reagent. Biodistribution and metabolism of 6-[(18)F]FDA was determined ex vivo in rats, and in vivo studies were done in pigs.

Results: 6-[(18)F]FDA was synthesised with 2.6 ± 1.1% radiochemical yield. The total amount of purified 6-[(18)F]FDA was 663 ± 291 MBq at the end of synthesis (EOS). SA, decay corrected to EOS, was 13.2 ± 2.7 GBq/μmol. Radiochemical purity exceeded 99.0%. Specific uptake of 6-[(18)F]FDA was demonstrated in heart, lung, pancreas, adrenal gland, lower large intestine (LLI), eye, thyroid gland, spleen and stomach tissue. 6-[(18)F]FDA in rat plasma declined rapidly, with a half-life of 2 min, indicating fast metabolism. In vivo PET studies in pigs confirmed the tracer could be used safely without pharmacological effects.

Conclusion: 6-[(18)F]FDA was synthesised with good radiopharmaceutical quality and yields high enough for several human PET studies. The SA of 6-[(18)F]FDA was improved by 50- to 500-fold compared to previous electrophilic methods. Uptake of 6-[(18)F]FDA was specific in various peripheral organs, indicating that 6-[(18)F]FDA PET can be used to investigate sympathoneural functions beyond cardiac studies when higher specific uptake is achieved.
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http://dx.doi.org/10.1007/s00259-011-2032-5DOI Listing
May 2012

Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms.

Proc Natl Acad Sci U S A 2011 Nov 7;108(46):18814-9. Epub 2011 Nov 7.

Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20521 Turku, Finland.

A switch from oxidative phosphorylation to glycolysis is frequently observed in cancer cells and is linked to tumor growth and invasion, but the underpinning molecular mechanisms controlling the switch are poorly understood. In this report we show that Notch signaling is a key regulator of cellular metabolism. Both hyper- and hypoactivated Notch induce a glycolytic phenotype in breast tumor cells, although by distinct mechanisms: hyperactivated Notch signaling leads to increased glycolysis through activation of the phosphatidylinositol 3-kinase/AKT serine/threonine kinase pathway, whereas hypoactivated Notch signaling attenuates mitochondrial activity and induces glycolysis in a p53-dependent manner. Despite the fact that cells with both hyper- and hypoactivated Notch signaling showed enhanced glycolysis, only cells with hyperactivated Notch promoted aggressive tumor growth in a xenograft mouse model. This phenomenon may be explained by that only Notch-hyperactivated, but not -hypoactivated, cells retained the capacity to switch back to oxidative phosphorylation. In conclusion, our data reveal a role for Notch in cellular energy homeostasis, and show that Notch signaling is required for metabolic flexibility.
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http://dx.doi.org/10.1073/pnas.1104943108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219154PMC
November 2011