Publications by authors named "Olli Eskola"

53 Publications

Multilingual publishing in the social sciences and humanities: A seven-country European study.

J Assoc Inf Sci Technol 2020 Nov 22;71(11):1371-1385. Epub 2020 Jan 22.

Nordic Institute for Studies in Innovation, Research and Education Oslo Norway.

We investigate the state of multilingualism across the social sciences and humanities (SSH) using a comprehensive data set of research outputs from seven European countries (Czech Republic, Denmark, Finland, Flanders [Belgium], Norway, Poland, and Slovenia). Although English tends to be the dominant language of science, SSH researchers often produce culturally and societally relevant work in their local languages. We collected and analyzed a set of 164,218 peer-reviewed journal articles (produced by 51,063 researchers from 2013 to 2015) and found that multilingualism is prevalent despite geographical location and field. Among the researchers who published at least three journal articles during this time period, over one-third from the various countries had written their work in at least two languages. The highest share of researchers who published in only one language were from Flanders (80.9%), whereas the lowest shares were from Slovenia (57.2%) and Poland (59.3%). Our findings show that multilingual publishing is an ongoing practice in many SSH research fields regardless of geographical location, political situation, and/or historical heritage. Here we argue that research is international, but multilingual publishing keeps locally relevant research alive with the added potential for creating impact.
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http://dx.doi.org/10.1002/asi.24336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687152PMC
November 2020

Hydroxysteroid (17β) dehydrogenase 12 is essential for metabolic homeostasis in adult mice.

Am J Physiol Endocrinol Metab 2020 09 21;319(3):E494-E508. Epub 2020 Jul 21.

Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.

Hydroxysteroid 17β dehydrogenase 12 (HSD17B12) is suggested to be involved in the elongation of very long chain fatty acids. Previously, we have shown a pivotal role for the enzyme during mouse development. In the present study we generated a conditional knockout (HSD17B12cKO) mouse model by breeding mice homozygous for a floxed allele with mice expressing the tamoxifen-inducible Cre recombinase at the ROSA26 locus. Gene inactivation was induced by administering tamoxifen to adult mice. The gene inactivation led to a 20% loss of body weight within 6 days, associated with drastic reduction in both white (83% males, 75% females) and brown (65% males, 60% females) fat, likely due to markedly reduced food and water intake. Furthermore, the knockout mice showed sickness behavior and signs of liver toxicity, specifically microvesicular hepatic steatosis and increased serum alanine aminotransferase (4.6-fold in males, 7.7-fold in females). The hepatic changes were more pronounced in females than males. Proinflammatory cytokines, such as interleukin-6 (IL-6), IL-17, and granulocyte colony-stimulating factor, were increased in the HSD17B12cKO mice indicating an inflammatory response. Serum lipidomics study showed an increase in the amount of dihydroceramides, despite the dramatic overall loss of lipids. In line with the proposed role for HSD17B12 in fatty acid elongation, we observed accumulation of ceramides, dihydroceramides, hexosylceramides, and lactosylceramides with shorter than 18-carbon fatty acid side chains in the serum. The results indicate that HSD17B12 is essential for proper lipid homeostasis and HSD17B12 deficiency rapidly results in fatal systemic inflammation and lipolysis in adult mice.
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http://dx.doi.org/10.1152/ajpendo.00042.2020DOI Listing
September 2020

Prediction of prostate cancer aggressiveness using F-Fluciclovine (FACBC) PET and multisequence multiparametric MRI.

Sci Rep 2020 06 10;10(1):9407. Epub 2020 Jun 10.

Department of Diagnostic Radiology, University of Turku, Turku, Finland.

The aim of this prospective single-institution clinical trial (NCT02002455) was to evaluate the potential of advanced post-processing methods for F-Fluciclovine PET and multisequence multiparametric MRI in the prediction of prostate cancer (PCa) aggressiveness, defined by Gleason Grade Group (GGG). 21 patients with PCa underwent PET/CT, PET/MRI and MRI before prostatectomy. DWI was post-processed using kurtosis (ADC, K), mono- (ADC), and biexponential functions (f, D, D) while Logan plots were used to calculate volume of distribution (V). In total, 16 unique PET (V, SUV) and MRI derived quantitative parameters were evaluated. Univariate and multivariate analysis were carried out to estimate the potential of the quantitative parameters and their combinations to predict GGG 1 vs >1, using logistic regression with a nested leave-pair out cross validation (LPOCV) scheme and recursive feature elimination technique applied for feature selection. The second order rotating frame imaging (RAFF), monoexponential and kurtosis derived parameters had LPOCV AUC in the range of 0.72 to 0.92 while the corresponding value for V was 0.85. he best performance for GGG prediction was achieved by K parameter of kurtosis function followed by quantitative parameters based on DWI, RAFF and F-FACBC PET. No major improvement was achieved using parameter combinations with or without feature selection. Addition of F-FACBC PET derived parameters (V, SUV) to DWI and RAFF derived parameters did not improve LPOCV AUC.
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http://dx.doi.org/10.1038/s41598-020-66255-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287051PMC
June 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

Correlation between F-1-amino-3-fluorocyclobutane-1-carboxylic acid (F-fluciclovine) uptake and expression of alanine-serine-cysteine-transporter 2 (ASCT2) and L-type amino acid transporter 1 (LAT1) in primary prostate cancer.

EJNMMI Res 2019 May 31;9(1):50. Epub 2019 May 31.

Turku PET Centre, Turku, Finland.

Purpose: To evaluate the expression of alanine-serine-cysteine-transporter 2 (ASCT2) and L-type amino acid transporter1 (LAT1) in prostate cancer (PCa) and their impact on uptake of F-1-amino-3-fluorocyclobutane-1-carboxylic acid (F-fluciclovine) which is approved for the detection of recurrent PCa.

Methods: Twenty-five hormone-naïve patients with histologically confirmed PCa underwent PET/CT before prostatectomy. Dynamic imaging was performed immediately after injection of 368 ± 10 MBq of F-fluciclovine and the uptake in PCa was expressed as SUV at six sequential 4-min time frames and as tracer distribution volume (V) using Logan plots over 0-24 min. The expression of ASCT2 and LAT1 was studied with immunohistochemistry (IHC) on a tissue microarray (TMA) containing three cores per carcinoma lesion. The TMA slides were scored independently by two trained readers based on visual intensity of ASCT2/LAT1 expression on a four-tiered scale. The correlations between ASCT2/LAT1 staining intensity, SUVmax/V, and Gleason grade group (GGG) were assessed using Spearman's rank correlation coefficient (ρ).

Results: Forty tumor foci (> 0.5 mm in diameter, max. 3 per patient) were available for TMA. In visual scoring, low, moderate, and high staining intensity of ASCT2 was observed in 4 (10%), 24 (60%), and 12 (30%) tumors, respectively. No tumors showed high LAT1 staining intensity while moderate intensity was found in 10 (25%), 25 (63%) showed low, and the remaining 5 (12%) were negative for staining with LAT1. Tumors with GGG > 2 showed significantly higher uptake of F-fluciclovine and higher LAT1 staining intensity (p < 0.05). The uptake of F-fluciclovine correlated significantly with LAT1 expression (ρ = 0.39, p = 0.01, for SUV at 2 min and ρ = 0.39, p = 0.01 for V). No correlation between ASCT2 expression and F-fluciclovine uptake or GGG was found.

Conclusions: Our findings suggest that LAT1 is moderately associated with the transport of F-fluciclovine in local PCa not exposed to hormonal therapy. Both high and low Gleason grade tumors express ASCT2 while LAT1 expression is less conspicuous and may be absent in some low-grade tumors. Our observations may be of importance when using F-fluciclovine imaging in the planning of focal therapies for PCa.
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http://dx.doi.org/10.1186/s13550-019-0518-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544711PMC
May 2019

Effect of genotype and age on cerebral [F]FDG uptake varies between transgenic APP-PS1 and Tg2576 mouse models of Alzheimer's disease.

Sci Rep 2019 04 5;9(1):5700. Epub 2019 Apr 5.

MediCity Research Laboratory, University of Turku, Tykistökatu 6 A, FI-20520, Turku, Finland.

Back-translation of clinical imaging biomarkers of Alzheimer's disease (AD), such as alterations in cerebral glucose metabolism detected by [F]FDG positron emission tomography (PET), would be valuable for preclinical studies evaluating new disease-modifying drugs for AD. However, previous confounding results have been difficult to interpret due to differences in mouse models and imaging protocols between studies. We used an equivalent study design and [F]FDG µPET imaging protocol to compare changes in cerebral glucose metabolism in commercial transgenic APP-PS1 (n = 12), Tg2576 (n = 15), and wild-type mice (n = 15 and 9). Dynamic [F]FDG scans were performed in young (6 months) and aged (12 or 17 months) mice and the results verified by ex vivo methods (i.e., tissue counting, digital autoradiography, and beta-amyloid and Iba-1 immunohistochemistry). [F]FDG uptake exhibited significant regional differences between genotypes (TG < WT) and ages (6 months <12 months) in the APP-PS1 model, whereas similar differences were not present in Tg2576 mice. In both models, only weak correlations were detected between regional beta-amyloid deposition or microgliosis and [F]FDG uptake. By using equivalent methodology, this study demonstrated differences in cerebral glucose metabolism dysfunction detected with [F]FDG PET between two widely used commercial AD mouse models.
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http://dx.doi.org/10.1038/s41598-019-42074-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450965PMC
April 2019

Amyloid-Targeting PET Tracer [F]Flutemetamol Accumulates in Atherosclerotic Plaques.

Molecules 2019 Mar 19;24(6). Epub 2019 Mar 19.

Turku PET Centre, University of Turku, FI-20520 Turku, Finland.

Atherosclerosis is characterized by the accumulation of oxidized lipids in the artery wall, which triggers an inflammatory response. Oxidized low-density lipoprotein (ox-LDL) presents amyloid-like structural properties, and different amyloid species have recently been recognized in atherosclerotic plaques. Therefore, we studied the uptake of the amyloid imaging agent [F]Flutemetamol in atherosclerotic plaques. The binding of [F]Flutemetamol to human carotid artery plaque was studied in vitro. In vivo uptake of the tracer was studied in hypercholesterolemic IGF-II/LDLRApoB mice and C57BL/6N controls. Tracer biodistribution was studied in vivo with PET/CT, and ex vivo by gamma counter and digital ex vivo autoradiography. The presence of amyloid, ox-LDL, and macrophages in the plaques was examined by immunohistochemistry. [F]Flutemetamol showed specific accumulation in human carotid plaque, especially in areas positive for amyloid beta. The aortas of IGF-II/LDLRApoB mice showed large thioflavin-S-positive atherosclerotic plaques containing ox-LDL and macrophages. Autoradiography revealed 1.7-fold higher uptake in the plaques than in a lesion-free vessel wall, but no difference in aortic tissue uptake between mouse strains were observed in the in vivo PET/CT. In conclusion, [F]Flutemetamol binds to amyloid-positive areas in human atherosclerotic plaques. Further studies are warranted to clarify the uptake mechanisms, and the potential of the tracer for in vivo imaging of atherosclerosis in patients.
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http://dx.doi.org/10.3390/molecules24061072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471324PMC
March 2019

Brain neurokinin-1 receptor availability in never-medicated patients with major depression - A pilot study.

J Affect Disord 2019 01 25;242:188-194. Epub 2018 Aug 25.

Turku PET Centre, Neuropsychiatric Imaging, Turku, Finland; Department of Psychiatry, University of Turku and Turku University Hospital, Turku, Finland. Electronic address:

Background: Neurotransmitter substance P (SP) and its preferred neurokinin-1 receptor (NK1R) have been implicated in the treatment of affective and addiction disorders. Despite promising preclinical data on antidepressant action, the clinical trials of NK1R antagonists in major depression have been disappointing. There are no direct in vivo imaging studies on NK1R characteristics in patients with a major depressive disorder (MDD).

Methods: In this cross-sectional case-control study, we recruited nine never-medicated patients with moderate to severe MDD and nine matched healthy controls. NK1R availability (NK1R binding potential, BP) was measured with in vivo 3-D positron emission tomography and a specific NK1 receptor tracer [F]SPA-RQ. Clinical symptoms were assessed with the 17-item Hamilton Rating Scale for Depression (HAM-D17).

Results: NK1R-BP did not differ statistically significantly between patients with MDD and healthy controls. HAM-D17 total scores (range 21-32) correlated positively with NK1R-BP in cortical and limbic areas. HAM-D17 subscale score for anxiety symptoms correlated positively with NK1R-BP in specific brain areas implicated in fear and anxiety.

Limitations: Small sample size. Low variability in the clinical HAM-D subscale ratings may affect the observed correlations.

Conclusions: Our preliminary results do not support a different baseline expression of NK1Rs in a representative sample of never-medicated patients with MDD during a current moderate/severe depressive episode. The modulatory effect of NK1Rs on affective symptoms is in line with early positive results on antidepressant action of NK1 antagonists. However, the effect is likely to be too weak for treatment of MDD with NK1R antagonists alone in clinical practice.
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http://dx.doi.org/10.1016/j.jad.2018.08.084DOI Listing
January 2019

Influence of transport line material on the molar activity of cyclotron produced [F]fluoride.

Nucl Med Biol 2018 Sep - Oct;64-65:8-15. Epub 2018 Jun 30.

Turku PET Centre, Radiopharmaceutical Chemistry Laboratory, University of Turku, Turku, Finland; Department of Chemistry, University of Turku, Turku, Finland. Electronic address:

Introduction: Production of fluorine-18-labeled radiopharmaceuticals is always associated with the varying levels of the same compound containing stable fluorine-19. In practice, this affects the molar activity (A), defined as amount of radioactivity divided by the molar quantity (Bq/mol). We have focused on studying how the material of the transport tubing connecting the cyclotron target chamber to the synthesis device affects the concentration of fluoride in the water arriving to the reaction vessel and subsequently the A of the fluorine-18 labeled radiopharmaceuticals produced.

Methods: Batches of irradiated and non-irradiated water were analyzed for fluoride content after being transported via non-fluorinated (PEEK, PP) and fluorinated (PTFE, ETFE) tubing or using no tubing at all. A for the [F]fluoride was determined and compared with the A of [F]fluciclatide, synthesized from the same [F]fluoride containing batches of water.

Results: Significantly higher concentrations of fluoride were seen in irradiated water that was transported in fluorinated tubing compared to non-irradiated water transported in tubing of the same material. This elevation of fluoride concentration is presumably caused by the interaction of ionizing radiation with the fluorinated tubing used between the target chamber and hot cell. Likewise, a significant difference was seen for PEEK tubing (non-fluorinated). This could be due to the fact that fluorine containing compounds are used in the manufacture of PEEK. When using fluorinated tubing for transport of the irradiated water, the resulting fluciclatide concentrations were significantly higher compared to when using non-fluorinated tubing. No significant difference was seen between fluciclatide concentrations when PTFE or ETFE tubing was compared to each other. Using no tubing resulted in lowest fluciclatide concentration.

Conclusions: Fluorinated tubing is a source of stable fluoride, and A can be increased by using non-fluorinated transport tubing. Of all the tubing materials studied PP is preferred.
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http://dx.doi.org/10.1016/j.nucmedbio.2018.06.004DOI Listing
February 2019

Positron Emission Tomography Imaging of Macrophages in Atherosclerosis with F-GE-180, a Radiotracer for Translocator Protein (TSPO).

Contrast Media Mol Imaging 2018 22;2018:9186902. Epub 2018 May 22.

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

Intraplaque inflammation plays an important role in the progression of atherosclerosis. The 18 kDa translocator protein (TSPO) expression is upregulated in activated macrophages, representing a potential target to identify inflamed atherosclerotic plaques. We preclinically evaluated F-GE-180, a novel third-generation TSPO radioligand, in a mouse model of atherosclerosis. . Nine hypercholesterolemic mice deficient in low density lipoprotein receptor and apolipoprotein B48 (LDLRApoB) and six healthy C57BL/6N mice were injected with 10 MBq of F-GE-180. Specificity of binding was demonstrated in three LDLRApoB mice by injection of nonradioactive reference compound of F-GE-180 before F-GE-180. Dynamic 30-minute PET was performed followed by contrast-enhanced CT, and the mice were sacrificed at 60 minutes after injection. Tissue samples were obtained for ex vivo biodistribution measurements, and aortas were cut into serial cryosections for digital autoradiography. The presence of macrophages and TSPO was studied by immunohistochemistry. The F-GE-180 retention in plaque areas with different macrophage densities and lesion-free vessel wall were compared. . The LDLRApoB mice showed large, inflamed plaques in the aorta. Autoradiography revealed significantly higher F-GE-180 retention in macrophage-rich plaque areas than in noninflamed areas (count densities 150 ± 45 PSL/mm versus 51 ± 12 PSL/mm, < 0.001). Prominent retention in the vessel wall without plaque was also observed (220 ± 41 PSL/mm). Blocking with nonradioactive GE-180 diminished the difference in count densities between macrophage-rich and noninflamed areas in atherosclerotic plaques and lowered the count density in vessel wall without plaque. . F-GE-180 shows specific uptake in macrophage-rich areas of atherosclerotic plaques in mice. However, retention in atherosclerotic lesions does not exceed that in lesion-free vessel wall. The third-generation TSPO radioligand F-GE-180 did not show improved characteristics for imaging atherosclerotic plaque inflammation compared to previously studied TSPO-targeting tracers.
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http://dx.doi.org/10.1155/2018/9186902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987326PMC
July 2019

Prospective evaluation of F-FACBC PET/CT and PET/MRI versus multiparametric MRI in intermediate- to high-risk prostate cancer patients (FLUCIPRO trial).

Eur J Nucl Med Mol Imaging 2018 03 16;45(3):355-364. Epub 2017 Nov 16.

Turku PET Centre, Turku, Finland.

Purpose: The purpose of this study was to evaluate F-FACBC PET/CT, PET/MRI, and multiparametric MRI (mpMRI) in detection of primary prostate cancer (PCa).

Methods: Twenty-six men with histologically confirmed PCa underwent PET/CT immediately after injection of 369 ± 10 MBq F-FACBC (fluciclovine) followed by PET/MRI started 55 ± 7 min from injection. Maximum standardized uptake values (SUV) were measured for both hybrid PET acquisitions. A separate mpMRI was acquired within a week of the PET scans. Logan plots were used to calculate volume of distribution (V). The presence of PCa was estimated in 12 regions with radical prostatectomy findings as ground truth. For each imaging modality, area under the curve (AUC) for detection of PCa was determined to predict diagnostic performance. The clinical trial registration number is NCT02002455.

Results: In the visual analysis, 164/312 (53%) regions contained PCa, and 41 tumor foci were identified. PET/CT demonstrated the highest sensitivity at 87% while its specificity was low at 56%. The AUC of both PET/MRI and mpMRI significantly (p < 0.01) outperformed that of PET/CT while no differences were detected between PET/MRI and mpMRI. SUV and V of Gleason score (GS) >3 + 4 tumors were significantly (p < 0.05) higher than those for GS 3 + 3 and benign hyperplasia. A total of 442 lymph nodes were evaluable for staging, and PET/CT and PET/MRI demonstrated true-positive findings in only 1/7 patients with metastatic lymph nodes.

Conclusions: Quantitative F-FACBC imaging significantly correlated with GS but failed to outperform MRI in lesion detection. F-FACBC may assist in targeted biopsies in the setting of hybrid imaging with MRI.
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http://dx.doi.org/10.1007/s00259-017-3875-1DOI Listing
March 2018

Head-to-Head Comparison of Ga-Citrate and F-FDG PET/CT for Detection of Infectious Foci in Patients with Bacteraemia.

Contrast Media Mol Imaging 2017 17;2017:3179607. Epub 2017 Oct 17.

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

Purpose: This study evaluated the potential of Ga-citrate positron emission tomography/computed tomography (PET/CT) for the detection of infectious foci in patients with bacteraemia by comparing it with 2-[F]fluoro-2-deoxy--glucose (F-FDG) PET/CT.

Methods: Four patients admitted to hospital due to bacteraemia underwent both F-FDG and Ga-citrate whole-body PET/CT scans to detect infectious foci.

Results: The time from hospital admission and the initiation of antibiotic treatment to the first PET/CT was 4-10 days. The time interval between F-FDG and Ga-citrate PET/CT was 1-4 days. Three patients had vertebral osteomyelitis (spondylodiscitis) and one had osteomyelitis in the toe; these were detected by both F-FDG (maximum standardised uptake value [SUV] 6.0 ± 1.0) and Ga-citrate (SUV  6.8 ± 3.5, = 0.61). Three patients had soft tissue infectious foci, with more intense F-FDG uptake (SUV  6.5 ± 2.5) than Ga-citrate uptake (SUV  3.9 ± 1.2, = 0.0033).

Conclusions: Our small cohort of patients with bacteraemia revealed that Ga-citrate PET/CT is comparable to F-FDG PET/CT for detection of osteomyelitis, whereas F-FDG resulted in a higher signal for the detection of soft tissue infectious foci.
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http://dx.doi.org/10.1155/2017/3179607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664237PMC
July 2018

Neuroinflammation Appears Early on PET Imaging and Then Plateaus in a Mouse Model of Alzheimer Disease.

J Nucl Med 2018 03 6;59(3):509-515. Epub 2017 Oct 6.

Turku PET Centre, Turku University Hospital, Turku, Finland; and.

Neuroinflammation has been associated with various neurologic diseases, including Alzheimer disease (AD). In AD, the translocator protein 18 kDa (TSPO) is overexpressed in the activated microglia that surround the β-amyloid plaques. In the current longitudinal study using a mouse model of AD, we evaluated the association between β-amyloid deposition and neuroinflammation in AD. To monitor the longitudinal changes in β-amyloid deposition and neuroinflammation, we used in vivo PET imaging and ex vivo autoradiography with Pittsburgh compound B (C-PIB) and a TSPO tracer, flutriciclamide (F-GE-180), in the APP23 mouse model of AD. We also applied immunohistochemistry to study β-amyloid and activated microglia in the mouse brain tissue. From 17 to 26 mo of age, the mice showed robust increased binding of C-PIB with aging in the frontal cortex, parietotemporal cortex, hippocampus, and thalamus whereas the increase in F-GE-180 binding with aging was minimal in areas of early amyloidosis such as the frontal cortex and hippocampus. A clear positive correlation between β-amyloid deposition and neuroinflammation was detected with C-PIB and F-GE-180 only in the parietotemporal cortex and thalamus. The neuroinflammation increase detected with F-GE-180 is less than the increase in amyloidosis detected with C-PIB. Furthermore, binding of F-GE-180 plateaus at an earlier stage of pathogenesis whereas amyloidosis continues to increase. We suggest that TSPO can be a good marker for early pathogenesis detection but not for tracking long-term disease progression.
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http://dx.doi.org/10.2967/jnumed.117.197608DOI Listing
March 2018

Brain glucose metabolism and its relation to amyloid load in middle-aged adults with childhood-onset epilepsy.

Epilepsy Res 2017 11 20;137:69-72. Epub 2017 Sep 20.

Departments of General Practice and Child Neurology, University of Turku, Finland; Department of Pediatrics and Adolescent Medicine, Turku University Hospital, Turku, Finland.

Uncomplicated childhood-onset epilepsy is associated with increased brain amyloid load at late middle age, but its possible association with Alzheimer-type neurodegenerative processes is unclear. After 50-year follow-up, 42 childhood onset epilepsy subjects and 45 matched controls were investigated with [F]fluorodeoxyglucose PET. There were no significant differences between the subjects and controls, but higher [F]fluorodeoxyglucose uptake was associated with a higher local amyloid load (as measured with [C]PIB PET) in the prefrontal cortex, parietal cortex, and posterior cingulate/precuneus in subjects but not in controls. These findings parallel reported observations in cognitively normal individuals with increased brain amyloid accumulation who are at risk for future Alzheimer's disease.
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http://dx.doi.org/10.1016/j.eplepsyres.2017.09.006DOI Listing
November 2017

Human Brown Adipose Tissue Temperature and Fat Fraction Are Related to Its Metabolic Activity.

J Clin Endocrinol Metab 2017 04;102(4):1200-1207

Turku PET Centre and.

Background And Aim: The metabolic activity of human brown adipose tissue (BAT) has been previously examined using positron emission tomography (PET). The aim of this study was to use proton magnetic resonance spectroscopy (1H MRS) to investigate whether the temperature and the fat fraction (FF) of BAT and white adipose tissue (WAT) are associated with BAT metabolic activity determined by deoxy-2-18F-fluoro-d-glucose (18F-FDG)-PET.

Materials And Methods: Ten healthy subjects (four women, six men; 25 to 45 years of age) were studied using PET-magnetic resonance imaging during acute cold exposure and at ambient room temperature. BAT and subcutaneous WAT 1H MRS were measured. The tissue temperature and the FF were derived from the spectra. Tissue metabolic activity was studied through glucose uptake using dynamic FDG PET scanning during cold exposure. A 2-hour hyperinsulinemic euglycemic clamp was performed on eight subjects.

Results: The metabolic activity of BAT associated directly with the heat production capacity and inversely with the FF of the tissue. In addition, the lipid-burning capacity of BAT associated with whole-body insulin sensitivity. During cold exposure, the FF of BAT was lower than at room temperature, and cold-induced FF of BAT associated inversely with high-density lipoprotein and directly with low-density lipoprotein cholesterol.

Conclusion: Both 1H MRS-derived temperature and FF are promising methods to study BAT activity noninvasively. The association between the lipid-burning capacity of BAT and whole-body insulin sensitivity emphasizes the role of BAT in glucose handling. Furthermore, the relation of FF to high-density lipoprotein and low-density lipoprotein cholesterol suggests that BAT has a role in lipid clearance, thus protecting tissues from excess lipid load.
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http://dx.doi.org/10.1210/jc.2016-3086DOI Listing
April 2017

Brain energy metabolism and neuroinflammation in ageing APP/PS1-21 mice using longitudinal F-FDG and F-DPA-714 PET imaging.

J Cereb Blood Flow Metab 2017 Aug 1;37(8):2870-2882. Epub 2016 Jan 1.

1 MediCity Research Laboratory, University of Turku, Turku, Finland.

Preclinical animal model studies of brain energy metabolism and neuroinflammation in Alzheimer's disease have produced conflicting results, hampering both the elucidation of the underlying disease mechanism and the development of effective Alzheimer's disease therapies. Here, we aimed to quantify the relationship between brain energy metabolism and neuroinflammation in the APP/PS1-21 transgenic mouse model of Alzheimer's disease using longitudinal in vivoF-FDG and F-DPA-714) PET imaging and ex vivo brain autoradiography. APP/PS1-21 (TG, n = 9) and wild type control mice (WT, n = 9) were studied longitudinally every third month from age 6 to 15 months with F-FDG and F-DPA-714 with a one-week interval between the scans. Additional TG (n = 52) and WT (n = 29) mice were used for ex vivo studies. In vivo, the F-FDG SUVs were lower and the F-DPA-714 binding ratios relative to the cerebellum were higher in the TG mouse cortex and hippocampus than in WT mice at age 12 to 15 months ( p < 0.05). The ex vivo cerebellum binding ratios supported the results of the in vivoF-DPA-714 studies but not the F-FDG studies. This longitudinal PET study demonstrated decreased energy metabolism and increased inflammation in the brains of APP/PS1-21 mice compared to WT mice.
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http://dx.doi.org/10.1177/0271678X16677990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536795PMC
August 2017

Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells.

J Neuroinflammation 2015 Apr 28;12:81. Epub 2015 Apr 28.

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

Background: Recently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Aβ) in the Alzheimer's disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice.

Findings: Transgenic APdE9 mice (5 months old) were treated with JZL184 (40 mg/kg) or vehicle every day for 1 month. In vivo binding of the neuroinflammation-related, microglia-specific translocator protein (TSPO) targeting radioligand [(18) F]GE-180 decreased slightly but statistically non-significantly in multiple brain areas compared to vehicle-treated mice. JZL184 treatment induced a significant decrease in expression levels of inflammation-induced, Iba1-immunoreactive microglia in the hippocampus (P < 0.01) and temporal and parietal (P < 0.05) cortices. JZL184 also induced a marked decrease in total Aβ burden in the temporal (P < 0.001) and parietal (P < 0.01) cortices and, to some extent, in the hippocampus. Adult microglial and astrocyte cultures pre-treated with JZL184 and then exposed to the neuroinflammation-inducing agents lipopolysaccharide (LPS), interferon-gamma (IFN-γ), and Aβ42 had significantly reduced proinflammatory responses compared to cells without JZL184 treatment.

Conclusions: JZL184 decreased the proinflammatory reactions of microglia and reduced the total Aβ burden and its precursors in the APdE9 mouse model. It also reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice.
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http://dx.doi.org/10.1186/s12974-015-0305-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416350PMC
April 2015

In vivo PET imaging demonstrates diminished microglial activation after fingolimod treatment in an animal model of multiple sclerosis.

J Nucl Med 2015 Feb 8;56(2):305-10. Epub 2015 Jan 8.

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

Unlabelled: There is a great need for the monitoring of microglial activation surrounding multiple sclerosis lesions because the activation of microglia is thought to drive widespread neuronal damage. Recently, second-generation PET radioligands that can reveal the extent of microglial activation by quantifying the increased expression of the 18-kDa translocator protein have been developed. Here, we investigate whether PET imaging can be used to demonstrate the reduction in microglial activation surrounding a chronic focal multiple sclerosis (MS)-like lesion after treatment with fingolimod, an established MS therapy.

Methods: Chronic focal experimental autoimmune encephalitis (EAE)-like lesions were induced in Lewis rats (n = 24) via stereotactic intrastriatal injection of heat-killed bacillus Calmette-Guérin (BCG) and subsequent activation using an intradermal injection of BCG in complete Freund adjuvant. This process resulted in a delayed-type hypersensitivity (DTH)-like EAE lesion. The extent of neuroinflammation surrounding the lesion was measured using (18)F-GE180 as a PET radioligand. The imaging was performed before and after treatment with fingolimod (0.3 mg/kg/d by mouth, 28 d) or vehicle as a control. In addition to imaging, autoradiography and immunohistochemistry experiments were performed to verify the in vivo results.

Results: The chronic DTH EAE lesion led to increased ligand binding in the ipsilateral, compared with contralateral, hemisphere when PET imaging was performed with the translocator protein-binding radioligand (18)F-GE180. Treatment with fingolimod led to a highly significant reduction in the binding potential, which could be demonstrated using both in vivo and ex vivo imaging (fingolimod vs. vehicle treatment, P < 0.0001). The area of increased (18)F-GE180 signal mapped closely to the area of activated microglial cells detected by immunohistochemistry.

Conclusion: PET imaging, unlike MR imaging, can be used to visualize the microglial activation surrounding a chronic DTH EAE lesion. Importantly, the treatment effect of fingolimod can be monitored in vivo by measuring the degree of microglial activation surrounding the chronic DTH EAE lesion. This work gives promise for the introduction of new outcome measures applicable in treatment studies of progressive MS.
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http://dx.doi.org/10.2967/jnumed.114.149955DOI Listing
February 2015

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

Mortality in Parkinson's disease is not associated with the severity of early dopaminergic defect.

Parkinsonism Relat Disord 2014 Aug 2;20(8):894-7. Epub 2014 Jun 2.

Division of Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland; Turku PET Centre, Turku University Hospital and University of Turku, Turku, Finland.

Background: Although there is a relationship between the extent of striatal dopaminergic defect and the severity of motor symptoms in Parkinson's disease (PD), studies investigating associations between dopamine and mortality in PD have been scarce. If a relationship were established, dopamine restoring neuroprotective treatments could be used to decrease mortality. The objective of this study was to determine whether the initial degree of hypodopaminergic defect, as measured by 6-[(18)F]fluoro-L-DOPA positron emission tomography (FDOPA-PET), can predict patient survival.

Methods: The study population included a cohort of 88 recently diagnosed and untreated patients with PD who were clinically examined and scanned with FDOPA-PET between the years 1998 and 2000. The date of exit for the survival analysis was in April 2013 with a follow-up interval of 13-15 years. The survival model included FDOPA uptake, age, sex and symptom severity as explaining factors. Death certificates of the patients were obtained, and causes of death were analyzed.

Results: Mortality rate was 56.8%. Although higher age (p < 0.001) and greater motor symptom severity (p < 0.05) were associated with increased mortality, there was no association between survival and FDOPA uptake in any striatal subregion (p > 0.48).

Conclusion: Unlike age and early motor symptom severity, dopamine synthesis capacity, as measured with PET, does not predict survival in PD.
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http://dx.doi.org/10.1016/j.parkreldis.2014.05.010DOI Listing
August 2014

Prognostic value of tumour blood flow, [¹⁸F]EF5 and [¹⁸F]FDG PET/CT imaging in patients with head and neck cancer treated with radiochemotherapy.

Eur J Nucl Med Mol Imaging 2014 Nov 5;41(11):2042-50. Epub 2014 Jun 5.

Turku PET Centre, Kiinamyllynkatu 4-8, 20521, Turku, Finland,

Purpose: In order to improve the treatment of squamous cell carcinoma of the head and neck, precise information on the treated tumour's biology is required and the prognostic importance of different biological parameters needs to be determined. The aim of our study was to determine the predictive value of pretreatment PET/CT imaging using [(18)F]FDG, a new hypoxia tracer [(18)F]EF5 and the perfusion tracer [(15)O]H₂O in patients with squamous cell cancer of the head and neck treated with radiochemotherapy.

Methods: The study group comprised 22 patients with confirmed squamous cell carcinoma of the head and neck who underwent a PET/CT scan using the above tracers before any treatment. Patients were later treated with a combination of radiochemotherapy and surgery. Parametric blood flow was calculated from dynamic [(15)O]H₂O PET images using a one-tissue compartment model. [(18)F]FDG images were analysed by calculating standardized uptake values (SUV) and metabolically active tumour volumes (MATV). [(18)F]EF5 images were analysed by calculating tumour-to-muscle uptake ratios (T/M ratio). A T/M ratio of 1.5 was considered a significant threshold and used to determine tumour hypoxic subvolumes (HS) and hypoxic fraction area. The findings were finally correlated with the pretreatment clinical findings (overall stage and TNM stage) as well as the outcome following radiochemotherapy in terms of local control and overall patient survival.

Results: Tumour stage and T-classification did not show any significant differences in comparison to the patients' metabolic and functional characteristics measured on PET. Using the Cox proportional hazards model, a shorter overall survival was associated with MATV (p = 0.008, HR = 1.108), maximum [(18)F]EF5 T/M ratio (p = 0.0145, HR = 4.084) and tumour HS (p = 0.0047, HR = 1.112). None of the PET parameters showed a significant effect on patient survival in the log-rank test, although [(18)F]EF5 maximum T/M ratio was the closest (p = 0.109). By contrast, tumour blood flow was not correlated with any of the clinical endpoints. There were no statistically significant correlations among [(18)F]FDG SUVmax, [(18)F]EF5 T/M ratio and blood flow.

Conclusion: Our study in a limited number of patients confirmed the importance of MATV in the prognosis of locally advanced squamous cell carcinoma of the head and neck. It is of interest that high uptake of the hypoxia tracer [(18)F]EF5 showed a stronger correlation with a poor clinical outcome than [(18)F]FDG uptake. This confirms the importance of hypoxia in treatment outcome and suggests that [(18)F]EF5 may act as a surrogate marker of radioresistance.
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http://dx.doi.org/10.1007/s00259-014-2818-3DOI Listing
November 2014

In vivo PET imaging of beta-amyloid deposition in mouse models of Alzheimer's disease with a high specific activity PET imaging agent [(18)F]flutemetamol.

EJNMMI Res 2014 1;4:37. Epub 2014 Aug 1.

Medicity/PET Preclinical Laboratory, Turku PET Centre, University of Turku, Tykistökatu 6 A, Turku 20520, Finland.

Background: The purpose of the study was to evaluate the applicability of (18) F-labelled amyloid imaging positron emission tomography (PET) agent [ (18) F]flutemetamol to detect changes in brain beta-amyloid (Aβ) deposition in vivo in APP23, Tg2576 and APPswe-PS1dE9 mouse models of Alzheimer's disease. We expected that the high specific activity of [ (18) F]flutemetamol would make it an attractive small animal Aβ imaging agent.

Methods: [ (18) F]flutemetamol uptake in the mouse brain was evaluated in vivo at 9 to 22 months of age with an Inveon Multimodality PET/CT camera (Siemens Medical Solutions USA, Knoxville, TN, USA). Retention in the frontal cortex (FC) was evaluated by Logan distribution volume ratios (DVR) and FC/cerebellum (CB) ratios during the late washout phase (50 to 60 min). [ (18) F]flutemetamol binding to Aβ was also evaluated in brain slices by in vitro and ex vivo autoradiography. The amount of Aβ in the brain slices was determined with Thioflavin S and anti-Aβ1-40 immunohistochemistry.

Results: In APP23 mice, [ (18) F]flutemetamol retention in the FC increased from 9 to 18 months. In younger mice, DVR and FC/CB50-60 were 0.88 (0.81) and 0.88 (0.89) at 9 months (N = 2), and 0.98 (0.93) at 12 months (N = 1), respectively. In older mice, DVR and FC/CB50-60 were 1.16 (1.15) at 15 months (N = 1), 1.13 (1.16) and 1.35 (1.35) at 18 months (N = 2), and 1.05 (1.31) at 21 months (N = 1). In Tg2576 mice, DVR and FC/CB50-60 showed modest increasing trends but also high variability. In APPswe-PS1dE9 mice, DVR and FC/CB50-60 did not increase with age. Thioflavin S and anti-Aβ1-40 positive Aβ deposits were present in all transgenic mice at 19 to 22 months, and they co-localized with [ (18) F]flutemetamol binding in the brain slices examined with in vitro and ex vivo autoradiography.

Conclusions: Increased [ (18) F]flutemetamol retention in the brain was detected in old APP23 mice in vivo. However, the high specific activity of [ (18) F]flutemetamol did not provide a notable advantage in Tg2576 and APPswe-PS1dE9 mice compared to the previously evaluated structural analogue [(11)C]PIB. For its practical benefits, [ (18) F]flutemetamol imaging with a suitable mouse model like APP23 is an attractive alternative.
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http://dx.doi.org/10.1186/s13550-014-0037-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412375PMC
May 2015

Reduced striatal dopamine synthesis capacity is associated with symptoms of depression in patients with de novo unmedicated Parkinson's disease.

J Parkinsons Dis 2013 Jan;3(3):325-9

Division of Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland Turku PET Centre, Turku University Hospital and University of Turku, Turku, Finland.

Previous studies have suggested that impaired striatal dopamine function might be independently related to depression in patients with Parkinson's disease (PD), but the results are not uniform. In this study, we investigated de novo unmedicated and medicated PD patients with more advanced disease using 18F-fluorodopa-PET. In unmedicated de novo patients, but not in medicated patients, higher depression scores were associated with lower striatal 18F-fluorodopa uptake. These results indicate that impaired striatal dopaminergic function in PD is related to depressive symptoms and that these effects can be observed in de novo patients without the confounding effects of advanced neurodegeneration and medications.
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http://dx.doi.org/10.3233/JPD-130205DOI Listing
January 2013

Seasonality of striatal dopamine synthesis capacity in Parkinson's disease.

Neurosci Lett 2012 Nov 2;530(1):80-4. Epub 2012 Oct 2.

Department of Neurology, University of Turku and Turku University Hospital, Turku, Finland.

Recent neuroimaging evidence suggests that the healthy human brain dopaminergic system may show seasonal rhythmicity, as striatal dopamine synthesis capacity has been reported to be higher during fall and winter. There is additional evidence about season of birth effects on morbidity in several neuropsychiatric disorders. We investigated possible seasonal changes in dopamine synthesis capacity in a relatively large sample of Parkinson's disease patients. 6-[(18)F]fluoro-l-DOPA brain PET scans for 109 Parkinson's disease patients were performed during different seasons and the effects of season of scanning and season of birth on striatal tracer uptake were studied, controlling for covariates such as age, sex and disease severity. The patients scanned during fall and winter had 15% higher tracer uptake in the right putamen compared to patients scanned during spring and summer (p=0.04). Patients born during winter and spring had 10% higher dopamine synthesis capacity in the left caudate (p=0.008), 8% higher capacity in the right caudate (p=0.04) and 16% higher capacity in the putamen contralateral to the side of predominant motor symptoms (p=0.02) compared to patients born during summer and fall (after correcting for differences in age, sex, disease severity, scanner and season of scanning). The results suggest that there are seasonal oscillations also in the hypoactive dopaminergic system of Parkinson's disease patients. Findings concerning season of birth further suggest that there may be gestational or perinatal seasonal factors, which influence dopaminergic function in adulthood.
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http://dx.doi.org/10.1016/j.neulet.2012.09.047DOI Listing
November 2012

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

Pharmacokinetics of [¹⁸F]flutemetamol in wild-type rodents and its binding to beta amyloid deposits in a mouse model of Alzheimer's disease.

Eur J Nucl Med Mol Imaging 2012 Nov 17;39(11):1784-95. Epub 2012 Jul 17.

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

Purpose: The aim of this study was to investigate the potential of [(18)F]flutemetamol as a preclinical PET tracer for imaging β-amyloid (Aβ) deposition by comparing its pharmacokinetics to those of [(11)C]Pittsburgh compound B ([(11)C]PIB) in wild-type Sprague Dawley rats and C57Bl/6N mice. In addition, binding of [(18)F]flutemetamol to Aβ deposits was studied in the Tg2576 transgenic mouse model of Alzheimer's disease.

Methods: [(18)F]Flutemetamol biodistribution was evaluated using ex vivo PET methods and in vivo PET imaging in wild-type rats and mice. Metabolism and binding of [(11)C]PIB and [(18)F]flutemetamol to plasma proteins were analysed using thin-layer chromatography and ultrafiltration methods, respectively. Radiation dose estimates were calculated from rat ex vivo biodistribution data. The binding of [(18)F]flutemetamol to Aβ deposits was also studied using ex vivo and in vitro autoradiography. The location of Aβ deposits in the brain was determined with thioflavine S staining and immunohistochemistry.

Results: The pharmacokinetics of [(18)F]flutemetamol resembled that of [(11)C]PIB in rats and mice. In vivo studies showed that both tracers readily entered the brain, and were excreted via the hepatobiliary pathway in both rats and mice. The metabolism of [(18)F]flutemetamol into radioactive metabolites was faster than that of [(11)C]PIB. [(18)F]Flutemetamol cleared more slowly from the brain than [(11)C]PIB, particularly from white matter, in line with its higher lipophilicity. Effective dose estimates for [(11)C]PIB and [(18)F]flutemetamol were 2.28 and 6.65 μSv/MBq, respectively. Autoradiographs showed [(18)F]flutemetamol binding to fibrillar Aβ deposits in the brain of Tg2576 mice.

Conclusion: Based on its pharmacokinetic profile, [(18)F]flutemetamol showed potential as a PET tracer for preclinical imaging. It showed good brain uptake and was bound to Aβ deposits in the brain of Tg2576 mice. However, its high lipophilicity might complicate the analysis of PET data, particularly in small-animal imaging.
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http://dx.doi.org/10.1007/s00259-012-2178-9DOI Listing
November 2012

[18F]CFT synthesis and binding to monoamine transporters in rats.

EJNMMI Res 2012 Jan 25;2(1). Epub 2012 Jan 25.

Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Porthaninkatu 3, Turku, 20500, Finland.

Background: We present the electrophilic synthesis of [18F]2β-carbomethoxy-3β-(4-fluoro)tropane [[18F]CFT] and the pharmacological specificity and selectivity of [18F]CFT for monoamine transporters in the brain and peripheral organs of rats. The human radiation dose is extrapolated from the animal data.

Methods: [18F]CFT was synthesized by electrophilic fluorination of a stannylated precursor by using post-target-produced [18F]F2 as a fluorinating agent. The ex vivo 18F-activity biodistribution of [18F]CFT in the brain of rats was studied by autoradiography. The binding of [18F]CFT to the monoamine transporters was studied using in vivo blocking experiments with dopamine transporter [DAT], norepinephrine transporter [NET], or serotonin transporter [SERT] inhibitors. In vivo animal positron emission tomography was used as a comparative method to determine tracer kinetics. Human radiation dose was assessed using OLINDA software.

Results: The radiochemical yield of [18F]CFT from the initial [18F]F-, decay corrected to the end of bombardment, was 3.2 ± 1.0%. The specific activity [SA] was 14.5 ± 3.4 GBq/μmol, decay corrected to the end of synthesis. Radiochemical purity exceeded 99%. DAT-specific binding was found in the striatum, locus coeruleus, and pancreas. NET-specific binding was found in the locus coeruleus. SERT-specific binding was not found in any of the studied organs. Effective dose equivalent [EDE] estimated for the standard human model was 12.8 μSv/MBq. Effective dose [ED] was 9.17 μSv/MBq.

Conclusions: Post-target-produced high-SA [18F]F2 was used to incorporate18F directly into the phenyl ring of [18F]CFT. The final product had high radiochemical and chemical purities and a high SA for DAT and NET studies in vivo. In periphery, [18F]CFT showed a specific uptake in the pancreas. EDE and ED corresponded well with other18F-radioligands.
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http://dx.doi.org/10.1186/2191-219X-2-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299608PMC
January 2012

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

Tracer level electrophilic synthesis and pharmacokinetics of the hypoxia tracer [(18)F]EF5.

Mol Imaging Biol 2012 Apr;14(2):205-12

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

Purpose: 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide labeled with [(18)F]-fluorine ([(18)F]EF5), a promising tracer for tumor hypoxia, has previously been synthesized in low yields and low specific radioactivity. In pharmacokinetic evaluations, in the presence of non-radioactive EF5, a uniform and low background uptake and high in vivo stability of [(18)F]EF5 have been demonstrated. Our purpose was to increase the specific radioactivity of [(18)F]EF5 to enable to study the pharmacokinetics at trace level.

Procedures: [(18)F]EF5 was synthesized using high specific radioactivity electrophilic [(18)F]F(2) as labelling reagent. Biodistribution of [(18)F]EF5 was determined in a prostate tumor mouse model, and formation of radiolabelled metabolites was studied in mouse, rat and human plasma.

Results: On average, 595 ± 153 MBq of [(18)F]EF5 was produced. Specific radioactivity was 6.6 ± 1.9 GBq/μmol and the radiochemical purity exceeded 99.0%. [(18)F]EF5 was distributed uniformly in tissues, with highest uptake in liver, kidney, and intestine. Several radiolabelled metabolites were detected in mouse plasma and tissues, whereas low amounts of metabolites were detected in human and rat plasma.

Conclusions: [(18)F]EF5 was synthesized by electrophilic labelling with high quality and high yields. Pharmacokinetics of [(18)F]EF5 was determined at trace level in several species. Our results suggest that the trace-level approach does not affect the biodistribution of [(18)F]EF5. Extensive metabolism was seen in mouse.
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http://dx.doi.org/10.1007/s11307-011-0484-4DOI Listing
April 2012

Comparison of 2beta-carbomethoxy-3beta-(4-[18F]fluorophenyl)tropane and N-(3-[18F]fluoropropyl)-2beta-carbomethoxy-3beta-(4-fluorophenyl)nortropane, tracers for imaging dopamine transporter in rat.

Mol Imaging Biol 2010 Jun 1;12(3):269-77. Epub 2009 Dec 1.

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

Purpose: This study compares 2beta-carbomethoxy-3beta-(4-[(18)F]fluorophenyl)tropane ([(18)F]beta-CFT) and N-(3-[(18)F]fluoropropyl)-2beta-carbomethoxy-3beta-(4-fluorophenyl)nortropane ([(18)F]beta-CFT-FP) as radiotracers for imaging the dopamine transporter (DAT) in rat.

Procedures: Biodistribution, specificity and selectivity of the radiotracers were studied ex vivo in rats pre-treated with specific antagonists for DAT, serotonin transporter (SERT) and noradrenalin transporter (NET) and in control rats. Positron emission tomography (PET) studies were performed using an HRRT scanner. Radiolabelled metabolites were analyzed with thin-layer chromatography.

Results: [(18)F]beta-CFT showed slow kinetics with a maximum striatum/cerebellum uptake ratio of 9.2 at 120 min. [(18)F]beta-CFT-FP showed fast kinetics with a maximum ratio of 3.1 at 5 min. Both tracers bound to DAT. [(18)F]beta-CFT also bound to NET. [(18)F]beta-CFT was more resistant to metabolism than [(18)F]beta-CFT-FP.

Conclusions: Structural modifications of [(18)F]beta-CFT significantly changed its biological properties, as shown by [(18)F]beta-CFT-FP. [(18)F]beta-CFT is a suitable tracer for both preclinical and human PET studies, but [(18)F]beta-CFT-FP is less suitable as a PET tracer.
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http://dx.doi.org/10.1007/s11307-009-0278-0DOI Listing
June 2010