Publications by authors named "Vesa Oikonen"

92 Publications

Kinetic analysis and optimisation of F-rhPSMA-7.3 PET imaging of prostate cancer.

Eur J Nucl Med Mol Imaging 2021 Apr 12. Epub 2021 Apr 12.

Clinical Research Services Turku - CRST Ltd, Turku, Finland.

Purpose: This phase 1 open-label study evaluated the uptake kinetics of a novel theranostic PET radiopharmaceutical, F-rhPSMA-7.3, to optimise its use for imaging of prostate cancer.

Methods: Nine men, three with high-risk localised prostate cancer, three with treatment-naïve hormone-sensitive metastatic disease and three with castration-resistant metastatic disease, underwent dynamic 45-min PET scanning of a target area immediately post-injection of 300 MBq F-rhPSMA-7.3, followed by two whole-body PET/CT scans acquired from 60 and 90 min post-injection. Volumes of interest (VoIs) corresponding to prostate cancer lesions and reference tissues were recorded. Standardised uptake values (SUV) and lesion-to-reference ratios were calculated for 3 time frames: 35-45, 60-88 and 90-118 min. Net influx rates (K) were calculated using Patlak plots.

Results: Altogether, 44 lesions from the target area were identified. Optimal visual lesion detection started 60 min post-injection. The F-rhPSMA-7.3 signal from prostate cancer lesions increased over time, while reference tissue signals remained stable or decreased. The mean (SD) SUV (g/mL) at the 3 time frames were 8.4 (5.6), 10.1 (7) and 10.6 (7.5), respectively, for prostate lesions, 11.2 (4.3), 13 (4.8) and 14 (5.2) for lymph node metastases, and 4.6 (2.6), 5.7 (3.1) and 6.4 (3.5) for bone metastases. The mean (SD) lesion-to-reference ratio increases from the earliest to the 2 later time frames were 40% (10) and 59% (9), respectively, for the prostate, 65% (27) and 125% (47) for metastatic lymph nodes and 25% (19) and 32% (30) for bone lesions. Patlak plots from lesion VoIs signified almost irreversible uptake kinetics. K, SUV and lesion-to-reference ratio estimates showed good agreement.

Conclusion: F-rhPSMA-7.3 uptake in prostate cancer lesions was high. Lesion-to-background ratios increased over time, with optimal visual detection starting from 60 min post-injection. Thus, F-rhPSMA-7.3 emerges as a very promising PET radiopharmaceutical for diagnostic imaging of prostate cancer.

Trial Registration: NCT03995888 (24 June 2019).
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http://dx.doi.org/10.1007/s00259-021-05346-8DOI Listing
April 2021

Insulin Resistance Is Associated With Enhanced Brain Glucose Uptake During Euglycemic Hyperinsulinemia: A Large-Scale PET Cohort.

Diabetes Care 2021 Mar 14;44(3):788-794. Epub 2021 Jan 14.

Turku PET Centre, University of Turku, Turku, Finland

Objective: Whereas insulin resistance is expressed as reduced glucose uptake in peripheral tissues, the relationship between insulin resistance and brain glucose metabolism remains controversial. Our aim was to examine the association of insulin resistance and brain glucose uptake (BGU) during a euglycemic hyperinsulinemic clamp in a large sample of study participants across a wide range of age and insulin sensitivity.

Research Design And Methods: [F]-fluorodeoxyglucose positron emission tomography (PET) data from 194 participants scanned under clamp conditions were compiled from a single-center cohort. BGU was quantified by the fractional uptake rate. We examined the association of age, sex, M value from the clamp, steady-state insulin and free fatty acid levels, C-reactive protein levels, HbA, and presence of type 2 diabetes with BGU using Bayesian hierarchical modeling.

Results: Insulin sensitivity, indexed by the M value, was associated negatively with BGU in all brain regions, confirming that in insulin-resistant participants BGU was enhanced during euglycemic hyperinsulinemia. In addition, the presence of type 2 diabetes was associated with additional increase in BGU. On the contrary, age was negatively related to BGU. Steady-state insulin levels, C-reactive protein and free fatty acid levels, sex, and HbA were not associated with BGU.

Conclusions: In this large cohort of participants of either sex across a wide range of age and insulin sensitivity, insulin sensitivity was the best predictor of BGU.
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http://dx.doi.org/10.2337/dc20-1549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896252PMC
March 2021

First-in-Humans Study of Ga-DOTA-Siglec-9, a PET Ligand Targeting Vascular Adhesion Protein 1.

J Nucl Med 2021 Apr 17;62(4):577-583. Epub 2020 Aug 17.

Turku PET Centre, University of Turku, Turku, Finland

Sialic acid-binding immunoglubulinlike lectin 9 (Siglec-9) is a ligand of vascular adhesion protein 1. A Ga-labeled peptide of Siglec-9, Ga-DOTA-Siglec-9, holds promise as a novel PET tracer for imaging of inflammation. This first-in-humans study investigated the safety, tolerability, biodistribution, and radiation dosimetry of this radiopharmaceutical. Six healthy men underwent dynamic whole-body PET/CT. Serial venous blood samples were drawn from 1 to 240 min after intravenous injection of 162 ± 4 MBq of Ga-DOTA-Siglec-9. In addition to γ-counting, the plasma samples were analyzed by high-performance liquid chromatography to detect intact tracer and radioactive metabolites. Radiation doses were calculated using the OLINDA/EXM software, version 2.2. In addition, a patient with early rheumatoid arthritis was studied with both Ga-DOTA-Siglec-9 and F-FDG PET/CT to determine the ability of the new tracer to detect arthritis. Ga-DOTA-Siglec-9 was well tolerated by all subjects. Ga-DOTA-Siglec-9 was rapidly cleared from the blood circulation, and several radioactive metabolites were detected. The organs with the highest absorbed doses were the urinary bladder wall (0.38 mSv/MBq) and kidneys (0.054 mSv/MBq). The mean effective dose was 0.022 mSv/MBq (range, 0.020-0.024 mSv/MBq). Most importantly, however, Ga-DOTA-Siglec-9 was comparable to F-FDG in detecting arthritis. Intravenous injection of Ga-DOTA-Siglec-9 was safe and biodistribution was favorable for testing of the tracer in larger group of patients with rheumatoid arthritis, as is planned for the next phase of clinical trials. The effective radiation dose of Ga-DOTA-Siglec-9 was within the same range as the effective radiation doses of other Ga-labeled tracers. Injection of 150 MBq of Ga-DOTA-Siglec-9 would expose a subject to 3.3 mSv. These findings support the possible repeated clinical use of Ga-DOTA-Siglec-9, such as in trials to elucidate the treatment efficacy of novel drug candidates.
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http://dx.doi.org/10.2967/jnumed.120.250696DOI Listing
April 2021

Human Bone Marrow Adipose Tissue is a Metabolically Active and Insulin-Sensitive Distinct Fat Depot.

J Clin Endocrinol Metab 2020 07;105(7)

Institute of Biomedicine, University of Turku, Turku, Finland.

Context: Bone marrow (BM) in adult long bones is rich in adipose tissue, but the functions of BM adipocytes are largely unknown. We set out to elucidate the metabolic and molecular characteristics of BM adipose tissue (BMAT) in humans.

Objective: Our aim was to determine if BMAT is an insulin-sensitive tissue, and whether the insulin sensitivity is altered in obesity or type 2 diabetes (T2DM).

Design: This was a cross-sectional and longitudinal study.

Setting: The study was conducted in a clinical research center.

Patients Or Other Participants: Bone marrow adipose tissue glucose uptake (GU) was assessed in 23 morbidly obese subjects (9 with T2DM) and 9 healthy controls with normal body weight. In addition, GU was assessed in another 11 controls during cold exposure. Bone marrow adipose tissue samples for molecular analyses were collected from non-DM patients undergoing knee arthroplasty.

Intervention(s): Obese subjects were assessed before and 6 months after bariatric surgery and controls at 1 time point.

Main Outcome Measure: We used positron emission tomography imaging with 2-[18F]fluoro-2-deoxy-D-glucose tracer to characterize GU in femoral and vertebral BMAT. Bone marrow adipose tissue molecular profile was assessed using quantitative RT-PCR.

Results: Insulin enhances GU in human BMAT. Femoral BMAT insulin sensitivity was impaired in obese patients with T2DM compared to controls, but it improved after bariatric surgery. Furthermore, gene expression analysis revealed that BMAT was distinct from brown and white adipose tissue.

Conclusions: Bone marrow adipose tissue is a metabolically active, insulin-sensitive and molecularly distinct fat depot that may play a role in whole body energy metabolism.
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http://dx.doi.org/10.1210/clinem/dgaa216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247553PMC
July 2020

Folate Receptor β-Targeted PET Imaging of Macrophages in Autoimmune Myocarditis.

J Nucl Med 2020 11 13;61(11):1643-1649. Epub 2020 Apr 13.

Turku PET Centre, University of Turku, Turku, Finland

Currently available imaging techniques have limited specificity for the detection of active myocardial inflammation. Aluminum F-labeled 1,4,7-triazacyclononane--triacetic acid conjugated folate (F-FOL) is a PET tracer targeting folate receptor β (FR-β), which is expressed on activated macrophages at sites of inflammation. We evaluated F-FOL PET for the detection of myocardial inflammation in rats with autoimmune myocarditis and studied the expression of FR-β in human cardiac sarcoidosis specimens. Myocarditis was induced by immunizing rats ( = 18) with porcine cardiac myosin in complete Freund adjuvant. Control rats ( = 6) were injected with Freund adjuvant alone. F-FOL was intravenously injected, followed by imaging with a small-animal PET/CT scanner and autoradiography. Contrast-enhanced high-resolution CT or F-FDG PET images were used for coregistration. Rat tissue sections and myocardial autopsy samples from 6 patients with cardiac sarcoidosis were studied for macrophages and FR-β. The myocardium of 10 of 18 immunized rats showed focal macrophage-rich inflammatory lesions, with FR-β expression occurring mainly in M1-polarized macrophages. PET images showed focal myocardial F-FOL uptake colocalizing with inflammatory lesions (SUV, 2.1 ± 1.1), whereas uptake in the remote myocardium of immunized rats and controls was low (SUV, 0.4 ± 0.2 and 0.4 ± 0.1, respectively; < 0.01). Ex vivo autoradiography of tissue sections confirmed uptake of F-FOL in myocardial inflammatory lesions. Uptake of F-FOL in inflamed myocardium was efficiently blocked by a nonlabeled FR-β ligand folate glucosamine in vivo. The myocardium of patients with cardiac sarcoidosis showed many FR-β-positive macrophages in inflammatory lesions. In a rat model of autoimmune myocarditis, F-FOL shows specific uptake in inflamed myocardium containing macrophages expressing FR-β, which were also present in human cardiac sarcoid lesions. Imaging of FR-β expression is a potential approach for the detection of active myocardial inflammation.
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http://dx.doi.org/10.2967/jnumed.119.241356DOI Listing
November 2020

(2S, 4R)-4-[F]Fluoroglutamine for In vivo PET Imaging of Glioma Xenografts in Mice: an Evaluation of Multiple Pharmacokinetic Models.

Mol Imaging Biol 2020 08;22(4):969-978

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

Purpose: The glutamine analogue (2S, 4R)-4-[F]fluoroglutamine ([F]FGln) was investigated to further characterize its pharmacokinetics and acquire in vivo positron emission tomography (PET) images of separate orthotopic and subcutaneous glioma xenografts in mice.

Procedures: [F]FGln was synthesized at a high radiochemical purity as analyzed by high-performance liquid chromatography. An orthotopic model was created by injecting luciferase-expressing patient-derived BT3 glioma cells into the right hemisphere of BALB/cOlaHsd-Foxn1 mouse brains (tumor growth monitored via in vivo bioluminescence), the subcutaneous model by injecting rat BT4C glioma cells into the flank and neck regions of Foxn1 mice. Dynamic PET images were acquired after injecting 10-12 MBq of the tracer into mouse tail veins. Animals were sacrificed 63 min after tracer injection, and ex vivo biodistributions were measured. Tumors and whole brains (with tumors) were cryosectioned, autoradiographed, and stained with hematoxylin-eosin. All images were analyzed with CARIMAS software. Blood sampling of 6 Foxn1 and 6 C57BL/6J mice was performed after 9-14 MBq of tracer was injected at time points between 5 and 60 min then assayed for erythrocyte uptake, plasma protein binding, and plasma parent-fraction of radioactivity to correct PET image-derived whole-blood radioactivity and apply the data to multiple pharmacokinetic models.

Results: Orthotopic human glioma xenografts displayed PET image tumor-to-healthy brain region ratio of 3.6 and 4.8 while subcutaneously xenografted BT4C gliomas displayed (n = 12) a tumor-to-muscle (flank) ratio of 1.9 ± 0.7 (range 1.3-3.4). Using PET image-derived blood radioactivity corrected by population-based stability analyses, tumor uptake pharmacokinetics fit Logan and Yokoi modeling for reversible uptake.

Conclusions: The results reinforce that [F]FGln has preferential uptake in glioma tissue versus that of corresponding healthy tissue and fits well with reversible uptake models.
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http://dx.doi.org/10.1007/s11307-020-01472-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343746PMC
August 2020

Folate receptor-targeted positron emission tomography of experimental autoimmune encephalomyelitis in rats.

J Neuroinflammation 2019 Dec 3;16(1):252. Epub 2019 Dec 3.

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

Background: Folate receptor-β (FR-β) is a cell surface receptor that is significantly upregulated on activated macrophages during inflammation and provides a potential target for folate-based therapeutic and diagnostic agents. FR-β expression in central nervous system inflammation remains relatively unexplored. Therefore, we used focally induced acute and chronic phases of experimental autoimmune encephalomyelitis (EAE) to study patterns of FR-β expression and evaluated its potential as an in vivo imaging target.

Methods: Focal EAE was induced in rats using heat-killed Bacillus Calmette-Guérin followed by activation with complete Freund's adjuvant supplemented with Mycobacterium tuberculosis. The rats were assessed with magnetic resonance imaging and positron emission tomography/computed tomography (PET/CT) at acute (14 days) and chronic (90 days) phases of inflammation. The animals were finally sacrificed for ex vivo autoradiography of their brains. PET studies were performed using FR-β-targeting aluminum [F]fluoride-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid conjugated folate ([F]AlF-NOTA-folate, F-FOL) and 18 kDa translocator protein (TSPO)-targeting N-acetyl-N-(2-[C]methoxybenzyl)-2-phenoxy-5-pyridinamine (C-PBR28). Post-mortem immunohistochemistry was performed using anti-FR-β, anti-cluster of differentiation 68 (anti-CD68), anti-inducible nitric oxide synthase (anti-iNOS), and anti-mannose receptor C-type 1 (anti-MRC-1) antibodies. The specificity of F-FOL binding was verified using in vitro brain sections with folate glucosamine used as a blocking agent.

Results: Immunohistochemical evaluation of focal EAE lesions demonstrated anti-FR-β positive cells at the lesion border in both acute and chronic phases of inflammation. We found that anti-FR-β correlated with anti-CD68 and anti-MRC-1 immunohistochemistry; for MRC-1, the correlation was most prominent in the chronic phase of inflammation. Both F-FOL and C-PBR28 radiotracers bound to the EAE lesions. Autoradiography studies verified that this binding took place in areas of anti-FR-β positivity. A blocking assay using folate glucosamine further verified the tracer's specificity. In the chronic phase of EAE, the lesion-to-background ratio of F-FOL was significantly higher than that of C-PBR28 (P = 0.016).

Conclusion: Our EAE results imply that FR-β may be a useful target for in vivo imaging of multiple sclerosis-related immunopathology. FR-β-targeted PET imaging with F-FOL may facilitate the monitoring of lesion development and complement the information obtained from TSPO imaging by bringing more specificity to the PET imaging armamentarium for neuroinflammation.
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http://dx.doi.org/10.1186/s12974-019-1612-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892159PMC
December 2019

Renal vascular resistance is increased in patients with kidney transplant.

BMC Nephrol 2019 11 27;20(1):437. Epub 2019 Nov 27.

Department of Nephrology, Turku University Hospital, PL 52,Kiinanmyllykatu 4-8, 20521, Turku, Finland.

Background: Despite improvement in short-term outcome of kidney transplants, the long-term survival of kidney transplants has not changed over past decades. Kidney biopsy is the gold standard of transplant pathology but it's invasive. Quantification of transplant blood flow could provide a novel non-invasive method to evaluate transplant pathology. The aim of this retrospective cross-sectional pilot study was to evaluate positron emission tomography (PET) as a method to measure kidney transplant perfusion and find out if there is correlation between transplant perfusion and histopathology.

Methods: Renal cortical perfusion of 19 kidney transplantation patients [average time from transplantation 33 (17-54) months; eGFR 55 (47-69) ml/min] and 10 healthy controls were studied by [ O]HO PET. Perfusion and Doppler resistance index (RI) of transplants were compared with histology of one-year protocol transplant biopsy.

Results: Renal cortical perfusion of healthy control subjects and transplant patients were 2.7 (2.4-4.0) ml min g and 2.2 (2.0-3.0) ml min g, respectively (p = 0.1). Renal vascular resistance (RVR) of the patients was 47.0 (36.7-51.4) mmHg mLming and that of the healthy 32.4 (24.6-39.6) mmHg mLming (p = 0.01). There was a statistically significant correlation between Doppler RI and perfusion of transplants (r = - 0.51, p = 0.026). Transplant Doppler RI of the group of mild fibrotic changes [0.73 (0.70-0.76)] and the group of no fibrotic changes [0.66 (0.61-0.72)] differed statistically significantly (p = 0.03). No statistically significant correlation was found between cortical perfusion and fibrosis of transplants (p = 0.56).

Conclusions: [ O]HO PET showed its capability as a method in measuring perfusion of kidney transplants. RVR of transplant patients with stage 2-3 chronic kidney disease was higher than that of the healthy, although kidney perfusion values didn't differ between the groups. Doppler based RI correlated with perfusion and fibrosis of transplants.
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http://dx.doi.org/10.1186/s12882-019-1617-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882025PMC
November 2019

Kinetic Modelling of [Ga]Ga-DOTA-Siglec-9 in Porcine Osteomyelitis and Soft Tissue Infections.

Molecules 2019 Nov 13;24(22). Epub 2019 Nov 13.

Department of Nuclear Medicine, Aalborg University Hospital, DK-9000 Aalborg, Denmark.

Background: [Ga]Ga-DOTA-Siglec-9 is a positron emission tomography (PET) radioligand for vascular adhesion protein 1 (VAP-1), a protein involved in leukocyte trafficking. The tracer facilitates the imaging of inflammation and infection. Here, we studied the pharmacokinetic modelling of [Ga]Ga-DOTA-Siglec-9 in osteomyelitis and soft tissue infections in pigs.

Methods: Eight pigs with osteomyelitis and soft tissue infections in the right hind limb were dynamically PET scanned for 60 min along with arterial blood sampling. The fraction of radioactivity in the blood accounted for by the parent tracer was evaluated with radio-high-performance liquid chromatography. One- and two-tissue compartment models were used for pharmacokinetic evaluation. Post-mortem soft tissue samples from one pig were analysed with anti-VAP-1 immunofluorescence. In each analysis, the animal's non-infected left hind limb was used as a control.

Results: Tracer uptake was elevated in soft tissue infections but remained low in osteomyelitis. The kinetics of [Ga]Ga-DOTA-Siglec-9 followed a reversible 2-tissue compartment model. The tracer metabolized quickly; however, taking this into account, produced more ambiguous results. Infected soft tissue samples showed endothelial cell surface expression of the Siglec-9 receptor VAP-1.

Conclusion: The kinetics of [Ga]Ga-DOTA-Siglec-9 uptake in porcine soft tissue infections are best described by the 2-tissue compartment model.
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http://dx.doi.org/10.3390/molecules24224094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891593PMC
November 2019

Renal hemodynamics and fatty acid uptake: effects of obesity and weight loss.

Am J Physiol Endocrinol Metab 2019 11 24;317(5):E871-E878. Epub 2019 Sep 24.

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

Human studies of renal hemodynamics and metabolism in obesity are insufficient. We hypothesized that renal perfusion and renal free fatty acid (FFA) uptake are higher in subjects with morbid obesity compared with lean subjects and that they both decrease after bariatric surgery. Cortical and medullary hemodynamics and metabolism were measured in 23 morbidly obese women and 15 age- and sex-matched nonobese controls by PET scanning of [O]-HO (perfusion) and 14()-[F]fluoro-6-thia-heptadecanoate (FFA uptake). Kidney volume and radiodensity were measured by computed tomography, cardiac output by MRI. Obese subjects were re-studied 6 mo after bariatric surgery. Obese subjects had higher renal volume but lower radiodensity, suggesting accumulation of water and/or lipid. Both cardiac output and estimated glomerular filtration rate (eGFR) were increased by ~25% in the obese. Total renal blood flow was higher in the obese [885 (317) (expressed as median and interquartile range) vs. 749 (300) (expressed as means and SD) ml/min of controls, = 0.049]. In both groups, regional blood perfusion was higher in the cortex than medulla; in either region, FFA uptake was ~50% higher in the obese as a consequence of higher circulating FFA levels. Following weight loss (26 ± 8 kg), total renal blood flow was reduced ( = 0.006). Renal volume, eGFR, cortical and medullary FFA uptake were decreased but not fully normalized. Obesity is associated with renal structural, hemodynamic, and metabolic changes. Six months after bariatric surgery, the hemodynamic changes are reversed and the structural changes are improved. On the contrary, renal FFA uptake remains increased, driven by high substrate availability.
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http://dx.doi.org/10.1152/ajpendo.00135.2019DOI Listing
November 2019

Myocardial Blood Flow and Metabolic Rate of Oxygen Measurement in the Right and Left Ventricles at Rest and During Exercise Using O-Labeled Compounds and PET.

Front Physiol 2019 19;10:741. Epub 2019 Jun 19.

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

Simultaneous measurement of right (RV) and left ventricle (LV) myocardial blood flow (MBF), oxygen extraction fraction (OEF), and oxygen consumption (MVO) non-invasively in humans would provide new possibilities to understand cardiac physiology and different patho-physiological states. We developed and tested an optimized novel method to measure MBF, OEF, and MVO simultaneously both in the RV and LV free wall (FW) using positron emission tomography in healthy young men at rest and during supine bicycle exercise. Resting MBF was not significantly different between the three myocardial regions. Exercise increased MBF in the LVFW and septum, but MBF was lower in the RV compared to septum and LVFW during exercise. Resting OEF was similar between the three different myocardial regions (~70%) and increased in response to exercise similarly in all regions. MVO increased approximately two to three times from rest to exercise in all myocardial regions, but was significantly lower in the RV during exercise as compared to septum LVFW. MBF, OEF, and MVO can be assessed simultaneously in the RV and LV myocardia at rest and during exercise. Although there are no major differences in the MBF and OEF between LV and RV myocardial regions in the resting myocardium, MVO per gram of myocardium appears to be lower the RV in the exercising healthy human heart due to lower mean blood flow. The presented method may provide valuable insights for the assessment of MBF, OEF and MVO in hearts in different pathophysiological states.
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http://dx.doi.org/10.3389/fphys.2019.00741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593089PMC
June 2019

Ga-DOTA chelate, a novel imaging agent for assessment of myocardial perfusion and infarction detection in a rodent model.

J Nucl Cardiol 2020 06 29;27(3):891-898. Epub 2019 May 29.

Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, 20521, Turku, Finland.

Background: Magnetic resonance imaging (MRI) with Gadolinium 1,4,7,10-tetraazacyclododecane-N',N″,N''',N″″-tetraacetic acid (Gd-DOTA) enables assessment of myocardial perfusion during first-pass of the contrast agent, while increased retention can signify areas of myocardial infarction (MI). We studied whether Gallium-68-labeled analog, Ga-DOTA, can be used to assess myocardial perfusion on positron emission tomography/computed tomography (PET/CT) in rats, comparing it with C-acetate.

Methods: Rats were studied with C-acetate and Ga-DOTA at 24 hours after permanent ligation of the left coronary artery or sham operation. One-tissue compartmental models were used to estimate myocardial perfusion in normal and infarcted myocardium. After the PET scan, hearts were sectioned for autoradiographic detection of Ga-DOTA distribution.

Results: C-acetate PET showed perfusion defects and histology showed myocardial necrosis in all animals after coronary ligation. Kinetic modeling of Ga-DOTA showed significantly higher k values in normal myocardium than in infarcted areas. There was a significant correlation (r = 0.82, P = 0.001) between k values obtained with Ga-DOTA and C-acetate. After 10 minutes of tracer distribution, the Ga-DOTA concentration was significantly higher in the infarcted than normal myocardium on PET imaging and autoradiography.

Conclusions: Our results indicate that acute MI can be detected as reduced perfusion, as well as increased late retention of Ga-DOTA.
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http://dx.doi.org/10.1007/s12350-019-01752-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326802PMC
June 2020

Glucagon-like peptide-1 receptor expression after myocardial infarction: Imaging study using Ga-NODAGA-exendin-4 positron emission tomography.

J Nucl Cardiol 2020 12 13;27(6):2386-2397. Epub 2018 Dec 13.

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

Background: Activation of glucagon-like peptide-1 receptor (GLP-1R) signaling protects against cardiac dysfunction and remodeling after myocardial infarction (MI). The aim of the study was to evaluate Ga-NODAGA-exendin-4 positron emission tomography (PET) for assessment of GLP-1R expression after MI in rats.

Methods And Results: Rats were studied at 3 days, 1 and 12 weeks after permanent coronary ligation or a sham-operation. Rats were injected with Ga-NODAGA-exendin-4 and scanned with PET and contrast-enhanced computed tomography (CT) followed by digital autoradiography and histology of left ventricle tissue sections. Ga-NODAGA-exendin-4 PET/CT showed focally increased tracer uptake in the infarcted regions peaking at 3 days and continuing at 1 week after MI. Pre-treatment with an unlabeled exendin-4 peptide significantly reduced Ga-NODAGA-exendin-4 uptake. By autoradiography, Ga-NODAGA-exendin-4 uptake was 8.6-fold higher in the infarcted region and slightly increased also in the remote, non-infarcted myocardium at 1 week and 12 weeks post-MI compared with sham. Uptake of Ga-NODAGA-exendin-4 correlated with the amount of CD68-positive macrophages in the infarcted area and alpha-smooth muscle actin staining in the remote myocardium.

Conclusions: Ga-NODAGA-exendin-4 PET detects up-regulation of cardiac GLP-1R expression during healing of MI in rats and may provide information on the activated repair mechanisms after ischemic myocardial injury.
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http://dx.doi.org/10.1007/s12350-018-01547-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749060PMC
December 2020

Correction to: Regulation of human brown adipose tissue by adenosine and A receptors - studies with [O]HO and [C]TMSX PET/CT.

Eur J Nucl Med Mol Imaging 2018 11;45(12):2244

Turku PET Centre, University of Turku, P.O. Box 52, FI-20520, Turku, Finland.

The original version of this article contained a mistake in the first sentence of the Results section of the Abstract.
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http://dx.doi.org/10.1007/s00259-018-4144-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828304PMC
November 2018

Regulation of human brown adipose tissue by adenosine and A receptors - studies with [O]HO and [C]TMSX PET/CT.

Eur J Nucl Med Mol Imaging 2019 03 13;46(3):743-750. Epub 2018 Aug 13.

Turku PET Centre, University of Turku, P.O. Box 52, FI-20520, Turku, Finland.

Purpose: Brown adipose tissue (BAT) has emerged as a potential target to combat obesity and diabetes, but novel strategies to activate BAT are needed. Adenosine and A receptor (A2AR) agonism activate BAT in rodents, and endogenous adenosine is released locally in BAT as a by-product of noradrenaline, but physiological data from humans is lacking. The purpose of this pilot study was to investigate the effects of exogenous adenosine on human BAT perfusion, and to determine the density of A2ARs in human BAT in vivo for the first time, using PET/CT imaging.

Methods: Healthy, lean men (n = 10) participated in PET/CT imaging with two radioligands. Perfusion of BAT, white adipose tissue (WAT) and muscle was quantified with [O]HO at baseline, during cold exposure and during intravenous administration of adenosine. A2AR density of the tissues was quantified with [C]TMSX at baseline and during cold exposure.

Results: Adenosine increased the perfusion of BAT even more than cold exposure (baseline 8.3 ± 4.5, cold 19.6 ± 9.3, adenosine 28.6 ± 7.9 ml/100 g/min, p < 0.01). Distribution volume of [C]TMSX in BAT was significantly lower during cold exposure compared to baseline. In cold, low [C]TMSX binding coincided with high concentrations of noradrenaline.

Conclusions: Adenosine administration caused a maximal perfusion effect in human supraclavicular BAT, indicating increased oxidative metabolism. Cold exposure increased noradrenaline concentrations and decreased the density of A2AR available for radioligand binding in BAT, suggesting augmented release of endogenous adenosine. Our results show that adenosine and A2AR are relevant for activation of human BAT, and A2AR provides a future target for enhancing BAT metabolism.
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http://dx.doi.org/10.1007/s00259-018-4120-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351510PMC
March 2019

The renal blood flow reserve in healthy humans and patients with atherosclerotic renovascular disease measured by positron emission tomography using [O]HO.

EJNMMI Res 2018 Jun 11;8(1):45. Epub 2018 Jun 11.

Department of Nephrology, Division of Medicine, Turku University Hospital, PL 52, Kiinamyllynkatu 4-8, 20521, Turku, Finland.

Background: Microvascular function plays an important role in ARVD (atherosclerotic renovascular disease). RFR (renal flow reserve), the capacity of renal vasculature to dilate, is known to reflect renal microvascular function. In this pilot study, we assessed PET (positron emission tomography)-based RFR values of healthy persons and renal artery stenosis patients. Seventeen patients with ARVD and eight healthy subjects were included in the study. Intravenous enalapril 1 mg was used as a vasodilatant, and the maximum response (blood pressure and RFR) to it was measured at 40 min. Renal perfusion was measured by means of oxygen-15-labeled water PET. RFR was calculated as a difference of stress flow and basal flow and was expressed as percent [(stress blood flow - basal blood flow)/basal blood flow] × 100%.

Results: RFR of the healthy was 22%. RFR of the stenosed kidneys of bilateral stenosis patients (27%) was higher than that of the stenosed kidneys of unilateral stenosis patients (15%). RFR of the contralateral kidneys of unilateral stenosis patients was 21%. There was no difference of statistical significance between RFR values of ARVD subgroups or between ARVD subgroups and the healthy. In the stenosed kidneys of unilateral ARVD patients, stenosis grade of the renal artery correlated negatively with basal (p = 0.04) and stress flow (p = 0.02). Dispersion of RFR values was high.

Conclusions: This study is the first to report [O]HO PET-based RFR values of healthy subjects and ARVD patients in humans. The difference between RFR values of ARVD patients and the healthy did not reach statistical significance perhaps because of high dispersion of RFR values. [O]HO PET is a valuable non-invasive and quantitative method to evaluate renal blood flow though high dispersion makes imaging challenging. Larger studies are needed to get more information about [O]HO PET method in evaluation of renal blood flow.
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http://dx.doi.org/10.1186/s13550-018-0395-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995766PMC
June 2018

Cannabinoid Type 1 Receptors Are Upregulated During Acute Activation of Brown Adipose Tissue.

Diabetes 2018 07 12;67(7):1226-1236. Epub 2018 Apr 12.

Turku PET Centre, University of Turku, Turku, Finland

Activating brown adipose tissue (BAT) could provide a potential approach for the treatment of obesity and metabolic disease in humans. Obesity is associated with upregulation of the endocannabinoid system, and blocking the cannabinoid type 1 receptor (CB1R) has been shown to cause weight loss and to decrease cardiometabolic risk factors. These effects may be mediated partly via increased BAT metabolism, since there is evidence that CB1R antagonism activates BAT in rodents. To investigate the significance of CB1R in BAT function, we quantified the density of CB1R in human and rodent BAT using the positron emission tomography radioligand [F]FMPEP- and measured BAT activation in parallel with the glucose analog [F]fluorodeoxyglucose. Activation by cold exposure markedly increased CB1R density and glucose uptake in the BAT of lean men. Similarly, β3-receptor agonism increased CB1R density in the BAT of rats. In contrast, overweight men with reduced BAT activity exhibited decreased CB1R in BAT, reflecting impaired endocannabinoid regulation. Image-guided biopsies confirmed CB1R mRNA expression in human BAT. Furthermore, CB1R blockade increased glucose uptake and lipolysis of brown adipocytes. Our results highlight that CB1Rs are significant for human BAT activity, and the CB1Rs provide a novel therapeutic target for BAT activation in humans.
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http://dx.doi.org/10.2337/db17-1366DOI Listing
July 2018

Pretargeted PET Imaging of -Cyclooctene-Modified Porous Silicon Nanoparticles.

ACS Omega 2017 Jan 6;2(1):62-69. Epub 2017 Jan 6.

Department of Chemistry - Radiochemistry, University of Helsinki, A.I. Virtasen aukio 1, 00560 Helsinki, Finland.

Pretargeted positron emission tomography (PET) imaging based on bioorthogonal chemical reactions has proven its potential in immunoimaging. It may also have great potential in nanotheranostic applications. Here, we report the first successful pretargeted PET imaging of -cyclooctene-modified mesoporous silicon nanoparticles, using F-labeled tetrazine as a tracer. The inverse electron-demand Diels-Alder cycloaddition (IEDDA) reaction was fast, resulting in high radioactivity accumulation in the expected organs within 10 min after the administration of the tracer. The highest target-to-background ratio was achieved 120 min after the tracer injection. A clear correlation between the efficiency of the in vivo IEDDA labeling reaction and the injected amount of the tracer was observed. The radioactivity accumulation decreased with the increased amount of the co-injected carrier, indicating saturation in the reaction sites. This finding was supported by the in vitro results. Our study suggests that pretargeted imaging has excellent potential in nanotheranostic PET imaging when using high-specific-activity tracers.
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http://dx.doi.org/10.1021/acsomega.6b00269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478181PMC
January 2017

Effects of meal and incretins in the regulation of splanchnic blood flow.

Endocr Connect 2017 Apr 3;6(3):179-187. Epub 2017 Mar 3.

Turku PET CentreUniversity of Turku, Turku, Finland

Objective: Meal ingestion is followed by a redistribution of blood flow (BF) within the splanchnic region contributing to nutrient absorption, insulin secretion and glucose disposal, but factors regulating this phenomenon in humans are poorly known. The aim of the present study was to evaluate the organ-specific changes in BF during a mixed-meal and incretin infusions.

Design: A non-randomized intervention study of 10 healthy adults to study splanchnic BF regulation was performed.

Methods: Effects of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) infusions and mixed-meal were tested in 10 healthy, glucose tolerant subjects using PET-MRI multimodal imaging technology. Intestinal and pancreatic BF and blood volume (BV) were measured with O-water and O-carbon monoxide, respectively.

Results: Ingestion of a mixed-meal led to an increase in pancreatic and jejunal BF, whereas duodenal BF was unchanged. Infusion of GIP and GLP-1 reduced BF in the pancreas. However, GIP infusion doubled blood flow in the jejunum with no effect of GLP-1.

Conclusion: Together, our data suggest that meal ingestion leads to increases in pancreatic BF accompanied by a GIP-mediated increase in jejunal but not duodenal blood flow.
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http://dx.doi.org/10.1530/EC-17-0015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428912PMC
April 2017

A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate.

PLoS One 2017 27;12(1):e0169964. Epub 2017 Jan 27.

Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.

Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac energy substrate usage during sunitinib treatment, hypothesising that these changes could represent a strategy for the early detection of cardiotoxicity. Balb/CJ mice or Sprague-Dawley rats were treated orally for 4 weeks with 40 or 20 mg/kg/day sunitinib. Cardiac positron emission tomography (PET) was implemented to investigate alterations in myocardial glucose and oxidative metabolism. Following treatment, blood pressure increased, and left ventricular ejection fraction decreased. Cardiac [18F]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [11C]Acetate-PET showed decreased myocardial perfusion following treatment. Electron microscopy revealed significant lipid accumulation in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top myocardial signalling pathways perturbed. Sunitinib treatment results in an increased reliance on glycolysis, increased myocardial lipid deposition and perturbed mitochondrial function, indicative of a fundamental energy crisis resulting in compromised myocardial energy metabolism and function. Our findings suggest that a cardiac PET strategy may represent a rational approach to non-invasively monitor metabolic pathway remodeling following sunitinib treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169964PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5271313PMC
August 2017

Brain Cholinergic Function and Response to Rivastigmine in Patients With Chronic Sequels of Traumatic Brain Injury: A PET Study.

J Head Trauma Rehabil 2018 Jan/Feb;33(1):25-32

The Division of Clinical Neurosciences (Drs Östberg, Rinne, and Tenovuo), and Turku Positron Emission Tomography Centre (Drs Virta and Rinne, Messrs Oikonen and Luoto, and Ms Arponen), Turku University Hospital, Finland; and Department of Nuclear Medicine, PET and Cyclotron Unit, Odense University Hospital, Denmark (Dr Någren).

Objective: To investigate quantitative positron emission tomography (PET) findings and to study whether the cholinergic function differs between respondents to cholinergic medication versus nonrespondents.

Setting: Outpatient clinic and university PET imaging center.

Participants: We studied 17 subjects for more than 1 year after at least moderate traumatic brain injury. Ten of the subjects were respondents and 7 nonrespondents to cholinergic medication.

Design: Cholinergic function was assessed with [methyl-C] N-methylpiperidyl-4-acetate-PET (C-MP4A-PET), which reflects the activity of the acetylcholinesterase (AChE) enzyme. The subjects were PET scanned twice: without medication and after a 4-week treatment with rivastigmine 1.5 mg twice a day.

Measures: Regional cerebral AChE activity was measured with PET.

Results: At baseline Statistical Parametric Mapping analyses showed significantly lower AChE activity in respondents bilaterally in the frontal cortex as compared with nonrespondents. Region of interest (ROI) analysis revealed that the difference was most pronounced in the lateral frontal cortex (-9.4%, P = .034) and anterior cingulate (-6.0%, P = .049). After rivastigmine treatment, AChE activity was notably lower throughout the cortex in both respondents and nonrespondents, without significant differences between them.

Conclusion: Our study suggests that frontal cholinergic dysfunction is associated with the clinical response to cholinergic stimulation in patients with traumatic brain injury.
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http://dx.doi.org/10.1097/HTR.0000000000000279DOI Listing
August 2019

Parametric Binding Images of the TSPO Ligand 18F-DPA-714.

J Nucl Med 2016 Oct 3;57(10):1543-1547. Epub 2016 Jun 3.

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

F-labeled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide (DPA-714) is a radioligand for the 18-kDa translocator protein. The purpose of the present study was to identify the best method for generating quantitative parametric images of F-DPA-714 binding.

Methods: Ninety-minute dynamic F-DPA-714 PET scans with full arterial sampling from 6 healthy subjects and 9 Alzheimer disease (AD) patients were used. Plasma-input-based Logan graphical analysis and spectral analysis were used to generate parametric volume of distribution (V) images. Five versions of Ichise, reference Logan, and 2 basis function implementations (receptor parametric mapping and simplified reference tissue model 2 [SRTM2]) of SRTM, all using gray matter cerebellum as the reference region, were applied to generate nondisplaceable binding potential (BP) images.

Results: Plasma-input Logan analysis (r = 0.99; slope, 0.88) and spectral analysis (r = 0.99, slope, 0.93) generated estimates of V that correlated well with values obtained using nonlinear regression. BP values generated using SRTM2 (r = 0.83; slope, 0.95) and reference Logan analysis (r = 0.88; slope, 1.01) correlated well with nonlinear regression-based estimates.

Conclusion: Both Logan analysis and spectral analysis can be used to obtain quantitatively accurate V images of F-DPA-714. In addition, SRTM2 and reference Logan analysis can provide accurate BP images. These parametric images could be used for voxel-based comparisons.
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http://dx.doi.org/10.2967/jnumed.116.173013DOI Listing
October 2016

Human brown adipose tissue [(15)O]O2 PET imaging in the presence and absence of cold stimulus.

Eur J Nucl Med Mol Imaging 2016 Sep 19;43(10):1878-86. Epub 2016 Mar 19.

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

Purpose: Brown adipose tissue (BAT) is considered a potential target for combatting obesity, as it produces heat instead of ATP in cellular respiration due to uncoupling protein-1 (UCP-1) in mitochondria. However, BAT-specific thermogenic capacity, in comparison to whole-body thermogenesis during cold stimulus, is still controversial. In our present study, we aimed to determine human BAT oxygen consumption with [(15)O]O2 positron emission tomography (PET) imaging. Further, we explored whether BAT-specific energy expenditure (EE) is associated with BAT blood flow, non-esterified fatty acid (NEFA) uptake, and whole-body EE.

Methods: Seven healthy study subjects were studied at two different scanning sessions, 1) at room temperature (RT) and 2) with acute cold exposure. Radiotracers [(15)O]O2, [(15)O]H2O, and [(18)F]FTHA were given for the measurements of BAT oxygen consumption, blood flow, and NEFA uptake, respectively, with PET-CT. Indirect calorimetry was performed to assess differences in whole-body EE between RT and cold.

Results: BAT-specific EE and oxygen consumption was higher during cold stimulus (approx. 50 %); similarly, whole-body EE was higher during cold stimulus (range 2-47 %). However, there was no association in BAT-specific EE and whole-body EE. BAT-specific EE was found to be a minor contributor in cold induced whole-body thermogenesis (almost 1 % of total whole-body elevation in EE). Certain deep muscles in the cervico-thoracic region made a major contribution to this cold-induced thermogenesis (CIT) without any visual signs or individual perception of shivering. Moreover, BAT-specific EE associated with BAT blood flow and NEFA uptake both at RT and during cold stimulus.

Conclusion: Our study suggests that BAT is a minor and deep muscles are a major contributor to CIT. In BAT, both in RT and during cold, cellular respiration is linked with circulatory NEFA uptake.
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http://dx.doi.org/10.1007/s00259-016-3364-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969352PMC
September 2016

Absorption, distribution and excretion of intravenously injected (68)Ge/ (68)Ga generator eluate in healthy rats, and estimation of human radiation dosimetry.

EJNMMI Res 2015 Dec 17;5(1):117. Epub 2015 Jul 17.

Turku PET Centre, Turku University Hospital, University of Turku, FI-20521, Turku, Finland,

Background: This study evaluated the absorption, distribution, and excretion of Gallium-68 ((68)Ga) radionuclide after a single intravenous (i.v.) injection of (68)Ge/(68)Ga generator eluate in healthy rats. Additionally, human radiation doses were estimated from the rat data.

Methods: Twenty-one female and 21 male Sprague-Dawley rats were i.v. injected with 47 ± 4 MBq of (68)Ge/(68)Ga generator eluate, and the radioactivity of excised organs was measured using a gamma counter at 5, 30, 60, 120, or 180 min afterwards (n = 3-7 for each time point). The radioactivity concentration and plasma pharmacokinetic parameters were calculated. Subsequently, the estimates for human radiation dosimetry were determined. Additionally, 4 female and 5 male rats were positron emission tomography (PET) imaged for in vivo visualization of biodistribution.

Results: (68)Ga radioactivity was cleared relatively slowly from blood circulation and excreted into the urine, with some retention in the liver and spleen. Notably, the (68)Ga radioactivity in female genital organs, i.e., the uterus and ovaries, was considerable higher compared with male genitals. Extrapolating from the female and male rat (68)Ga data, the estimated effective dose was 0.0308 mSv/MBq for a 57-kg woman and 0.0191 mSv/MBq for a 70-kg man.

Conclusions: The estimated human radiation burden of the (68)Ge/(68)Ga generator eluate was slightly higher for females and similar for males as compared with somatostatin receptor ligands (68)Ga-DOTANOC, (68)Ga-DOTATOC, and (68)Ga-DOTATATE, which is probably due to the retention in the liver and spleen. Our results revealed some differences between female and male rat data, which, at least in part, may be explained by the small sample size.
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http://dx.doi.org/10.1186/s13550-015-0117-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504870PMC
December 2015

The effects of bariatric surgery on pancreatic lipid metabolism and blood flow.

J Clin Endocrinol Metab 2015 May 3;100(5):2015-23. Epub 2015 Mar 3.

Turku PET Centre (H.H., J.K., J.C.H., J.J.T., H.K.K., H.I., V.O., T.T., P.N.), University of Turku, 20520 Turku, Finland; Department of Endocrinology (M.S., P.N.) and Division of Digestive Surgery and Urology (P.S.), Turku University Hospital, 20520 Turku, Finland; Faculty of Medicine (N.K.), Kagawa University, Kagawa 760-0016, Japan; Institute of Biomedical Engineering (A.M.), National Research Council, 35127 Padua, Italy; and Institute of Clinical Physiology (P.I.), National Research Council, 56124 Pisa, Italy.

Context: Bariatric surgery leads to a rapid and sustained weight loss often accompanied with improvement in glucose homeostasis.

Objective: The objective of this study was to investigate the effects of bariatric surgery on pancreatic lipid metabolism, blood flow, and glycemic control.

Design: This was a longitudinal study.

Setting: The study was conducted in a clinical research center.

Participants: This study included 27 morbidly obese and 15 healthy control subjects.

Interventions: Measurements were performed using positron emission tomography with the palmitate analog 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid and radiowater ([(15)O]H2O) and computed tomography. In morbidly obese subjects, positron emission tomography/computed tomography imaging studies were performed before and 6 months after bariatric surgery (either Roux-en-Y gastric bypass or sleeve gastrectomy).

Main Outcome Measures: Pancreatic fat and fat-free volume, fatty acid uptake and blood flow were measured as well as parameters of β-cell function, glucose tolerance, and insulin sensitivity.

Results: Six months after bariatric surgery, 23% excess weight loss was observed (P < .0001), and diabetes remission was seen in 7 of 10 patients. When compared with preoperative values, after surgery, notable decreases in pancreatic fat volume (P < .01), fatty acid uptake, and blood flow (both P < .05) were seen, whereas no change was seen in pancreatic fat-free volume. The decrease in pancreatic fat volume and the preservation of blood flow were associated with favorable glucose homeostasis and β-cell function.

Conclusions: Bariatric surgery elicits marked alterations in pancreatic lipid metabolism and blood flow, which may contribute to the observed improvement in glucose homeostasis and remission of type 2 diabetes.
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http://dx.doi.org/10.1210/jc.2014-4236DOI Listing
May 2015

Quantification of [18F]DPA-714 binding in the human brain: initial studies in healthy controls and Alzheimer's disease patients.

J Cereb Blood Flow Metab 2015 May 4;35(5):766-72. Epub 2015 Feb 4.

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

Fluorine-18 labelled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide ([(18)F]DPA-714) binds to the 18-kDa translocator protein (TSPO) with high affinity. The aim of this initial methodological study was to develop a plasma input tracer kinetic model for quantification of [(18)F]DPA-714 binding in healthy subjects and Alzheimer's disease (AD) patients, and to provide a preliminary assessment whether there is a disease-related signal. Ten AD patients and six healthy subjects underwent a dynamic positron emission tomography (PET) study along with arterial sampling and a scan protocol of 150 minutes after administration of 250 ± 10 MBq [(18)F]DPA-714. The model that provided the best fits to tissue time activity curves (TACs) was selected based on Akaike Information Criterion and F-test. The reversible two tissue compartment plasma input model with blood volume parameter was the preferred model for quantification of [(18)F]DPA-714 kinetics, irrespective of scan duration, volume of interest, and underlying volume of distribution (VT). Simplified reference tissue model (SRTM)-derived binding potential (BPND) using cerebellar gray matter as reference tissue correlated well with plasma input-based distribution volume ratio (DVR). These data suggest that [(18)F]DPA-714 cannot be used for separating individual AD patients from healthy subjects, but further studies including TSPO binding status are needed to substantiate these findings.
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http://dx.doi.org/10.1038/jcbfm.2014.261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420859PMC
May 2015

Validation of [(11) C]ORM-13070 as a PET tracer for alpha2c -adrenoceptors in the human brain.

Synapse 2015 Mar 8;69(3):172-81. Epub 2015 Jan 8.

Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland; Clinical Research Services Turku CRST, Turku, Finland; Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland.

This study explored the use of the α2C -adrenoceptor PET tracer [(11) C]ORM-13070 to monitor α2C -AR occupancy in the human brain. The subtype-nonselective α2 -AR antagonist atipamezole was administered to eight healthy volunteer subjects to determine its efficacy and potency (Emax and EC50 ) at inhibiting tracer uptake. We also explored whether the tracer could reveal changes in the synaptic concentrations of endogenous noradrenaline in the brain, in response to several pharmacological and sensory challenge conditions. We assessed occupancy from the bound-to-free ratio measured during 5-30 min post injection. Based on extrapolation of one-site binding, the maximal extent of inhibition of striatal [(11) C]ORM-13070 uptake (Emax ) achievable by atipamezole was 78% (95% CI 69-87%) in the caudate nucleus and 65% (53-77%) in the putamen. The EC50 estimates of atipamezole (1.6 and 2.5 ng/ml, respectively) were in agreement with the drug's affinity to α2C -ARs. These findings represent clear support for the use of [(11) C]ORM-13070 for monitoring drug occupancy of α2C -ARs in the living human brain. Three of the employed noradrenaline challenges were associated with small, approximately 10-16% average reductions in tracer uptake in the dorsal striatum (atomoxetine, ketamine, and the cold pressor test; P < 0.05 for all), but insulin-induced hypoglycemia did not affect tracer uptake. The tracer is suitable for studying central nervous system receptor occupancy by α2C -AR ligands in human subjects. [(11) C]ORM-13070 also holds potential as a tool for in vivo monitoring of synaptic concentrations of noradrenaline, but this remains to be further evaluated in future studies.
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http://dx.doi.org/10.1002/syn.21798DOI Listing
March 2015

Positron emission tomography imaging of the 18-kDa translocator protein (TSPO) with [18F]FEMPA in Alzheimer's disease patients and control subjects.

Eur J Nucl Med Mol Imaging 2015 Mar 21;42(3):438-46. Epub 2014 Nov 21.

Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden,

Purpose: Imaging of the 18-kDa translocator protein (TSPO) is a potential tool for examining microglial activation and neuroinflammation in early Alzheimer's disease (AD). [(18)F]FEMPA is a novel high-affinity second-generation TSPO radioligand that has displayed suitable pharmacokinetic properties in preclinical studies. The aims of this study were to quantify the binding of [(18)F]FEMPA to TSPO in AD patients and controls and to investigate whether higher [(18)F]FEMPA binding in AD patients than in controls could be detected in vivo.

Methods: Ten AD patients (five men, five women; age 66.9 ± 7.3 years; MMSE score 25.5 ± 2.5) and seven controls (three men, four women; age 63.7 ± 7.2 years, MMSE score 29.3 ± 1.0) were studied using [(18)F]FEMPA at Turku (13 subjects) and at Karolinska Institutet (4 subjects). The in vitro binding affinity for TSPO was assessed using PBR28 in a competition assay with [(3)H]PK11195 in seven controls and eight AD patients. Cortical and subcortical regions of interest were examined. Quantification was performed using a two-tissue compartment model (2TCM) and Logan graphical analysis (GA). The outcome measure was the total distribution volume (V T). Repeated measures analysis of variance was used to assess the effect of group and TSPO binding status on V T.

Results: Five AD patients and four controls were high-affinity binders (HABs). Three AD patients and three controls were mixed-affinity binders. V T estimated with Logan GA was significantly correlated with V T estimated with the 2TCM in both controls (r = 0.97) and AD patients (r = 0.98) and was selected for the final analysis. Significantly higher V T was found in the medial temporal cortex in AD patients than in controls (p = 0.044) if the TSPO binding status was entered as a covariate. If only HABs were included, significantly higher V T was found in the medial and lateral temporal cortex, posterior cingulate, caudate, putamen, thalamus and cerebellum in AD patients than in controls (p < 0.05).

Conclusion: [(18)F]FEMPA seems to be a suitable radioligand for detecting increased TSPO binding in AD patients if their binding status is taken into account.
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http://dx.doi.org/10.1007/s00259-014-2955-8DOI Listing
March 2015

Automated reference region extraction and population-based input function for brain [(11)C]TMSX PET image analyses.

J Cereb Blood Flow Metab 2015 Jan 5;35(1):157-65. Epub 2014 Nov 5.

1] Turku PET Centre, Turku University Hospital and University of Turku, Turku, Finland [2] Division of Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland.

[(11)C]TMSX ([7-N-methyl-(11)C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine) is a selective adenosine A2A receptor (A2AR) radioligand. In the central nervous system (CNS), A2AR are linked to dopamine D2 receptor function in striatum, but they are also important modulators of inflammation. The golden standard for kinetic modeling of brain [(11)C]TMSX positron emission tomography (PET) is to obtain arterial input function via arterial blood sampling. However, this method is laborious, prone to errors and unpleasant for study subjects. The aim of this work was to evaluate alternative input function acquisition methods for brain [(11)C]TMSX PET imaging. First, a noninvasive, automated method for the extraction of gray matter reference region using supervised clustering (SCgm) was developed. Second, a method for obtaining a population-based arterial input function (PBIF) was implemented. These methods were created using data from 28 study subjects (7 healthy controls, 12 multiple sclerosis patients, and 9 patients with Parkinson's disease). The results with PBIF correlated well with original plasma input, and the SCgm yielded similar results compared with cerebellum as a reference region. The clustering method for extracting reference region and the population-based approach for acquiring input for dynamic [(11)C]TMSX brain PET image analyses appear to be feasible and robust methods, that can be applied in patients with CNS pathology.
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http://dx.doi.org/10.1038/jcbfm.2014.194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294409PMC
January 2015