Publications by authors named "Pauliina Luoto"

29 Publications

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Prospective study on the effect of short-term androgen deprivation therapy on PSMA uptake evaluated with Ga-PSMA-11 PET/MRI in men with treatment-naïve prostate cancer.

Eur J Nucl Med Mol Imaging 2020 03 26;47(3):665-673. Epub 2019 Dec 26.

Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland.

Purpose: Based on in vitro studies, it is known that androgen deprivation therapy (ADT) increases prostate-specific membrane antigen (PSMA) expression. Therefore, we hypothesised that ADT improves the performance of PSMA-PET imaging in primary staging of prostate cancer. The purpose of the study was to demonstrate the time course effect of ADT on PSMA uptake in different types of metastatic lesions evaluated with Ga-PSMA-11 PET/MRI.

Methods: Nine men with treatment-naïve prostate cancer were enrolled to a prospective, registered (NCT03313726) clinical trial. A Ga-PSMA-11 PET/MRI was performed once before and 3 times post-ADT (degarelix, Firmagon). Change of maximum standardised uptake values (SUVmax) in prostate, lymph nodes, bone metastases, and physiologically PSMA-avid organs were evaluated in a time frame of 1-8 weeks.

Results: All patients reached castration levels within 10 days, and 50% decrease in prostate-specific antigen (PSA) concentration was observed 14 days post-ADT. A heterogeneous increase in PSMA uptake was observed 3 to 4 weeks post-ADT. This phenomenon was definitively more evident in bone metastases: 13 (57%) of the metastasis, with a mean (range) SUVmax increase of 77% (8-238%). In one patient, already having bone metastases at baseline, three new bone metastases were observed post-ADT. Of lesions with reduced SUVmax, none disappeared.

Conclusions: Both in patient and region level, increase in PSMA uptake post-ADT is heterogenous and is seen most evidently in bone metastases. Preliminary results on a small cohort of patients suggest the clinical impact of ADT on improving the performance of Ga-PSMA PET in staging seems to be minor. However, the optimal imaging time point might be 3 to 4 weeks post-ADT. Since none of the metastases with decreasing SUVmax disappeared, it seems that short-term usage of ADT does not interfere with the interpretation of Ga-PSMA PET.

Trial Registration: NCT03313726, registered 18 October 2017; EUDRA-CT, 2017-002345-29.
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http://dx.doi.org/10.1007/s00259-019-04635-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081750PMC
March 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

A Comparative Ga-Citrate and Ga-Chloride PET/CT Imaging of Osteomyelitis in the Rat Tibia.

Contrast Media Mol Imaging 2018 25;2018:9892604. Epub 2018 Feb 25.

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

There may be some differences in the behavior of Ga-chloride and Ga-citrate leading to different accumulation profiles. This study compared Ga-citrate and Ga-chloride PET/CT imaging under standardized experimental models. Diffuse tibial osteomyelitis and uncomplicated bone healing rat models were used ( = 32). Two weeks after surgery, PET/CT imaging was performed on consecutive days using Ga-citrate or Ga-chloride, and tissue accumulation was confirmed by analysis. In addition, peripheral quantitative computed tomography and conventional radiography were performed. Osteomyelitis was verified by microbiological analysis and specimens were also processed for histomorphometry. In PET/CT imaging, the SUV of Ga-chloride and Ga-citrate in the osteomyelitic tibias (3.6 ± 1.4 and 4.7 ± 1.5, resp.) were significantly higher ( = 0.0019 and = 0.0020, resp.) than in the uncomplicated bone healing (2.7 ± 0.44 and 2.5 ± 0.49, resp.). In osteomyelitic tibias, the SUV of Ga-citrate was significantly higher than the uptake of Ga-chloride ( = 0.0017). In animals with uncomplicated bone healing, no difference in the SUV of Ga-chloride or Ga-citrate was seen in the operated tibias. This study further corroborates the use of Ga-citrate for PET imaging of osteomyelitis.
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http://dx.doi.org/10.1155/2018/9892604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845485PMC
July 2019

PET/CT to detect adverse reactions to metal debris in patients with metal-on-metal hip arthroplasty: an exploratory prospective study.

Clin Physiol Funct Imaging 2018 Sep 27;38(5):847-855. Epub 2017 Dec 27.

Orthopaedic Research Unit, Department of Orthopaedic Surgery and Traumatology, Turku University Hospital and University of Turku, Turku, Finland.

Metal-on-metal (MoM) bearings in total hip arthroplasties and hip resurfacing arthroplasties have recently shown a new type of complication: adverse reactions to metal debris (ARMD). ARMD is characterized by local severe inflammation and tissue necrosis leading to implant failures. The gluteal muscle region is important for the patient outcome after revision surgery. This prospective positron emission tomography/computed tomography (PET/CT) study was undertaken to evaluate the characteristics of 2-deoxy-2-[ F]fluoro-d-glucose ([ F]FDG) and [ Ga]Gallium citrate ([ Ga]Citrate) PET/CT in ARMD patients. [ F]FDG and [ Ga]Citrate PET/CT were performed in 18 hip arthroplasty patients: 12 ARMD patients (with 16 MoM hips) and six arthroplasty controls without ARMD. Tracer uptake was evaluated visually, and maximum standardized uptake (SUV ) was measured in the gluteal muscle region. ARMD severity was graded by metal artefact reduction sequence-magnetic resonance imaging (MARS-MRI). Periprosthetic [ F]FDG uptake was observed in 15 of 16 hips, [ Ga]Citrate uptake in three of 16 hips, respectively. The distribution of tracer uptake resembled infection in three hips. In the gluteal muscle region, the SUV of [ F]FDG was significantly greater in hips with moderate and severe ARMD compared with the controls (P = 0·009 for [ F]FDG and P = 0·217 for [ Ga]Citrate). In patients who needed revision surgery, an intraoperative finding of gluteal muscle necrosis was associated with increased local SUV as detected by preoperative [ F]FDG (P = 0·039), but not by [ Ga]Citrate (P = 0·301). In conclusion, the inflammatory reaction to metal debris in hip arthroplasty patients is best visualized with [ F]FDG.
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http://dx.doi.org/10.1111/cpf.12493DOI Listing
September 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

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

Comparison of Somatostatin Receptor 2-Targeting PET Tracers in the Detection of Mouse Atherosclerotic Plaques.

Mol Imaging Biol 2016 Feb;18(1):99-108

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

Purpose: Rupture-prone atherosclerotic plaques are characterized by accumulation of macrophages, which have shown to express somatostatin type 2 receptors. We aimed to investigate whether somatostatin receptor-targeting positron emission tomography (PET) tracers, [(68)Ga]DOTANOC, [(18)F]FDR-NOC, and [(68)Ga]DOTATATE, can detect inflamed atherosclerotic plaques.

Procedures: Atherosclerotic IGF-II/LDLR(-/-)ApoB(100/100) mice were studied in vivo and ex vivo for tracer uptake into atherosclerotic plaques. Furthermore, [(68)Ga]DOTANOC and [(68)Ga]DOTATATE were compared in a head-to-head setting for in vivo PET/X-ray computed tomography (CT) imaging characteristics.

Results: Ex vivo uptake of [(68)Ga]DOTANOC and [(68)Ga]DOTATATE in the aorta was higher in atherosclerotic mice compared to control C57Bl/6N mice, while the aortic uptake of [(18)F]FDR-NOC showed no genotype difference. Unlike [(18)F]FDR-NOC, [(68)Ga]DOTANOC and [(68)Ga]DOTATATE showed preferential binding to atherosclerotic plaques with plaque-to-wall ratio of 1.7 ± 0.3 and 2.1 ± 0.5, respectively. However, the aortic uptake and aorta-to-blood ratio of [(68)Ga]DOTANOC were higher compared to [(68)Ga]DOTATATE in in vivo PET/CT imaging.

Conclusion: Our results demonstrate superior applicability for [(68)Ga]DOTANOC and [(68)Ga]DOTATATE in the detection of atherosclerotic plaques compared to [(18)F]FDR-NOC.
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http://dx.doi.org/10.1007/s11307-015-0873-1DOI Listing
February 2016

Somatostatin receptor subtype 2 in high-grade gliomas: PET/CT with (68)Ga-DOTA-peptides, correlation to prognostic markers, and implications for targeted radiotherapy.

EJNMMI Res 2015 22;5:25. Epub 2015 Apr 22.

Department of Oncology and Radiotherapy, Turku University Hospital, Hämeentie 11, 20521 Turku, Finland.

Background: High-grade gliomas (HGGs) express somatostatin receptors (SSTR), rendering them candidates for peptide receptor radionuclide therapy (PRRT). Our purpose was to evaluate the potential of (68)Ga-DOTA-1-Nal(3)-octreotide ((68)Ga-DOTANOC) or (68)Ga-DOTA-Tyr(3)-octreotide ((68)Ga-DOTATOC) to target SSTR subtype 2 (SSTR2) in HGGs, and to study the association between SSTR2 expression and established biomarkers.

Methods: Twenty-seven patients (mean age 52 years) with primary or recurrent HGG prospectively underwent (68)Ga-DOTA-peptide positron emission tomography/computed tomography (PET/CT) before resection. Maximum standardized uptake values (SUVmax) and receptor binding potential (BP) were calculated on PET/CT and disruption of blood-brain barrier (BBB) from contrast-enhanced T1-weighted magnetic resonance imaging (MRI-T1-Gad). Tumor volume concordance between PET and MRI-T1-Gad was assessed by Dice similarity coefficient (DC) and correlation by Spearman's rank. Immunohistochemically determined SSTR2 status was compared to receptor imaging findings, prognostic biomarkers, and survival with Kruskal-Wallis, Pearson chi-square, and multivariate Cox regression, respectively.

Results: All 19 HGGs with disrupted BBB demonstrated tracer uptake. Tumor SUVmax (2.25 ± 1.33) correlated with MRI-T1-Gad (r = 0.713, P = 0.001) although DC 0.41 ± 0.19 suggested limited concordance. SSTR2 immunohistochemistry was regarded as positive in nine HGGs (32%) but no correlation with SUVmax or BP was found. By contrast, SSTR2 expression was associated with IDH1 mutation (P = 0.007), oligodendroglioma component (P = 0.010), lower grade (P = 0.005), absence of EGFR amplification (P = 0.021), and longer progression-free survival (HR 0.161, CI 0.037 to 0.704, P = 0.015).

Conclusions: In HGGs, uptake of (68)Ga-DOTA-peptides is associated with disrupted BBB and cannot be predicted by SSTR2 immunohistochemistry. Thus, PET/CT shows limited value to detect HGGs suitable for PRRT. However, high SSTR2 expression portends favorable outcome along with established biomarkers such as IDH1 mutation.

Trial Registration: ClinicalTrials.gov NCT01460706.
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http://dx.doi.org/10.1186/s13550-015-0106-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420768PMC
May 2015

Sensitivity of [(11)C]ORM-13070 to increased extracellular noradrenaline in the CNS - a PET study in human subjects.

Psychopharmacology (Berl) 2015 Nov 29;232(21-22):4169-78. Epub 2015 Apr 29.

Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.

Rationale: No validated methods have been available for studying brain noradrenergic neurotransmission in vivo in humans. Positron emission tomography (PET) radiotracers are widely used in clinical drug development targeted to brain receptors and can also in some cases be employed to monitor extracellular (synaptic) neurotransmitter concentrations.

Objectives: The objective of this study is to test the sensitivity of [(11)C]ORM-13070 uptake to increased concentrations of extracellular (synaptic) noradrenaline in the human brain.

Methods: Eight subjects underwent a control PET scan with [(11)C]ORM-13070, a subtype-selective α2C-adrenoceptor antagonist radioligand, and two PET scans after two different noradrenaline challenges, i.e. during ketamine infusion and after a dose of atomoxetine combined with cold stimulation. Tracer uptake in the caudate nucleus and putamen was described with AUC values in scan time windows of 10-20 and 5-30 min post injection and quantified with the ratio method. Voxel-based analysis was performed with average bound per free (B/F) ratio images.

Results: Both noradrenaline challenges were consistently associated with 10-20 % (p < 0.05) reductions in tracer uptake in the dorsal striatum, as determined with region-of-interest-based analysis. Voxel-based analysis revealed significant reductions in B/F ratios in the dorsal striatum, in the brain stem and in several cortical areas. Reductions of 24 and 23 % were detected in the peak putamen clusters with ketamine and atomoxetine + cold, respectively.

Conclusion: Direct experimental support was gained for the suitability of [(11)C]ORM-13070 for imaging of brain noradrenergic neurotransmission.
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http://dx.doi.org/10.1007/s00213-015-3941-yDOI Listing
November 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

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

Test-retest reliability of (11)C-ORM-13070 in PET imaging of α2C-adrenoceptors in vivo in the human brain.

Eur J Nucl Med Mol Imaging 2015 Jan 9;42(1):120-7. Epub 2014 Sep 9.

Clinical Research Services Turku CRST, University of Turku, Itäinen Pitkäkatu 4 B, 20520, Turku, Finland,

Purpose: α2C-Adrenoceptors share inhibitory presynaptic functions with the more abundant α2A-adrenoceptor subtype, but they also have widespread postsynaptic modulatory functions in the brain. Research on the noradrenergic system of the human brain has been hampered by the lack of suitable PET tracers targeted to the α2-adrenoceptor subtypes.

Methods: PET imaging with the specific α2C-adrenoceptor antagonist tracer [(11)C]ORM-13070 was performed twice in six healthy male subjects to investigate the test-retest reliability of tracer binding.

Results: The bound/free ratio of tracer uptake relative to nonspecific uptake into the cerebellum during the time interval of 5 - 30 min was most prominent in the dorsal striatum: 0.77 in the putamen and 0.58 in the caudate nucleus. Absolute test-retest variability in bound/free ratios of tracer ranged from 4.3 % in the putamen to 29 % in the hippocampus. Variability was also <10 % in the caudate nucleus and thalamus. Intraclass correlation coefficients (ICC) ranged from 0.50 in the hippocampus to 0.89 in the thalamus (ICC >0.70 was also reached in the caudate nucleus, putamen, lateral frontal cortex and parietal cortex). The pattern of [(11)C]ORM-13070 binding, as determined by PET, was in good agreement with receptor density results previously derived from post-mortem autoradiography. PET data analysis results obtained with a compartmental model fit, the simplified reference tissue model and a graphical reference tissue analysis method were convergent with the tissue ratio method.

Conclusion: The results of this study support the use of [(11)C]ORM-13070 PET in the quantitative assessment of α2C-adrenoceptors in the human brain in vivo. Reliable assessment of specific tracer binding in the dorsal striatum is possible with the help of reference tissue ratios.
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http://dx.doi.org/10.1007/s00259-014-2899-zDOI Listing
January 2015

Myocardial blood flow and its transit time, oxygen utilization, and efficiency of highly endurance-trained human heart.

Basic Res Cardiol 2014 Jul 28;109(4):413. Epub 2014 May 28.

Turku PET Centre, University of Turku and Turku University Hospital, PO Box 52, 20521, Turku, Finland,

Highly endurance-trained athlete's heart represents the most extreme form of cardiac adaptation to physical stress, but its circulatory alterations remain obscure. In the present study, myocardial blood flow (MBF), blood mean transit time (MTT), oxygen extraction fraction (OEF) and consumption (MVO2), and efficiency of cardiac work were quantified in highly trained male endurance athletes and control subjects at rest and during supine cycling exercise using [(15)O]-labeled radiotracers and positron emission tomography. Heart rate and MBF were lower in athletes both at rest and during exercise. OEF increased in response to exercise in both groups, but was higher in athletes (70 ± 21 vs. 63 ± 11 % at rest and 86 ± 13 vs. 73 ± 10 % during exercise). MTT was longer and vascular resistance higher in athletes both at rest and during exercise, but arterial content of 2,3-diphosphoglycerate (oxygen affinity) was unchanged. MVO2 per gram of myocardium trended (p = 0.08) lower in athletes both at rest and during exercise, while myocardial efficiency of work and MVO2 per beat were not different between groups. Arterial levels of free fatty acids were ~twofold higher in athletes likely leading to higher myocardial fatty acid oxidation and hence oxygen cost, which may have blunted the bradycardia-induced decrease in MVO2. Finally, the observed group differences in MBF, OEF, MTT and vascular resistance remained significant also after they were controlled for differences in MVO2. In conclusion, in highly endurance-trained human heart, increased myocardial blood transition time enables higher oxygen extraction levels with a lower myocardial blood flow and higher vascular resistance. These physiological adaptations to exercise training occur independently of the level of oxygen consumption and together with training-induced bradycardia may serve as mechanisms to increase functional reserve of the human heart.
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http://dx.doi.org/10.1007/s00395-014-0413-1DOI Listing
July 2014

¹¹C-ORM-13070, a novel PET ligand for brain α₂C-adrenoceptors: radiometabolism, plasma pharmacokinetics, whole-body distribution and radiation dosimetry in healthy men.

Eur J Nucl Med Mol Imaging 2014 Oct 17;41(10):1947-56. Epub 2014 May 17.

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

Purpose: (11)C-labelled 1-[(S)-1-(2,3-dihydrobenzo[1,2]dioxin-2-yl)methyl]-4-(3-methoxy-methylpyridin-2-yl)-piperazine ((11)C-ORM-13070) is a novel PET tracer for imaging of α2C-adrenoceptors in the human brain. Brain α2C-adrenoceptors may be therapeutic targets in several neuropsychiatric disorders, including depression, schizophrenia and Alzheimer's disease. To validate the use of (11)C-ORM-13070 in humans, we investigated its radiometabolism, pharmacokinetics, whole-body distribution and radiation dose.

Methods: Radiometabolism was studied in a test-retest setting in six healthy men. After intravenous injection of (11)C-ORM-13070, blood samples were drawn over 60 min. Plasma samples were analysed by radio-HPLC for intact tracer and its radioactive metabolites. Metabolite-corrected plasma time-activity curves were used for calculation of pharmacokinetics. In a separate group of 12 healthy men, the whole-body distribution of (11)C-ORM-13070 and radiation exposure were investigated by dynamic PET/CT imaging without blood sampling.

Results: Two radioactive metabolites of (11)C-ORM-13070 were detected in human arterial plasma. The proportion of unchanged (11)C-ORM-13070 decreased from 81 ± 4 % of total radioactivity at 4 min after tracer injection to 23 ± 4 % at 60 min. At least one of the radioactive metabolites penetrated into red blood cells, while the parent tracer remained in plasma. The apparent elimination rate constant and corresponding half-life of unchanged (11)C-ORM-13070 in arterial plasma were 0.0117 ± 0.0056 min(-1) and 73.6 ± 35.8 min, respectively. The organs with the highest absorbed doses were the liver (12 μSv/MBq), gallbladder wall (12 μSv/MBq) and pancreas (9.1 μSv/MBq). The mean effective dose was 3.9 μSv/MBq, with a range of 3.6 - 4.2 μSv/MBq.

Conclusion: (11)C-ORM-13070 was rapidly metabolized in human subjects after intravenous injection. The effective radiation dose of (11)C-ORM-13070 was in the same range as that of other (11)C-labelled brain receptor tracers. An injection of 500 MBq of (11)C-ORM-13070 would expose a subject to 2.0 mSv of radiation. This supports the use of (11)C-ORM-13070 in repeated PET scans, for example, in receptor occupancy trials with novel drug candidates.
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http://dx.doi.org/10.1007/s00259-014-2782-yDOI Listing
October 2014

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

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

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

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

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

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

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

Preclinical evaluation of a radioiodinated fully human antibody for in vivo imaging of vascular adhesion protein-1-positive vasculature in inflammation.

J Nucl Med 2013 Aug 11;54(8):1315-9. Epub 2013 Jul 11.

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

Unlabelled: Vascular adhesion protein-1 (VAP-1) is an endothelial glycoprotein mediating leukocyte trafficking from blood to sites of inflammation. BTT-1023 is a fully human monoclonal anti-VAP-1 antibody developed to treat inflammatory diseases. In this study, we preclinically evaluated radioiodinated BTT-1023 for inflammation imaging.

Methods: Rabbits were intravenously injected with radioiodinated BTT-1023. Distribution and pharmacokinetics were assessed by PET/CT up to 72 h after injection. Human radiation dose estimates for (124)I-BTT-1023 were extrapolated. Additionally, rabbits with chemically induced synovitis were imaged with (123)I-BTT-1023 SPECT/CT.

Results: Radioiodinated BTT-1023 cleared rapidly from blood circulation and distributed to liver and thyroid. Inflamed joints were delineated by SPECT/CT. The estimated human effective dose due to (124)I-BTT-1023 was 0.55 mSv/MBq, if blockage of thyroid uptake is assumed.

Conclusion: The radioiodinated BTT-1023 was able to detect mild inflammation in vivo. Clinical (124)I-BTT-1023 PET studies with injected radioactivity of 0.5-0.7 MBq/kg may be justified.
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http://dx.doi.org/10.2967/jnumed.113.120295DOI Listing
August 2013

Adenosine A2A receptors in secondary progressive multiple sclerosis: a [(11)C]TMSX brain PET study.

J Cereb Blood Flow Metab 2013 Sep 22;33(9):1394-401. Epub 2013 May 22.

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

In this study, positron emission tomography (PET) imaging with a radioligand to adenosine A2A receptors (A2AR)-a potent regulator of inflammation-was used to gain insight into the molecular alterations in normal-appearing white matter (NAWM) and gray matter (GM) in secondary progressive multiple sclerosis (SPMS). Normal-appearing white matter and GM, despite seeming normal in conventional magnetic resonance imaging (MRI), are important loci of widespread inflammation, neuronal damage, and source of progressive disability in multiple sclerosis (MS). Dynamic PET imaging using A2AR-specific [(11)C]TMSX and brain MRI with diffusion tensor imaging were performed to eight SPMS patients and seven healthy controls. Distribution volumes (VT) of [(11)C]TMSX were analyzed from 13 regions of interest using Logan plot with arterial plasma input. The SPMS patients had significantly increased [(11)C]TMSX-VT in NAWM compared with controls (mean (s.d.): 0.55 (±0.08) vs. 0.45 (±0.05); P=0.036). Both the increased VT and the decreased fractional anisotropy (FA) in NAWM were associated with higher expanded disability status scale (EDSS) scores (P=0.030 and P=0.012, respectively), whereas the T2-lesion load of SPMS patients did not correlate with EDSS. This study shows, that A2ARs are increased in the brain of SPMS patients, and that [(11)C]TMSX-PET provides a novel approach to learn about central nervous system pathology in SPMS in vivo.
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http://dx.doi.org/10.1038/jcbfm.2013.85DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764386PMC
September 2013

Plasma pharmacokinetics, whole-body distribution, metabolism, and radiation dosimetry of 68Ga bombesin antagonist BAY 86-7548 in healthy men.

J Nucl Med 2013 Jun 5;54(6):867-72. Epub 2013 Apr 5.

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

Unlabelled: This first-in-human study investigated the safety, tolerability, metabolism, pharmacokinetics, biodistribution, and radiation dosimetry of (68)Ga-bombesin antagonist (68)Ga-DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (BAY 86-7548).

Methods: Five healthy men underwent dynamic whole-body PET/CT after an intravenous injection of BAY 86-7548 (138 ± 5 MBq). Besides total radioactivity, plasma samples were analyzed by radio-high-performance liquid chromatography for metabolism of the tracer. Dosimetry was calculated using the OLINDA/EXM software.

Results: Three radioactive plasma metabolites were detected. The proportion of unchanged BAY 86-7548 decreased from 92% ± 9% at 1 min after injection to 19% ± 2% at 65 min. The organs with the highest absorbed doses were the urinary bladder wall (0.62 mSv/MBq) and the pancreas (0.51 mSv/MBq). The mean effective dose was 0.051 mSv/MBq. BAY 86-7548 was well tolerated by all subjects.

Conclusion: Intravenously injected BAY 86-7548 is safe, and rapid metabolism is demonstrated. A 150-MBq injection of BAY 86-7548 results in an effective dose of 7.7 mSv, which could be reduced to 5.7 mSv with frequent bladder voids.
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http://dx.doi.org/10.2967/jnumed.112.114082DOI Listing
June 2013

Matrix metalloproteinase 9 targeting peptides: syntheses, 68Ga-labeling, and preliminary evaluation in a rat melanoma xenograft model.

Bioconjug Chem 2010 Sep;21(9):1612-21

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

Biopanning of tumor cells was used in order to identify matrix metalloproteinase 9 (MMP-9) targeting peptides. The tumor cell targeting peptide (TCTP-1) and two modified versions thereof were evaluated as imaging agents for positron emission tomography (PET) using a rat melanoma xenograft model. For the PET imaging purposes, the 3 peptides were 1,4,7,10-tetraazacyclo-dodecane-N',N'',N''',N''''-tetraacetic acid (DOTA) conjugated and labeled with Gallium-68 ((68)Ga) and preliminarily evaluated: (1) cyclic (68)Ga-DOTA-TCTP-1 with cystine bridge, (2) cyclic (68)Ga-DOTA-lactam-TCTP-1 with a lactam bridge, and (3) linear (68)Ga-DOTA-lin-TCTP-1. The whole-body distribution kinetics and tumor targeting of the intravenously administered (68)Ga-DOTA-peptides were evaluated in vivo by PET and ex vivo by measuring the radioactivity of excised tissues. In addition, the in vivo stability of the radiolabeled peptides in rat plasma, tumor tissue, and urine was studied. All (68)Ga-DOTA-peptides were cleared via the liver and kidneys, and approximately 44% of injected radioactivity was excreted in urine during 120 min after injection. Ex vivo biodistribution studies showed a tumor-to-muscle ratio of 5.5 ± 1.3 (mean ± SD) for (68)Ga-DOTA-TCTP-1, 3.2 ± 0.2 for (68)Ga-DOTA-lactam-TCTP-1, and 3.2 ± 0.6 for (68)Ga-DOTA-lin-TCTP-1 at 120 min after injection. The (68)Ga-DOTA-lactam-TCTP-1 peptide appeared to be the most stable in vivo. The fraction of intact (68)Ga-DOTA-lactam-TCTP-1 in tumor was 59 ± 4.2% at 120 min after injection. The stability was moderate for (68)Ga-DOTA-TCTP-1 and poor for (68)Ga-DOTA-lin-TCTP-1. The possibility of imaging tumors that overexpress MMP-9, such as melanoma, by using radiolabeled TCTP peptides in PET imaging makes these peptides highly attractive for diagnostic and therapeutic applications. However, further modifications to improve the stability and affinity of the peptides are needed.
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http://dx.doi.org/10.1021/bc1000643DOI Listing
September 2010

PET imaging of inflammation and adenocarcinoma xenografts using vascular adhesion protein 1 targeting peptide 68Ga-DOTAVAP-P1: comparison with 18F-FDG.

Eur J Nucl Med Mol Imaging 2010 Oct 4;37(10):1918-25. Epub 2010 Jun 4.

Turku PET Centre, University of Turku and Turku University Hospital, 20521 Turku, Finland.

Purpose: The aim of this study was to evaluate inflammation and tumour imaging with a vascular adhesion protein 1 (VAP-1) targeting peptide (68)Ga-DOTAVAP-P1 in comparison with (18)F-FDG.

Methods: Rats with both subcutaneous human pancreatic adenocarcinoma xenografts and turpentine oil-induced acute sterile inflammation were evaluated by dynamic positron emission tomography (PET) and by digital autoradiography of tissue cryosections. Subsequently, the autoradiographs were combined with histological and immunohistological analysis of the sections.

Results: (68)Ga-DOTAVAP-P1 delineated acute, sterile inflammation comparable with (18)F-FDG. However, the tumour uptake of (68)Ga-DOTAVAP-P1 was low in contrast to prominent (18)F-FDG uptake. The standardised uptake values of inflammation and tumours by PET were 1.1 +/- 0.4 (mean +/- SEM) and 0.4 +/- 0.1 for (68)Ga-DOTAVAP-P1 and 2.0 +/- 0.5 and 1.6 +/- 0.8 for (18)F-FDG, respectively. In addition, PET studies showed inflammation to muscle and tumour to muscle ratios of 5.1 +/- 3.1 and 1.7 +/- 0.3 for (68)Ga-DOTAVAP-P1 and 6.2 +/- 0.7 and 4.6 +/- 2.2 for (18)F-FDG, respectively. Immunohistochemistry revealed increased expression of luminal VAP-1 on the endothelium at the site of inflammation and low expression in the tumour

Conclusion: The (68)Ga-DOTAVAP-P1 PET was able to visualise inflammation better than tumour, which was in accordance with the luminal expression of VAP-1 on vasculature in these experimental models.
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http://dx.doi.org/10.1007/s00259-010-1497-yDOI Listing
October 2010

Uptake of 11C-choline in mouse atherosclerotic plaques.

J Nucl Med 2010 May 15;51(5):798-802. Epub 2010 Apr 15.

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

Unlabelled: The purpose of this study was to explore the feasibility of (11)C-choline in the assessment of the degree of inflammation in atherosclerotic plaques.

Methods: Uptake of (11)C-choline was studied ex vivo in tissue samples and aortic sections excised from 6 atherosclerotic mice deficient for both low-density lipoprotein receptor and apolipoprotein B48 (LDLR(-/-)ApoB(100/100)) and 5 control mice. The autoradiographs were compared with the immunohistology of the arterial sites.

Results: The uptake of (11)C-choline (percentage of the injected activity per gram of tissue) in the atherosclerotic aortas of the LDLR(-/-)ApoB(100/100) mice was significantly higher (1.9-fold, P = 0.0016) than that in the aortas of the control mice. The autoradiography analysis showed significantly higher uptake of (11)C-choline in the plaques than in healthy vessel wall (mean ratio, 2.3 +/- 0.6; P = 0.014), prominently in inflamed plaques, compared with noninflamed plaque areas.

Conclusion: We observed a high (11)C-choline uptake in the aortic plaques of atherosclerotic mice. Our data suggest that macrophages may be responsible for the uptake of (11)C-choline in the plaques.
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http://dx.doi.org/10.2967/jnumed.109.071704DOI Listing
May 2010

Human dosimetry of carbon-11 labeled N-butan-2-yl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide extrapolated from whole-body distribution kinetics and radiometabolism in rats.

Mol Imaging Biol 2010 Aug 26;12(4):435-42. Epub 2009 Nov 26.

Turku PET Center, University of Turku, FI-20521, Turku, Finland,

Purpose: Carbon-11 labeled N-butan-2-yl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide ([11C]PK11195) is a peripheral benzodiazepine receptor (PBR) antagonist that is used as a positron emission tomography (PET) radiopharmaceutical for neuroinflammatory imaging. This study was designed to investigate the radiation dosimetry of [11C]PK11195.

Procedures: Whole-body distribution kinetics of intravenously administered [11C]PK11195 in rats was assessed by means of dynamic PET imaging, and estimates for human radiation dosimetry were calculated. Rat plasma and various tissue homogenates obtained at different time points after intravenous injection of [11C]PK11195 were analyzed by reversed-phase gradient radio-HPLC method using online radiodetection. In addition, in vitro stability of [11C]PK11195 was determined in rat brain homogenate by incubation at +37 degrees C.

Results: PET imaging of rats showed the highest radioactivity levels in heart, kidneys, thyroid gland, liver, and lungs. The radioactivity cleared rapidly from lungs and slowly from heart and liver. However, much of the radioactivity retained in kidneys, which was in concordance with the observed low urinary excretion of [11C]PK11195. Extrapolating from the rat data, the effective dose of [11C]PK11195 for a 70-kg man was estimated to be 4.2 +/- 0.3 microSv/MBq. Five different radiometabolites were detected in rat plasma, and the level of intact [11C]PK11195 decreased from 80% +/- 11% (mean +/- SD) at 10 min to 44% +/- 5% at 40 min after injection. In rat heart, brain, kidney, and lung homogenates, more than 90% of total radioactivity originated from intact [11C]PK11195. In liver, however, the amount of [11C]PK11195 was approximately 70% and decreased over time, indicating metabolism by liver enzymes.

Conclusions: [11C]PK11195 showed a fast uptake in many rat tissues and it was metabolized relatively fast in vivo, but not in brain in vitro. The estimated effective dose for humans speaks for the use of [11C]PK11195 in human PET imaging.
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http://dx.doi.org/10.1007/s11307-009-0293-1DOI Listing
August 2010

Preliminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptide targeting vascular adhesion protein-1.

Clin Physiol Funct Imaging 2010 Jan 14;30(1):75-8. Epub 2009 Oct 14.

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

Summary Introduction: Expression of vascular adhesion protein-1 (VAP-1) is induced at the sites of inflammation where extravasation of leukocytes from blood to the peripheral tissue occurs. VAP-1 is a potential target for anti-inflammatory therapy and for in vivo imaging of inflammation. Purpose of this study was to preliminarily evaluate a novel VAP-1-targeting peptide as a potential PET imaging agent.

Methods: Cyclic 17-amino-acid peptide selected from phage display libraries was 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) conjugated via 8-amino-3,6-diooxaoctanoyl linker (polyethylene glycol, PEG derivative) and labelled with (68)Ga ((68)Ga-DOTAVAP-PEG-P2). In vitro stability of (68)Ga-DOTAVAP-PEG-P2 was determined in saline, rat plasma and human plasma by radio-HLPC. Lipophilicity was measured by calculating octanol-water partition coefficient (logP). Whole-body distribution kinetics and stability after intravenous injection in healthy rats was studied in vivo by PET imaging, ex vivo by measuring radioactivity of excised tissues, and by radio-HPLC.

Results: In vitro the (68)Ga-DOTAVAP-PEG-P2 remained stable >4 h in saline and rat plasma, but degraded slowly in human plasma after 2 h of incubation. The logP value of (68)Ga-DOTAVAP-PEG-P2 was -1.3. In rats, (68)Ga-radioactivity cleared rapidly from blood circulation and excreted quickly in urine. At 120 min after injection the fraction of intact (68)Ga-DOTAVAP-PEG-P2 were 77 +/- 6.0% and 99 +/- 1.0% in rat plasma and urine, respectively.

Conclusions: These basic and essential in vitro and in vivo studies of the new VAP-1 targeting peptide revealed promising properties for an imaging agent. Further investigations to clarify in vivo VAP-1 targeting are warranted.
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http://dx.doi.org/10.1111/j.1475-097X.2009.00907.xDOI Listing
January 2010

68Ga-chloride PET reveals human pancreatic adenocarcinoma xenografts in rats--comparison with FDG.

Mol Imaging Biol 2010 Jun 2;12(3):259-68. Epub 2009 Oct 2.

Turku PET Centre, Turku University Hospital, 20521, Turku, Finland.

Purpose: The aim of the study was to compare (68)Ga-chloride with 2-[(18)F]fluoro-2-deoxy-D: -glucose (FDG) for the imaging of pancreatic xenografts.

Procedures: Rats with subcutaneous human pancreatic adenocarcinoma xenografts were evaluated in vivo by dynamic positron emission tomography (PET) and ex vivo by measuring radioactivity of excised tissues and by digital autoradiography of tumor cryosections.

Results: Both tracers were capable of delineating all subcutaneous tumors from surrounding tissues by PET. The standardized uptake values of tumors by PET were 0.9 +/- 0.3 (mean +/- SD) for (68)Ga-chloride (n = 13) and 1.8 +/- 1.2 for FDG (n = 11). Ex vivo studies showed tumor-to-muscle ratio of 4.0 +/- 0.3 for (68)Ga-chloride (n = 4) and 7.9 +/- 3.2 for FDG (n = 4).

Conclusions: (68)Ga-chloride delineated subcutaneously implanted pancreatic adenocarcinoma xenografts by PET, but the uptake was lower than FDG. Further studies to clarify the value of (68)Ga-chloride for PET imaging of tumors are warranted.
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http://dx.doi.org/10.1007/s11307-009-0267-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864902PMC
June 2010

68Ga-DOTA-RGD peptide: biodistribution and binding into atherosclerotic plaques in mice.

Eur J Nucl Med Mol Imaging 2009 Dec;36(12):2058-67

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

Purpose: Increased expression of αvβ3/αvβ5 integrin is involved in angiogenesis and the inflammatory process in atherosclerotic plaques. The novel 68Ga-DOTA-RGD peptide binds with high affinity to αvβ3/αvβ5 integrin. The aim of this study was to investigate the uptake of the 68Ga-DOTA-RGD peptide in atherosclerotic plaques.

Methods: Uptake of intravenously administered 68Ga-DOTA-RGD peptide was studied ex vivo in excised tissue samples and aortic sections of LDLR-/-ApoB100/100 atherosclerotic mice. The uptake of the tracer in aortic cryosections was examined by using digital autoradiography. Subsequently, the autoradiographs were combined with histological and immunohistological analysis of the sections.

Results: DOTA-RGD peptide was successfully labelled with the generator-produced 68Ga. The tracer had reasonably good specific radioactivity (8.7 ± 1.1 GBq/μmol) and was quite stable in vivo. According to ex vivo biodistribution results, 68Ga-DOTA-RGD was cleared rapidly from the blood circulation and excreted through the kidneys to the urine with high radioactivity in the intestine, lungs, spleen and liver. Autoradiography results showed significantly higher uptake of 68Ga-DOTA-RGD peptide in the atherosclerotic plaques compared to healthy vessel wall (mean ratio ± SD 1.4 ± 0.1, p = 0.0004). Conclusion We observed that 68Ga-DOTA-RGD is accumulated into the plaques of atherosclerotic mice. However, this data only shows the feasibility of the approach, while the clinical significance still remains to be proven. Further studies are warranted to assess the uptake of this tracer into human atherosclerotic plaques.
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http://dx.doi.org/10.1007/s00259-009-1220-zDOI Listing
December 2009