Publications by authors named "Tuula Tolvanen"

38 Publications

Assessment of a digital and an analog PET/CT system for accurate myocardial perfusion imaging with a flow phantom.

J Nucl Cardiol 2021 May 4. Epub 2021 May 4.

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

In Myocardial Perfusion Imaging (MPI) with Positron Emission Tomography/Computed Tomography (PET/CT) systems, accurate quantification is essential. We assessed flow quantification accuracy over various injected activities using a flow phantom.

Methods: The study was performed on the digital 4-ring Discovery MI (DMI-20) and analog Discovery 690 (D690) PET/CT systems, using 325-1257 MBq of [O]HO. PET performance and flow quantification accuracy were assessed in terms of count-rates, dead-time factors (DTF), scatter fractions (SF), time-activity curves (TACs), areas-under-the-curves (AUCs) and flow values.

Results: On DMI-20, prompts of 12.8 Mcps, DTF of 2.06 and SF of 46.1% were measured with 1257 MBq of activity. On the D690, prompts of 6.85 Mcps, DTF of 1.57 and SF of 32.5% were measured with 1230 MBq of activity. AUC values were linear over all activities. Mean wash-in flow error was - 9% for both systems whereas wash-out flow error was - 5% and - 6% for DMI-20 and D690. With the highest activity, wash-out flow error was - 12% and - 7% for the DMI-20 and D690.

Conclusion: DMI-20 and D690 preserved accurate flow quantification over all injected activities, with maximum error of - 12%. In the future, flow quantification accuracy over the activities and count-rates evaluated in this study should be assessed.
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http://dx.doi.org/10.1007/s12350-021-02631-9DOI Listing
May 2021

Safety, Biodistribution, and Radiation Dosimetry of F-rhPSMA-7.3 in Healthy Adult Volunteers.

J Nucl Med 2021 May 16;62(5):679-684. Epub 2020 Oct 16.

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

This first-in-humans study investigated the safety, biodistribution, and radiation dosimetry of a novel F-labeled radiohybrid prostate-specific membrane antigen (rhPSMA) PET imaging agent, F-rhPSMA-7.3. Six healthy volunteers (3 men, 3 women) underwent multiple whole-body PET acquisitions at scheduled time points up to 248 min after the administration of F-rhPSMA-7.3 (mean activity, 220; range, 210-228 MBq). PET scans were conducted in 3 separate sessions, and subjects were encouraged to void between sessions. Blood and urine samples were collected for up to 4 h after injection to assess metabolite-corrected radioactivity in whole blood, plasma, and urine. Quantitative measurements of F radioactivity in volumes of interest over target organs were determined directly from the PET images at 8 time points, and normalized time-activity concentration curves were generated. These normalized cumulated activities were then inputted into the OLINDA/EXM package to calculate the internal radiation dosimetry and the subjects' effective dose. F-rhPSMA-7.3 was well tolerated. One adverse event (mild headache, not requiring medication) was considered possibly related to F-rhPSMA-7.3. The calculated effective dose was 0.0141 mSv/MBq when using a 3.5-h voiding interval. The organs with the highest mean absorbed dose per unit of administered radioactivity were the adrenals (0.1835 mSv/MBq), the kidneys (0.1722 mSv/MBq), the submandibular glands (0.1479 mSv), and the parotid glands (0.1137 mSv/MBq). At the end of the first scanning session (mean time, 111 min after injection), an average of 7.2% (range, 4.4%-9.0%) of the injected radioactivity of F-rhPSMA-7.3 was excreted into urine. The safety, biodistribution, and internal radiation dosimetry of F-rhPSMA-7.3 are considered favorable for PET imaging.
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http://dx.doi.org/10.2967/jnumed.120.252114DOI Listing
May 2021

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

J Nucl Med 2021 04 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049366PMC
April 2021

Radiosynthesis and preclinical evaluation of [Ga]Ga-NOTA-folate for PET imaging of folate receptor β-positive macrophages.

Sci Rep 2020 08 12;10(1):13593. Epub 2020 Aug 12.

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

Folate receptor β (FR-β), a marker expressed on macrophages, is a promising target for imaging of inflammation. Here, we report the radiosynthesis and preclinical evaluation of [Ga]Ga-NOTA-folate (Ga-FOL). After determining the affinity of Ga-FOL using cells expressing FR-β, we studied atherosclerotic mice with Ga-FOL and F-FDG PET/CT. In addition, we studied tracer distribution and co-localization with macrophages in aorta cryosections using autoradiography, histology, and immunostaining. The specificity of Ga-FOL was assessed in a blocking study with folate glucosamine. As a final step, human radiation doses were extrapolated from rat PET data. We were able to produce Ga-FOL with high radiochemical purity and moderate molar activity. Cell binding studies revealed that Ga-FOL had 5.1 nM affinity for FR-β. Myocardial uptake of Ga-FOL was 20-fold lower than that of F-FDG. Autoradiography and immunohistochemistry of the aorta revealed that Ga-FOL radioactivity co-localized with Mac-3-positive macrophage-rich atherosclerotic plaques. The plaque-to-healthy vessel wall ratio of Ga-FOL was significantly higher than that of F-FDG. Blocking studies verified that Ga-FOL was specific for FR. Based on estimations from rat data, the human effective dose was 0.0105 mSv/MBq. Together, these findings show that Ga-FOL represents a promising new FR-β-targeted tracer for imaging macrophage-associated inflammation.
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http://dx.doi.org/10.1038/s41598-020-70394-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423886PMC
August 2020

Myocardial perfusion reserve of kidney transplant patients is well preserved.

EJNMMI Res 2020 Feb 10;10(1). Epub 2020 Feb 10.

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

Background: Chronic kidney disease (CKD) is associated with endothelial dysfunction and increased cardiovascular mortality. Endothelial dysfunction can be studied measuring myocardial perfusion reserve (MPR). MPR is the ratio of stress and rest myocardial perfusion (MP) and reflects the capacity of vascular bed to increase perfusion and microvascular responsiveness. In this pilot study, our aim was to assess MPR of 19 patients with kidney transplant (CKD stages 2-3) and of ten healthy controls with quantitative [O]HO positron emission tomography (PET) method.

Results: Basal MP was statistically significantly higher at rest in the kidney transplant patients than in the healthy controls [1.3 (0.4) ml/min/g and 1.0 (0.2) ml/min/g, respectively, p = 0.0015]. After correction of basal MP by cardiac workload [MP = basal MP/individual rate pressure product (RPP) × average RPP of the healthy controls], the difference between the groups disappeared [0.9 (0.2)  ml/min/g and 1.0 (0.3) ml/min/g, respectively, p = 0.55)]. There was no difference in stress MP between the kidney transplant patients and the healthy subjects [3.8 (1.0) ml/min/g and 4.0 (0.9) ml/min/g, respectively, p = 0.53]. Although MPR was reduced, MPR (stress MP/basal MP) did not differ between the kidney transplant patients and the healthy controls [4.1 (1.1) and 4.3 (1.6), respectively, p = 0.8].

Conclusions: MP during stress is preserved in kidney transplant patients with CKD stage 2-3. The reduced MPR appears to be explained by increased resting MP. This is likely linked with increased cardiac workload due to sympathetic overactivation in kidney transplant patients.
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http://dx.doi.org/10.1186/s13550-020-0606-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010868PMC
February 2020

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

Assessment of myocardial viability with [O]water PET: A validation study in experimental myocardial infarction.

J Nucl Cardiol 2019 Jul 17. Epub 2019 Jul 17.

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

Background: Assessment of myocardial viability is often needed in patients with chest pain and reduced ejection fraction. We evaluated the performance of reduced resting MBF, perfusable tissue fraction (PTF), and perfusable tissue index (PTI) in the assessment of myocardial viability in a pig model of myocardial infarction (MI).

Methods And Results: Pigs underwent resting [O]water PET perfusion study 12 weeks after surgical (n = 16) or 2 weeks after catheter-based (n = 4) occlusion of the proximal left anterior descending coronary artery. MBF, PTF, and PTI were compared with volume fraction of MI in matched segments as assessed by triphenyl tetrazolium chloride staining of LV slices. MBF and PTF were lower in infarcted than non-infarcted segments. Segmental analysis of MBF showed similar area under the curve (AUC) of 0.85, 0.86, and 0.90 with relative MBF, PTF, and PTI for the detection of viable myocardium defined as infarct volume fraction of < 75%. Cut-off values of relative MBF of ≥ 67% and PTF of ≥ 66% resulted in accuracies of 90% and 81%, respectively.

Conclusions: Our results indicate that resting MBF, PTF, and PTI based on [O]water PET perfusion imaging are useful for the assessment of myocardial viability.
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http://dx.doi.org/10.1007/s12350-019-01818-5DOI Listing
July 2019

Determinants of Myocardial Strain in Experimental Chronic Myocardial Infarction.

Ultrasound Med Biol 2019 02 19;45(2):568-578. Epub 2018 Nov 19.

Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland; Heart Center, Turku University Hospital and University of Turku, Turku, Finland; Institute of Clinical Medicine, University of Turku, Turku, Finland.

We evaluated the relationships between regional myocardial strain measured by speckle tracking echocardiography and viability, fibrosis, hypertrophy and oxygen consumption in the infarcted or remote myocardium in a pig model of chronic myocardial infarction (MI). Thirteen farm pigs with surgical occlusion of the left anterior descending coronary artery and five sham-operated pigs were studied 3 mo post-MI. Computed tomography revealed significant left ventricle remodeling. Reduced radial or circumferential strain identified areas of transmural infarction (area under the curve: 0.82 and 0.79, respectively). In the remote non-infarcted area, radial strain correlated inversely with the amount of fibrosis (r = -0.66, p = 0.04) and myocyte hypertrophy (r = -0.68, p = 0.03). Radial strain rate inversely correlated with myocardial resting oxygen consumption assessed with C-labeled acetate positron emission tomography (r = -0.71, p = 0.006). In conclusion, myocardial strain and strain rate reflect fibrosis, hypertrophy and oxygen consumption of the remote areas after MI.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2018.10.005DOI Listing
February 2019

The Accuracy of Left Ventricular and Left Atrial Volumetry Using 64-Slice Computed Tomography: In Vitro Validation Study With Human Cardiac Cadaveric Casts.

J Comput Assist Tomogr 2018 Sep/Oct;42(5):754-759

Division of Cardiology, Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki.

Objective: We aimed to validate the accuracy of imaging of left atrial and ventricular volumes using cardiac cadaveric silicone casts.

Methods: Left atrial (n = 14) and ventricular (n = 15) casts were imaged using 64-slice computed tomography (CT). Water displacement (WD) of cardiac casts was used as the gold standard for volume measurements.

Results: Compared with WD, CT resulted in slightly higher left atrial and ventricular volumes (54 ± 25 vs 56 ± 26 mL [P = 0.003] and 57 ± 47 vs 66 ± 47 mL [P = 0.0001]). Variability between left atrial and ventricular volumes by CT and WD was low (coefficients of variation [CVs], 4% [intraclass correlation coefficient {ICC}, 0.99] and 12% [ICC, 0.97]). Intraobserver variability of CT was low for both the left atrium and the left ventricle (CVs, 1% [ICC, 1.00] and 4% [ICC, 1.00]).

Conclusions: Cardiac CT is both accurate and reproducible in assessment of left ventricular and atrial chamber volumes.
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http://dx.doi.org/10.1097/RCT.0000000000000773DOI Listing
September 2018

Comparison of Ga-DOTA-Siglec-9 and F-Fluorodeoxyribose-Siglec-9: Inflammation Imaging and Radiation Dosimetry.

Contrast Media Mol Imaging 2017 31;2017:7645070. Epub 2017 Dec 31.

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

Sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) is a ligand of inflammation-inducible vascular adhesion protein-1 (VAP-1). We compared Ga-DOTA- and F-fluorodeoxyribose- (FDR-) labeled Siglec-9 motif peptides for PET imaging of inflammation. . Firstly, we examined Ga-DOTA-Siglec-9 and F-FDR-Siglec-9 in rats with skin/muscle inflammation. We then studied F-FDR-Siglec-9 for the detection of inflamed atherosclerotic plaques in mice and compared it with previous Ga-DOTA-Siglec-9 results. Lastly, we estimated human radiation dosimetry from the rat data. . In rats, Ga-DOTA-Siglec-9 (SUV, 0.88 ± 0.087) and F-FDR-Siglec-9 (SUV, 0.77 ± 0.22) showed comparable ( = 0.29) imaging of inflammation. In atherosclerotic mice, F-FDR-Siglec-9 detected inflamed plaques with a target-to-background ratio (1.6 ± 0.078) similar to previously tested Ga-DOTA-Siglec-9 ( = 0.35). Human effective dose estimates for Ga-DOTA-Siglec-9 and F-FDR-Siglec-9 were 0.024 and 0.022 mSv/MBq, respectively. . Both tracers are suitable for PET imaging of inflammation. The easier production and lower cost of Ga-DOTA-Siglec-9 present advantages over F-FDR-Siglec-9, indicating it as a primary choice for clinical studies.
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http://dx.doi.org/10.1155/2017/7645070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804415PMC
October 2018

Imaging of αβ integrin expression in experimental myocardial ischemia with [Ga]NODAGA-RGD positron emission tomography.

J Transl Med 2017 06 19;15(1):144. Epub 2017 Jun 19.

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

Background: Radiolabeled RGD peptides detect αβ integrin expression associated with angiogenesis and extracellular matrix remodeling after myocardial infarction. We studied whether cardiac positron emission tomography (PET) with [Ga]NODAGA-RGD detects increased αβ integrin expression after induction of flow-limiting coronary stenosis in pigs, and whether αβ integrin is expressed in viable ischemic or injured myocardium.

Methods: We studied 8 Finnish landrace pigs 13 ± 4 days after percutaneous implantation of a bottleneck stent in the proximal left anterior descending coronary artery. Antithrombotic therapy was used to prevent stent occlusion. Myocardial uptake of [Ga]NODAGA-RGD (290 ± 31 MBq) was evaluated by a 62 min dynamic PET scan. The ischemic area was defined as the regional perfusion abnormality during adenosine-induced stress by [O]water PET. Guided by triphenyltetrazolium chloride staining, tissue samples from viable and injured myocardial areas were obtained for autoradiography and histology.

Results: Stent implantation resulted in a partly reversible myocardial perfusion abnormality. Compared with remote myocardium, [Ga]NODAGA-RGD PET showed increased tracer uptake in the ischemic area (ischemic-to-remote ratio 1.3 ± 0.20, p = 0.0034). Tissue samples from the injured areas, but not from the viable ischemic areas, showed higher [Ga]NODAGA-RGD uptake than the remote non-ischemic myocardium. Uptake of [Ga]NODAGA-RGD correlated with immunohistochemical detection of αβ integrin that was expressed in the injured myocardial areas.

Conclusions: Cardiac [Ga]NODAGA-RGD PET demonstrates increased myocardial αβ integrin expression after induction of flow-limiting coronary stenosis in pigs. Localization of [Ga]NODAGA-RGD uptake indicates that it reflects αβ integrin expression associated with repair of recent myocardial injury.
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http://dx.doi.org/10.1186/s12967-017-1245-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477135PMC
June 2017

Quantitative Evaluation of 2 Scatter-Correction Techniques for F-FDG Brain PET/MRI in Regard to MR-Based Attenuation Correction.

J Nucl Med 2017 10 23;58(10):1691-1698. Epub 2017 Mar 23.

Department of Medical Physics, Turku University Hospital, Turku, Finland.

In PET, corrections for photon scatter and attenuation are essential for visual and quantitative consistency. MR attenuation correction (MRAC) is generally conducted by image segmentation and assignment of discrete attenuation coefficients, which offer limited accuracy compared with CT attenuation correction. Potential inaccuracies in MRAC may affect scatter correction, because the attenuation image (μ-map) is used in single scatter simulation (SSS) to calculate the scatter estimate. We assessed the impact of MRAC to scatter correction using 2 scatter-correction techniques and 3 μ-maps for MRAC. The tail-fitted SSS (TF-SSS) and a Monte Carlo-based single scatter simulation (MC-SSS) algorithm implementations on the Philips Ingenuity TF PET/MR were used with 1 CT-based and 2 MR-based μ-maps. Data from 7 subjects were used in the clinical evaluation, and a phantom study using an anatomic brain phantom was conducted. Scatter-correction sinograms were evaluated for each scatter correction method and μ-map. Absolute image quantification was investigated with the phantom data. Quantitative assessment of PET images was performed by volume-of-interest and ratio image analysis. MRAC did not result in large differences in scatter algorithm performance, especially with TF-SSS. Scatter sinograms and scatter fractions did not reveal large differences regardless of the μ-map used. TF-SSS showed slightly higher absolute quantification. The differences in volume-of-interest analysis between TF-SSS and MC-SSS were 3% at maximum in the phantom and 4% in the patient study. Both algorithms showed excellent correlation with each other with no visual differences between PET images. MC-SSS showed a slight dependency on the μ-map used, with a difference of 2% on average and 4% at maximum when a μ-map without bone was used. The effect of different MR-based μ-maps on the performance of scatter correction was minimal in non-time-of-flight F-FDG PET/MR brain imaging. The SSS algorithm was not affected significantly by MRAC. The performance of the MC-SSS algorithm is comparable but not superior to TF-SSS, warranting further investigations of algorithm optimization and performance with different radiotracers and time-of-flight imaging.
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http://dx.doi.org/10.2967/jnumed.117.190231DOI Listing
October 2017

Accuracy of echocardiographic area-length method in chronic myocardial infarction: comparison with cardiac CT in pigs.

Cardiovasc Ultrasound 2017 Jan 9;15(1). Epub 2017 Jan 9.

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

Background: We evaluated echocardiographic area-length methods to measure left ventricle (LV) volumes and ejection fraction (EF) in parasternal short axis views in comparison with cardiac computed tomography (CT) in pigs with chronic myocardial infarction (MI).

Methods: Male farm pigs with surgical occlusion of the left anterior descending coronary artery (n = 9) or sham operation (n = 5) had transthoracic echocardiography and cardiac-CT 3 months after surgery. We measured length of the LV in parasternal long axis view, and both systolic and diastolic LV areas in parasternal short axis views at the level of mitral valve, papillary muscles and apex. Volumes and EF of the LV were calculated using Simpson's method of discs (tri-plane area) or Cylinder-hemiellipsoid method (single plane area).

Results: The pigs with coronary occlusion had anterior MI scars and reduced EF (average EF 42 ± 10%) by CT. Measurements of LV volumes and EF were reproducible by echocardiography. Compared with CT, end-diastolic volume (EDV) measured by echocardiography showed good correlation and agreement using either Simpson's method (r = 0.90; mean difference -2, 95% CI -47 to 43 mL) or Cylinder-hemiellipsoid method (r = 0.94; mean difference 3, 95% CI -44 to 49 mL). Furthermore, End-systolic volume (ESV) measured by echocardiography showed also good correlation and agreement using either Simpson's method (r = 0.94; mean difference 12 ml, 95% CI: -16 to 40) or Cylinder-hemiellipsoid method (r = 0.97; mean difference:13 ml, 95% CI: -8 to 33). EF was underestimated using either Simpson's method (r = 0.78; mean difference -6, 95% CI -11 to 1%) or Cylinder-hemiellipsoid method (r = 0.74; mean difference -4, 95% CI-10 to 2%).

Conclusion: Our results indicate that measurement of LV volumes may be accurate, but EF is underestimated using either three or single parasternal short axis planes by echocardiography in a large animal model of chronic MI.
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http://dx.doi.org/10.1186/s12947-016-0093-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223339PMC
January 2017

Low kidney uptake of GLP-1R-targeting, beta cell-specific PET tracer, F-labeled [Nle,Lys]exendin-4 analog, shows promise for clinical imaging.

EJNMMI Res 2016 Dec 13;6(1):91. Epub 2016 Dec 13.

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

Background: Several radiometal-labeled, exendin-based tracers that target glucagon-like peptide-1 receptors (GLP-1R) have been intensively explored for β cell imaging. The main obstacle has been the high uptake of tracer in the kidneys. This study aimed to develop a novel GLP1-R-specific tracer, with fluorine-18 attached to exendin-4, to label β cells for clinical imaging with PET (positron emission tomography). We hypothesized that this tracer would undergo reduced kidney uptake. F-labeled [Nle,Lys]exendin-4 analog ([F]exendin-4) was produced via Cu-catalyzed click chemistry. The biodistribution of [F]exendin-4 was assessed with ex vivo organ γ-counting and in vivo PET imaging. We also tested the in vivo stability of the radiotracer. The localization of F radioactivity in rat and human pancreatic tissue sections was investigated with autoradiography. Receptor specificity was assessed with unlabeled exendin-3. Islet labeling was confirmed with immunohistochemistry. The doses of radiation in humans were estimated based on biodistribution results in rats.

Results: [F]exendin-4 was synthesized with high yield and high specific activity. Results showed specific, sustained [F]exendin-4 uptake in pancreatic islets. In contrast to previous studies that tested radiometal-labeled exendin-based tracers, we observed rapid renal clearance of [F]exendin-4.

Conclusions: [F]exendin-4 showed promise as a tracer for clinical imaging of pancreatic β cells, due to its high specific uptake in native β cells and its concomitant low kidney radioactivity uptake.
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http://dx.doi.org/10.1186/s13550-016-0243-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153397PMC
December 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

Effect of Attenuation Correction on Regional Quantification Between PET/MR and PET/CT: A Multicenter Study Using a 3-Dimensional Brain Phantom.

J Nucl Med 2016 May 28;57(5):818-24. Epub 2016 Jan 28.

National Cerebral and Cardiovascular Center, Osaka, Japan.

Unlabelled: A spatial bias in brain PET/MR exists compared with PET/CT, because of MR-based attenuation correction. We performed an evaluation among 4 institutions, 3 PET/MR systems, and 4 PET/CT systems using an anthropomorphic brain phantom, hypothesizing that the spatial bias would be minimized with CT-based attenuation correction (CTAC).

Methods: The evaluation protocol was similar to the quantification of changes in neurologic PET studies. Regional analysis was conducted on 8 anatomic volumes of interest (VOIs) in gray matter on count-normalized, resolution-matched, coregistered data. On PET/MR systems, CTAC was applied as the reference method for attenuation correction.

Results: With CTAC, visual and quantitative differences between PET/MR and PET/CT systems were minimized. Intersystem variation between institutions was +3.42% to -3.29% in all VOIs for PET/CT and +2.15% to -4.50% in all VOIs for PET/MR. PET/MR systems differed by +2.34% to -2.21%, +2.04% to -2.08%, and -1.77% to -5.37% when compared with a PET/CT system at each institution, and these differences were not significant (P ≥ 0.05).

Conclusion: Visual and quantitative differences between PET/MR and PET/CT systems can be minimized by an accurate and standardized method of attenuation correction. If a method similar to CTAC can be implemented for brain PET/MRI, there is no reason why PET/MR should not perform as well as PET/CT.
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http://dx.doi.org/10.2967/jnumed.115.166165DOI Listing
May 2016

Effect of levosimendan therapy on myocardial infarct size and left ventricular function after acute coronary occlusion.

Heart 2016 Mar 13;102(6):465-71. Epub 2016 Jan 13.

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

Background: Levosimendan is an inotropic agent with cardioprotective and vasodilating properties used for the management of acutely decompensated heart failure. We studied the effects of levosimendan treatment on the size of myocardial infarction (MI) and left ventricular (LV) function in experimental pig model of post MI heart failure.

Methods: After occlusion of the left anterior descending (LAD) coronary artery, animals received levosimendan 5 mg/kg/day orally for 8 weeks (n=7) or no treatment (n=18). One week after stopping treatment, transthoracic echocardiography, CT scan and positron emission tomography were performed to evaluate myocardial function, perfusion and oxidative metabolism. Histology was used to confirm the size of MI and features of LV remodelling.

Results: The size of MI was significantly smaller in the levosimendan group than in the controls (12±13% vs 27±15% of the LV, p=0.03). End-diastolic volume (EDV) and end-systolic volume (ESV) were smaller in the levosimendan than in the control group (EDV 161±29 mL vs 245±84 mL, p=0.06; ESV 81±18 mL vs 149±67 mL, p=0.03), whereas ejection fraction tended to be higher in the levosimendan group (50±6% vs 41±8%, p=0.06).

Conclusions: Eight weeks of levosimendan therapy after recent LAD occlusion decreases the size of MI and leads to better preservation of LV function as well as reduced LV remodelling.
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http://dx.doi.org/10.1136/heartjnl-2015-308137DOI Listing
March 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

[18F]FDG Accumulation in Early Coronary Atherosclerotic Lesions in Pigs.

PLoS One 2015 29;10(6):e0131332. Epub 2015 Jun 29.

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

Objective: Inflammation is an important contributor to atherosclerosis progression. A glucose analogue 18F-fluorodeoxyglucose ([18F]FDG) has been used to detect atherosclerotic inflammation. However, it is not known to what extent [18F]FDG is taken up in different stages of atherosclerosis. We aimed to study the uptake of [18F]FDG to various stages of coronary plaques in a pig model.

Methods: First, diabetes was caused by streptozotocin injections (50 mg/kg for 3 days) in farm pigs (n = 10). After 6 months on high-fat diet, pigs underwent dual-gated cardiac PET/CT to measure [18F]FDG uptake in coronary arteries. Coronary segments (n = 33) were harvested for ex vivo measurement of radioactivity and autoradiography (ARG).

Results: Intimal thickening was observed in 16 segments and atheroma type plaques in 10 segments. Compared with the normal vessel wall, ARG showed 1.7±0.7 times higher [18F]FDG accumulation in the intimal thickening and 4.1±2.3 times higher in the atheromas (P = 0.004 and P = 0.003, respectively). Ex vivo mean vessel-to-blood ratio was higher in segments with atheroma than those without atherosclerosis (2.6±1.2 vs. 1.3±0.7, P = 0.04). In vivo PET imaging showed the highest target-to-background ratio (TBR) of 2.7. However, maximum TBR was not significantly different in segments without atherosclerosis (1.1±0.5) and either intimal thickening (1.2±0.4, P = 1.0) or atheroma (1.6±0.6, P = 0.4).

Conclusions: We found increased uptake of [18F]FDG in coronary atherosclerotic lesions in a pig model. However, uptake in these early stage lesions was not detectable with in vivo PET imaging. Further studies are needed to clarify whether visible [18F]FDG uptake in coronary arteries represents more advanced, highly inflamed plaques.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131332PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487365PMC
March 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

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

Cardiac remodeling in a new pig model of chronic heart failure: Assessment of left ventricular functional, metabolic, and structural changes using PET, CT, and echocardiography.

J Nucl Cardiol 2015 Aug 20;22(4):655-65. Epub 2015 Feb 20.

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

Aims: Large animal models are needed to study disease mechanisms in heart failure (HF). In the present study we characterized the functional, metabolic, and structural changes of myocardium in a novel pig model of chronic myocardial infarction (MI) by using multimodality imaging and histology.

Methods And Results: Male farm pigs underwent a two-step occlusion of the left anterior descending coronary artery with concurrent distal ligation and implantation of a proximal ameroid constrictor (HF group), or sham operation (control group). Three months after the operation, cardiac output and wall stress were measured by echocardiography. Left ventricle (LV) volumes and mass were measured by computed tomography (CT). Myocardial perfusion was evaluated by [(15)O]water and oxygen consumption using [(11)C]acetate positron emission tomography, and the efficiency of myocardial work was calculated. Histological examinations were conducted to detect MI, hypertrophy, and fibrosis. Animals in the HF group had a large anterior MI scar. CT showed larger LV diastolic volume and lower ejection fraction in HF pigs than in controls. Perfusion and oxygen consumption in the remote non-infarcted myocardium were preserved in HF pigs as compared to controls. Global LV work and efficiency were significantly lower in HF than control pigs and was associated with increased wall stress. Histology showed myocyte hypertrophy but not increased interstitial fibrosis in the remote segments in HF pigs.

Conclusions: The chronic post-infarction model of HF is suitable for studies aimed to evaluate LV remodeling and changes in oxidative metabolism and can be useful for testing new therapies for HF.
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http://dx.doi.org/10.1007/s12350-015-0068-9DOI Listing
August 2015

64Cu- and 68Ga-labelled [Nle(14),Lys(40)(Ahx-NODAGA)NH2]-exendin-4 for pancreatic beta cell imaging in rats.

Mol Imaging Biol 2014 Apr;16(2):255-63

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

Purpose: Glucagon-like peptide-1 receptor (GLP-1R) is a molecular target for imaging of pancreatic beta cells. We compared the ability of [Nle(14),Lys(40)(Ahx-NODAGA-(64)Cu)NH2]-exendin-4 ([(64)Cu]NODAGA-exendin-4) and [Nle(14),Lys(40)(Ahx-NODAGA-(68)Ga)NH2]-exendin-4 ([(68)Ga]NODAGA-exendin-4) to detect native pancreatic islets in rodents.

Procedures: The stability, lipophilicity and affinity of the radiotracers to the GLP-1R were determined in vitro. The biodistribution of the tracers was assessed using autoradiography, ex vivo biodistribution and PET imaging. Estimates for human radiation dosimetry were calculated.

Results: We found GLP-1R-specific labelling of pancreatic islets. However, the pancreas could not be visualised in PET images. The highest uptake of the tracers was observed in the kidneys. Effective dose estimates for [(64)Cu]NODAGA-exendin-4 and [(68)Ga]NODAGA-exendin-4 were 0.144 and 0.012 mSv/MBq, respectively.

Conclusion: [(64)Cu]NODAGA-exendin-4 might be more effective for labelling islets than [(68)Ga]NODAGA-exendin-4. This is probably due to the lower specific radioactivity of [(68)Ga]NODAGA-exendin-4 compared to [(64)Cu]NODAGA-exendin-4. The radiation dose in the kidneys may limit the use of [(64)Cu]NODAGA-exendin-4 as a clinical tracer.
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http://dx.doi.org/10.1007/s11307-013-0691-2DOI Listing
April 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

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

Evaluation of 68Ga-labeled tracers for PET imaging of myocardial perfusion in pigs.

Nucl Med Biol 2012 Jul 20;39(5):715-23. Epub 2012 Jan 20.

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

Purpose: We evaluated four potential gallium-68 (68Ga)-labeled tracers for positron emission tomography (PET) imaging of myocardial perfusion in comparison with oxygen-15-labeled water ([15O]water) in healthy pigs. Four hexadentate salicylaldimine ligands derived from bis(3-aminopropyl)ethylenediamine (BAPEN) that showed promise in previous rat experiments were selected for this study.

Methods: Following an evaluation of myocardial blood flow with [15O]water PET, the pigs (total n=14) underwent a dynamic 90-min PET study with one of four 68Ga-labeled BAPEN derivatives (n=3-5 per tracer) either at rest or under adenosine stress. Serial arterial blood samples were collected during the imaging for the measurements of total radioactivity, radiometabolites, plasma protein binding and blood-to-plasma ratio for the 68Ga chelates. Time-activity curves of the left ventricular blood pool and myocardium were derived from PET images, and metabolite-corrected arterial input function was used for kinetic modeling. Also, ex vivo biodistribution of 68Ga radioactivity was analyzed.

Results: All four 68Ga tracers showed undesirably slow myocardial accumulation over time, but their in vivo stability, clearance from blood and the kinetics of the myocardium uptake varied. [68Ga][Ga-(sal)2BAPDMEN]1+ showed the highest myocardial uptake in PET images and tissue samples (myocardium-to-blood ratio 7.63±1.89, myocardium-to-lung ratio 3.03±0.33 and myocardium-to-liver ratio 1.80±0.82). However, there was no correlation between the myocardial perfusion measured with [15O]water and the net uptake rates or K1 values of the 68Ga chelates.

Conclusion: Our results revealed that myocardial accumulation of the 68Ga chelates proposed for myocardial perfusion imaging with PET was slow and not determined by myocardial perfusion in a large animal model. These findings suggest that the studied tracers are not suitable for clinical imaging of myocardial perfusion.
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http://dx.doi.org/10.1016/j.nucmedbio.2011.11.007DOI Listing
July 2012

Biodistribution and radiation dosimetry of [(11)C]choline: a comparison between rat and human data.

Eur J Nucl Med Mol Imaging 2010 May 13;37(5):874-83. Epub 2010 Jan 13.

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

Purpose: Methyl-(11)C-choline ([(11)C]choline) is a radiopharmaceutical used for oncological PET studies. We investigated the biodistribution and biokinetics of [(11)C]choline and provide estimates of radiation doses in humans.

Methods: The distribution of [(11)C]choline was evaluated ex vivo in healthy rats (n=9) by measuring the radioactivity of excised organs, and in vivo in tumour-bearing rats (n=4) by PET. In addition to estimates of human radiation doses extrapolated from rat data, more accurate human radiation doses were calculated on the basis of PET imaging of patients with rheumatoid arthritis (n=6) primarily participating in a synovitis imaging project with [(11)C]choline. Dynamic data were acquired from the thorax and abdomen after injection of 423+/-11 MBq (mean+/-SD) of tracer. Following PET imaging, the radioactivity in voided urine was measured. The experimental human data were used for residence time estimations. Radiation doses were calculated with OLINDA/EXM.

Results: In rats, the radioactivity distributed mainly to the kidneys, lungs, liver and adrenal gland. The effective dose in a human adult of about 70 kg was 0.0044 mSv/MBq, which is equivalent to 2.0 mSv from 460 MBq of [(11)C]choline PET. The highest absorbed doses in humans were 0.021 mGy/MBq in the kidneys, 0.020 mGy/MBq in the liver and 0.029 mGy/MBq in the pancreas. Only 2.0% of injected radioactivity was excreted in the urine during the 1.5 h after injection.

Conclusion: The absorbed radiation doses after administration of 460 MBq of [(11)C]choline were low. Except for the pancreas, biodistribution in the rat was in accordance with that in humans, but rat data may underestimate the effective dose, suggesting that clinical measurements are needed for a more detailed estimation. The observed effective doses suggest the feasibility of [(11)C]choline PET for human studies.
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http://dx.doi.org/10.1007/s00259-009-1346-zDOI Listing
May 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

Whole-body distribution and metabolism of [N-methyl-11C](R)-1-(2-chlorophenyl)-N-(1-methylpropyl)-3-isoquinolinecarboxamide in humans; an imaging agent for in vivo assessment of peripheral benzodiazepine receptor activity with positron emission tomography.

Eur J Nucl Med Mol Imaging 2009 Apr 3;36(4):671-82. Epub 2008 Dec 3.

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

Purpose: (11)C-PK11195 is a radiopharmaceutical for in vivo assessment of peripheral benzodiazepine receptor (PBR) activity using PET. We sought to clarify the metabolic fate of (11)C-PK11195 in a test-retest setting using radio-HPLC in comparison with radio-TLC, and the whole-body distribution in humans.

Materials And Methods: In order to evaluate the reproducibility of radio-HPLC metabolite analyses, ten patients with Alzheimer's disease (AD) underwent two successive (11)C-PK11195 examinations on separate days. For comparison of different analytical methods, plasma samples from seven patients were also analysed by radio-TLC. In addition, we evaluated the whole-body distribution of (11)C-PK11195 and its uptake in the brain.

Results: The level of unmetabolized (11)C-PK11195 decreased slowly from 96.3 +/- 1.6% (mean+/-SD) at 5 min to 62.7 +/- 8.3% at 40 min after injection. Large individual variation was observed in the amount of plasma (11)C-PK11195 radiometabolites. The whole-body distribution of (11)C-PK11195 showed the highest radioactivity levels in urinary bladder, adrenal gland, liver, salivary glands, heart, kidneys, and vertebral column. In addition, the hip bone and breast bone were clearly visualized by PET. In patients with AD, (11)C-PK11195 uptake in the brain was the highest in the basal ganglia and thalamus, followed by the cortical grey matter regions and the cerebellum. Low (11)C-PK11195 uptake was observed in the white matter.

Conclusion: Our results indicate that (11)C-PK11195 is eliminated both through the renal and hepatobiliary systems. Careful analysis of plasma metabolites is required to determine the accurate arterial input function for quantitative PET measurement.
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http://dx.doi.org/10.1007/s00259-008-1000-1DOI Listing
April 2009
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