Publications by authors named "Sarita Forsback"

49 Publications

The neural substrates of risky rewards and losses in healthy volunteers and patient groups: a PET imaging study.

Psychol Med 2021 Feb 11:1-9. Epub 2021 Feb 11.

Department of Psychiatry, University of Cambridge, Cambridge, UK.

Background: Risk is an essential trait of most daily decisions. Our behaviour when faced with risks involves evaluation of many factors including the outcome probabilities, the valence (gains or losses) and past experiences. Several psychiatric disorders belonging to distinct diagnostic categories, including pathological gambling and addiction, show pathological risk-taking and implicate abnormal dopaminergic, opioidergic and serotonergic neurotransmission. In this study, we adopted a transdiagnostic approach to delineate the neurochemical substrates of decision making under risk.

Methods: We recruited 39 participants, including 17 healthy controls, 15 patients with pathological gambling and seven binge eating disorder patients, who completed an anticipatory risk-taking task. Separately, participants underwent positron emission tomography (PET) imaging with three ligands, [18F]fluorodopa (FDOPA), [11C]MADAM and [11C]carfentanil to assess presynaptic dopamine synthesis capacity and serotonin transporter and mu-opioid receptor binding respectively.

Results: Risk-taking behaviour when faced with gains positively correlated with dorsal cingulate [11C]carfentanil binding and risk-taking to losses positively correlated with [11C]MADAM binding in the caudate and putamen across all subjects.

Conclusions: We show distinct neurochemical substrates underlying risk-taking with the dorsal cingulate cortex mu-opioid receptor binding associated with rewards and dorsal striatal serotonin transporter binding associated with losses. Risk-taking and goal-directed control appear to dissociate between dorsal and ventral fronto-striatal systems. Our findings thus highlight the potential role of pharmacological agents or neuromodulation on modifying valence-specific risk-taking biases.
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http://dx.doi.org/10.1017/S0033291720005450DOI Listing
February 2021

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

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

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

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

The feasibility of [F]EF5-PET/CT to image hypoxia in ovarian tumors: a clinical study.

EJNMMI Res 2020 Sep 10;10(1):103. Epub 2020 Sep 10.

Department of Obstetrics and Gynecology, Turku University Hospital, Turku, Finland.

Rationale: Evaluation of the feasibility of [F]EF5-PET/CT scan in identifying hypoxic lesions in ovarian tumors in prospective clinical setting.

Methods: Fifteen patients with a suspected malignant ovarian tumor were scanned with [F]EF5 and [F]FDG-PET/CT preoperatively. The distribution of [F]EF5-uptake, total intraabdominal metabolic tumor volume (TMTV), and hypoxic subvolume (HSV) were assessed.

Results: [F]EF5-PET/CT suggested hypoxia in 47% (7/15) patients. The median HSV was 87 cm (31% of TMTV). The [F]EF5-uptake was detected in primary tumors and in four patients also in intra-abdominal metastases. The [F]EF5-uptake in cancer tissue was low compared to physiological excretory pathways, complicating the interpretation of PET/CT images.

Conclusions: [F]EF5-PET/CT is not feasible in ovarian cancer imaging in clinical setting due to physiological intra-abdominal [F]EF5-accumulation. However, it may be useful when used complementarily to FDG-PET/CT.
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http://dx.doi.org/10.1186/s13550-020-00689-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483702PMC
September 2020

The FLUKA Monte Carlo code coupled with an OER model for biologically weighted dose calculations in proton therapy of hypoxic tumors.

Phys Med 2020 Aug 16;76:166-172. Epub 2020 Jul 16.

Department of Physics and Technology, University of Bergen, Allégaten 55, 5007 Bergen, Norway.

Introduction: The increased radioresistance of hypoxic cells compared to well-oxygenated cells is quantified by the oxygen enhancement ratio (OER). In this study we created a FLUKA Monte Carlo based tool for inclusion of both OER and relative biological effectiveness (RBE) in biologically weighted dose (ROWD) calculations in proton therapy and applied this to explore the impact of hypoxia.

Methods: The RBE-weighted dose was adapted for hypoxia by making RBE model parameters dependent on the OER, in addition to the linear energy transfer (LET). The OER depends on the partial oxygen pressure (pO) and LET. To demonstrate model performance, calculations were done with spread-out Bragg peaks (SOBP) in water phantoms with pO ranging from strongly hypoxic to normoxic (0.01-30 mmHg) and with a head and neck cancer proton plan optimized with an RBE of 1.1 and pO estimated voxel-by-voxel using [F]-EF5 PET. An RBE of 1.1 and the Rørvik RBE model were used for the ROWD calculations.

Results: The SOBP in water had decreasing ROWD with decreasing pO. In the plans accounting for oxygenation, the median target doses were approximately a factor 1.1 lower than the corresponding plans which did not consider the OER. Hypoxia adapted target ROWDs were considerably more heterogeneous than the RBE-weighted doses.

Conclusion: We realized a Monte Carlo based tool for calculating the ROWD. Read-in of patient pO and estimation of ROWD with flexibility in choice of RBE model was achieved, giving a tool that may be useful in future clinical applications of hypoxia-guided particle therapy.
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http://dx.doi.org/10.1016/j.ejmp.2020.07.003DOI Listing
August 2020

Automated GMP production and long-term experience in radiosynthesis of CB tracer [ F]FMPEP-d.

J Labelled Comp Radiopharm 2020 Jul 1;63(9):408-418. Epub 2020 Jul 1.

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

Here, we describe the development of an in-house-built device for the fully automated multistep synthesis of the cannabinoid CB receptor imaging tracer (3R,5R)-5-(3-([ F]fluoromethoxy-d )phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one ([ F]FMPEP-d ), following good manufacturing practices. The device is interfaced to a HPLC and a sterile filtration unit in a clean room hot cell. The synthesis involves the nucleophilic F-fluorination of an alkylating agent and its GC purification, the subsequent F-fluoroalkylation of a precursor molecule, the semipreparative HPLC purification of the F-fluoroalkylated product, and its formulation for injection. We have optimized the duration and temperature of the F-fluoroalkylation reaction and addressed the radiochemical stability of the formulated product. During the past 5 years (2013-2018), we have performed a total of 149 syntheses for clinical use with a 90% success rate. The activity yield of the formulated product has been 1.0 ± 0.4 GBq starting from 11 ± 2 GBq and the molar activity 600 ± 300 GBq/μmol at the end of synthesis.
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http://dx.doi.org/10.1002/jlcr.3845DOI Listing
July 2020

The neurochemical substrates of habitual and goal-directed control.

Transl Psychiatry 2020 03 3;10(1):84. Epub 2020 Mar 3.

Clinical Neurosciences, University of Turku, Turku, Finland.

Our daily decisions are governed by the arbitration between goal-directed and habitual strategies. However, the neurochemical basis of this arbitration is unclear. We assessed the contribution of dopaminergic, serotonergic, and opioidergic systems to this balance across reward and loss domains. Thirty-nine participants (17 healthy controls, 15 patients with pathological gambling, and 7 with binge eating disorder) underwent positron emission tomography (PET) imaging with [F]FDOPA, [C]MADAM and [C]carfentanil to assess presynaptic dopamine, and serotonin transporter and mu-opioid receptor binding potential. Separately, participants completed a modified two-step task, which quantifies the degree to which decision-making is influenced by goal-directed or habitual strategies. All participants completed a version with reward outcomes; healthy controls additionally completed a version with loss outcomes. In the context of rewarding outcomes, we found that greater serotonin transporter binding potential in prefrontal regions was associated with habitual control, while greater serotonin transporter binding potential in the putamen was marginally associated with goal-directed control; however, the findings were no longer significant when controlling for the opposing valence (loss). In blocks with loss outcomes, we found that the opioidergic system, specifically greater [C]carfentanil binding potential, was positively associated with goal-directed control and negatively associated with habit-directed control. Our findings illuminate the complex neurochemical basis of goal-directed and habitual behavior, implicating differential roles for prefrontal and subcortical serotonin in decision-making across healthy and pathological populations.
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http://dx.doi.org/10.1038/s41398-020-0762-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054261PMC
March 2020

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

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

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

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

Comparison of high and low molar activity TSPO tracer [F]F-DPA in a mouse model of Alzheimer's disease.

J Cereb Blood Flow Metab 2020 05 29;40(5):1012-1020. Epub 2019 May 29.

Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku and Turku University Central Hospital, Turku, Finland.

[F]F-DPA, a novel translocator protein 18 kDa (TSPO)-specific radioligand for imaging neuroinflammation, has to date been synthesized with low to moderate molar activities (A's). In certain cases, low A can skew the estimation of specific binding. The high proportion of the non-radioactive component can reduce the apparent-specific binding by competitively binding to receptors. We developed a nucleophilic synthesis of [F]F-DPA resulting in high A (990 ± 150 GBq/µmol) and performed in vivo comparison with low A (9.0 ± 2.9 GBq/µmol) [F]F-DPA in the same APP/PS1-21 and wild-type mice (injected masses: 0.34 ± 0.13 µg/kg and 38 ± 15 µg/kg, respectively). The high level of microgliosis in the APP/PS1-21 mouse model enables good differentiation between diseased and healthy animals and serves better to distinguish the effect of differing A on specific binding. The differing injected masses affect the washout profile and shape of the time-activity curves. Ratios of standardized uptake values obtained with high and low A [F]F-DPA demonstrate that there is a 1.5-fold higher uptake of radioactivity in the brains of APP/PS1-21 animals when imaging is carried out with high A [F]F-DPA. The differences between APP/PS1-21 and wild-type animals showed higher significance when high A was used.
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http://dx.doi.org/10.1177/0271678X19853117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181084PMC
May 2020

Radiosynthesis and Preclinical Evaluation of an α-Adrenoceptor Tracer Candidate, 6-[F]Fluoro-marsanidine.

Mol Imaging Biol 2019 10;21(5):879-887

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

Purpose: The α-adrenoceptors mediate many effects of norepinephrine and epinephrine, and participate in the regulation of neuronal, endocrine, cardiovascular, vegetative, and metabolic functions. Of the three receptor subtypes, only α and α are found in the brain in significant amounts. Subtype-selective positron emission tomography (PET) imaging of α-adrenoceptors has been limited to the α subtype. Here, we report the synthesis of 6-[F]fluoro-marsanidine, a subtype-selective PET tracer candidate for α-adrenoceptors, and its preclinical evaluation in rats and mice.

Procedures: 6-[F]Fluoro-marsanidine was synthesized using electrophilic F-18 fluorination with [F]Selectfluor bis(triflate). The tracer was evaluated in Sprague Dawley rats and in α-knockout (KO) and wild-type (WT) mice for subtype selectivity. In vivo PET imaging and ex vivo brain autoradiography were performed to determine the tracer distribution in the brain. The specificity of the tracer for the target was determined by pretreatment with the subtype-non-selective α-agonist medetomidine. The peripheral biodistribution and extent of metabolism of 6-[F]fluoro-marsanidine were also analyzed.

Results: 6-[F]Fluoro-marsanidine was synthesized with [F]Selectfluor bis(triflate) in a radiochemical yield of 6.4 ± 1.7 %. The molar activity was 3.1 to 26.6 GBq/μmol, and the radiochemical purity was > 99 %. In vivo studies in mice revealed lower uptake in the brains of α-KO mice compared to WT mice. The results for selectivity were confirmed by ex vivo brain autoradiography. Blocking studies revealed reduced uptake in α-adrenoceptor-rich brain regions in pretreated animals, demonstrating the specificity of the tracer. Metabolite analyses revealed very rapid metabolism of 6-[F]fluoro-marsanidine with blood-brain barrier-permeable metabolites in both rats and mice.

Conclusion: 6-[F]Fluoro-marsanidine was synthesized and evaluated as a PET tracer candidate for brain α-adrenoceptors. However, rapid metabolism, extensive presence of labeled metabolites in the brain, and high non-specific uptake in mouse and rat brain make 6-[F]fluoro-marsanidine unsuitable for α-adrenoceptor targeting in rodents in vivo.
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http://dx.doi.org/10.1007/s11307-019-01317-6DOI Listing
October 2019

characterization of a novel norepinephrine transporter PET tracer [F]NS12137 in adult and immature Sprague-Dawley rats.

Theranostics 2019 1;9(1):11-19. Epub 2019 Jan 1.

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

Norepinephrine modulates cognitive processes such as working and episodic memory. Pathological changes in norepinephrine and norepinephrine transporter (NET) function and degeneration of the locus coeruleus produce irreversible impairments within the whole norepinephrine system, disrupting cognitive processes. Monitoring these changes could enhance diagnostic accuracy and support development of novel therapeutic components for several neurodegenerative diseases. Thus, we aimed to develop a straightforward nucleophilic fluorination method with high molar activity for the novel NET radiotracer [F]NS12137 and to demonstrate the ability of [F]NS12137 to quantify changes in NET expression. We applied an F-radiolabeling method in which a brominated precursor was debrominated by nucleophilic F-fluorination in dimethyl sulfoxide. Radiolabeling was followed by a deprotection step, purification, and formulation of the radiotracer The [F]NS12137 brain uptake and distribution were studied with PET/CT and autoradiography using both adult and immature Sprague-Dawley rats because postnatal NET expression peaks at 10-20 days post birth. The NET specificity for the tracer was demonstrated by pretreatment of the animals with nisoxetine, which is well-known to have a high affinity for NET. [F]NS12137 was successfully synthesized with radiochemical yields of 18.6±5.6%, radiochemical purity of >99%, and molar activity of >500 GBq/μmol at the end of synthesis. The [F]NS12137 uptake showed peak standard uptake values (SUV) of over 1.5 (adult) and 2.2 (immature) in the different brain regions. Peak SUV/30 min and peak SUV/60 min ratios were calculated for the different brain regions of the adult and immature rats, with a peak SUV/60 min ratio of more than 4.5 in the striatum of adult rats. As expected, studies demonstrated uptake of the tracer in brain areas rich in NET, particularly thalamus, neocortex, and striatum, and remarkably also in the locus coeruleus, a quite small volume for imaging with PET. The uptake was significantly higher in immature rats compared to the adult animals. studies using autoradiography showed very strong specific binding in NET-rich areas such as the locus coeruleus and the bed nucleus of the stria terminalis, and high binding in larger grey matter areas such as the neocortex and striatum. The uptake of [F]NS12137 was dramatically reduced both and by pretreatment with nisoxetine, demonstrating the specificity of binding. [F]NS12137 was synthesized in good yield and high molar activity and demonstrated the characteristics of a good radiotracer, such as good brain penetration, fast washout, and high specific binding to NET.
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http://dx.doi.org/10.7150/thno.29740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332804PMC
December 2019

[F]F-DPA for the detection of activated microglia in a mouse model of Alzheimer's disease.

Nucl Med Biol 2018 12 26;67:1-9. Epub 2018 Sep 26.

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

Introduction: Neuroinflammation is associated with several neurological disorders, including Alzheimer's disease (AD). The translocator protein 18 kDa (TSPO), due to its overexpression during microglial activation and relatively low levels in the brain under normal neurophysiological conditions, is commonly used as an in vivo biomarker for neuroinflammation. Reported here is the preclinical evaluation of [F]F-DPA, a promising new TSPO-specific radioligand, as a tool for the detection of activated microglia at different ages in the APP/PS1-21 mouse model of AD and a blocking study to determine the specificity of the tracer.

Methods: [F]F-DPA was synthesised by the previously reported electrophilic F-fluorination methodology. In vivo PET and ex vivo brain autoradiography were used to observe the tracer distribution in the brains of APP/PS1-21 and wildtype mice at different ages (4.5-24 months). The biodistribution and degree of metabolism of [F]F-DPA were analysed and the specificity of [F]F-DPA for its target was determined by pre-treatment with PK11195.

Results: The in vivo PET imaging and ex vivo brain autoradiography data showed that [F]F-DPA uptake in the brains of the transgenic animals increased with age, however, there was a drop in the tracer uptake at 19 mo. Despite the slight increase in [F]F-DPA uptake with age in healthy animal brains, significant differences between wildtype and transgenic animals were seen in vivo at 9 months and ex vivo already at 4.5 months. The specificity study demonstrated that PK11195 can be used to significantly block [F]F-DPA uptake in all the brain regions studied.

Conclusions: In vivo time activity curves plateaued at approximately 20-40 min suggesting that this is the optimal imaging time. Significant differences in vivo are seen at 9 and 12 mo. Due to the higher resolution, ex vivo autoradiography with [F]F-DPA can be used to visualise activated microglia at an early stage of AD pathology.
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http://dx.doi.org/10.1016/j.nucmedbio.2018.09.001DOI Listing
December 2018

Dopamine synthesis capacity correlates with µ-opioid receptor availability in the human basal ganglia: A triple-tracer PET study.

Neuroimage 2018 12 2;183:1-6. Epub 2018 Aug 2.

Division of Clinical Neurosciences, Turku University Hospital, PO Box 52, FIN-20521, Turku, Finland; Department of Neurology, University of Turku, PO Box 52, FIN-20521, Turku, Finland; Turku PET Centre, University of Turku, PO Box 52, FIN-20521, Turku, Finland.

Animal studies have suggested that dopamine and opioid neurotransmitter systems interact in brain regions that are relevant for reward functions, but data in humans are very limited. The interaction is potentially important in disorders affecting these neurotransmitter systems, such as addiction. Here, we investigated whether subcortical μ-opioid receptor (MOR) availability and presynaptic dopamine synthesis capacity are correlated in the healthy human brain or in pathological gamblers (PGs) using positron emission tomography with 6-[F]fluoro-l-dopa and [C]carfentanil. The specificity of the findings was further investigated by including a serotonin transporter ligand, [C]MADAM, as a negative control. Thirteen PG patients and 15 age-, sex- and weight-matched controls underwent the scans. In both groups, presynaptic dopamine synthesis capacity was associated with MOR availability in the putamen, caudate nucleus and globus pallidus. No similar associations were observed between dopamine synthesis capacity and [C]MADAM binding, supporting a specific interplay between presynaptic dopamine neurotransmission and opioid receptor function in the basal ganglia. Correlations were similar between the groups, suggesting that the dopamine-opioid link is general and unaffected by behavioral addiction. The results provide in vivo human evidence of a connection between endogenous opioid and dopamine signaling in the brain.
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http://dx.doi.org/10.1016/j.neuroimage.2018.07.069DOI Listing
December 2018

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

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

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

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

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

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

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

Reversibility of myocardial metabolism and remodelling in morbidly obese patients 6 months after bariatric surgery.

Diabetes Obes Metab 2018 04 17;20(4):963-973. Epub 2018 Jan 17.

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

Aims: To study myocardial substrate uptake, structure and function, before and after bariatric surgery, to clarify the interaction between myocardial metabolism and cardiac remodelling in morbid obesity.

Methods: We studied 46 obese patients (age 44 ± 10 years, body mass index [BMI] 42 ± 4 kg/m ), including 18 with type 2 diabetes (T2D) before and 6 months after bariatric surgery and 25 healthy age-matched control group subjects. Myocardial fasting free fatty acid uptake (MFAU) and insulin-stimulated myocardial glucose uptake (MGU) were measured using positron-emission tomography. Myocardial structure and function, and myocardial triglyceride content (MTGC) and intrathoracic fat were measured using magnetic resonance imaging and magnetic resonance spectroscopy.

Results: The morbidly obese study participants, with or without T2D, had cardiac hypertrophy, impaired myocardial function and substrate metabolism compared with the control group. Surgery led to marked weight reduction and remission of T2D in most of the participants. Postoperatively, myocardial function and structure improved and myocardial substrate metabolism normalized. Intrathoracic fat, but not MTGC, was reduced. Before surgery, BMI and MFAU correlated with left ventricular hypertrophy, and BMI, age and intrathoracic fat mass were the main variables associated with cardiac function. The improvement in whole-body insulin sensitivity correlated positively with the increase in MGU and the decrease in MFAU.

Conclusions: In the present study, obesity and age, rather than myocardial substrate uptake, were the causes of cardiac remodelling in morbidly obese patients with or without T2D. Cardiac remodelling and impaired myocardial substrate metabolism are reversible after surgically induced weight loss and amelioration of T2D.
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http://dx.doi.org/10.1111/dom.13183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888194PMC
April 2018

F-labeled norepinephrine transporter tracer [F]NS12137: radiosynthesis and preclinical evaluation.

Nucl Med Biol 2018 Jan 24;56:39-46. Epub 2017 Oct 24.

Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Turku, Finland; Department of Chemistry, University of Turku, Turku, Finland; Accelerator Laboratory, Åbo Akademi University, Turku, Finland.

Introduction: Several psychiatric and neurodegenerative diseases are associated with malfunction of brain norepinephrine transporter (NET). However, current clinical evaluations of NET function are limited by the lack of sufficiently sensitive methods of detection. To this end, we have synthesized exo-3-[(6-[F]fluoro-2-pyridyl)oxy]-8-azabicyclo[3.2.1]-octane ([F]NS12137) as a radiotracer for positron emission tomography (PET) and have demonstrated that it is highly specific for in vivo detection of NET-rich regions of rat brain tissue.

Methods: We applied two methods of electrophilic, aromatic radiofluorination of the precursor molecule, exo-3-[(6-trimethylstannyl-2-pyridyl)oxy]-8-azabicyclo-[3.2.1]octane-8-carboxylate: (1) direct labeling with [F]F, and (2) labeling with [F]Selectfluor, a derivative of [F]F, using post-target produced [F]F. The time-dependent distribution of [F]NS12137 in brain tissue of healthy, adult Sprague-Dawley rats was determined by ex vivo autoradiography. The specificity of [F]NS12137 binding was demonstrated on the basis of competitive binding by nisoxetine, a known NET antagonist of high specificity.

Results: [F]NS12137 was successfully synthesized with radiochemical yields of 3.9% ± 0.3% when labeled with [F]F and 10.2% ± 2.7% when labeled with [F]Selectfluor. The molar activity of radiotracer was 8.8 ± 0.7 GBq/μmol with [F]F labeling and 6.9 ± 0.4 GBq/μmol with [F]Selectfluor labeling at the end of synthesis of [F]NS12137. Uptake of [F]NS12137 in NET-rich areas in rat brain was demonstrated with the locus coeruleus (LCoe) having the highest regional uptake. Prior treatment of rats with nisoxetine showed no detectable [F]NS12137 in the LCoe. Analyses of whole brain samples for radiometabolites showed only the parent compound [F]NS12137. Uptake of F-radioactivity in bone increased with time.

Conclusions: The two electrophilic F-labeling methods proved to be suitable for synthesis of [F]NS12137 with the [F]Selectfluor method providing an approximate three-fold higher yield than the [F]F method. As an electrostatically neutral radiotracer [F]NS12137 crosses the blood-brain barrier and enabled specific labeling of NET-rich regions of rat brain tissue with the highest concentration in the LCoe.
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http://dx.doi.org/10.1016/j.nucmedbio.2017.10.005DOI Listing
January 2018

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

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

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

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

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

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

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

Vacuum ultraviolet photon-mediated production of [ F]F.

J Labelled Comp Radiopharm 2017 04 15;60(4):186-193. Epub 2017 Mar 15.

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

The chemistry of F and its derivatives are amenable to facile aliphatic or aromatic substitution, as well as electrophilic addition. The main limitation in the use of [ F]F for radiopharmaceutical synthesis is the low specific activity achieved by the traditional methods of production. The highest specific activities, 55 GBq/μmol, for [ F]F have been achieved so far by using electrical discharge in the post-target production of [ F]F gas from [ F]CH F. We demonstrate that [ F]F is produced by illuminating a gas mixture of neon/F /[ F]CH F with vacuum ultraviolet photons generated by an excimer laser. We tested several illumination chambers and production conditions. The effects of the initial amount of [ F]F , amount of carrier F , and number of 193-nm laser pulses at constant power were evaluated regarding radiochemical yield and specific activity. The specific activity attained for [ F]F -derived [ F]NFSi was 10.3 ± 0.9 GBq/μmol, and the average radiochemical yield over a wide range of conditions was 6.7% from [ F]F . The production can be improved by optimization of the synthesis device and procedures. The use of a commercially available excimer laser and the simplicity of the process can make this method relatively easy for adaptation in radiochemistry laboratories.
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http://dx.doi.org/10.1002/jlcr.3489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413832PMC
April 2017

Radiosynthesis and Preclinical Evaluation of [F]F-DPA, A Novel Pyrazolo[1,5a]pyrimidine Acetamide TSPO Radioligand, in Healthy Sprague Dawley Rats.

Mol Imaging Biol 2017 Oct;19(5):736-745

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

Purpose: Many neurological conditions result in the overexpression of the translocator protein 18 kDa (TSPO), today recognized as a biomarker for microglial activation and neuroinflammation imaging. The pyrazolo[1,5-a]pyrimidine acetamides are a particularly attractive class of TSPO-specific ligands, prompting the development of several positron emission tomography (PET) radiotracers. This includes F-DPA, a recently reported fluorinated ligand (K  = 1.7 nM), wherein the fluorine atom is directly linked to the phenyl moiety without the presence of an alkyl or alkoxy spacer chain. Reported here is the preparation of [F]F-DPA using [F]Selectfluor bis(triflate) and the preliminary evaluation of [F]F-DPA in healthy rats. Its metabolic profile and biodistribution in rats are compared with that of [F]DPA-714, a closely related structure.

Procedures: [F]F-DPA was synthesized by electrophilic fluorination using [F]Selectfluor bis(triflate), [F]DPA-714 was synthesized by conventional nucleophilic fluorination. The biodistribution of both radiotracers was compared in Sprague Dawley rats. Radiometabolites of both radiotracers in plasma and brain homogenates were analyzed by radioTLC.

Results: The radiochemical yield of [F]F-DPA was 15 ± 3 % and the specific activity was 7.8 ± 0.4 GBq/μmol. The radiochemical purity exceeded 99 %. The in vivo time activity curves of [F]F-DPA demonstrate rapid entry into the brain and a concentration equilibrium at 20-30 min after injection. The metabolic profiles at 90 min after radiotracer injection in the plasma show that unchanged [F]F-DPA and [F]DPA-714 account for 28.3 ± 6.4 and 11.1 ± 2.6 % of the remaining radioactivity, respectively. In the brain, unchanged [F]F-DPA accounts for 93.5 ± 2.8 % of the radioactivity; whereas for [F]DPA-714, this value is 53.6 ± 1.6 %.

Conclusions: [F]Selectfluor bis(triflate) was successfully used to label F-DPA with fluorine-18. The labeling position on the aromatic moiety imparts a higher stability compared to [F]DPA-714 with regard to in vivo metabolism. [F]F-DPA is a promising new radiotracer and warrants further investigation in animal models of disease.
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http://dx.doi.org/10.1007/s11307-016-1040-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574958PMC
October 2017

Dopamine and Opioid Neurotransmission in Behavioral Addictions: A Comparative PET Study in Pathological Gambling and Binge Eating.

Neuropsychopharmacology 2017 Apr 24;42(5):1169-1177. Epub 2016 Nov 24.

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

Although behavioral addictions share many clinical features with drug addictions, they show strikingly large variation in their behavioral phenotypes (such as in uncontrollable gambling or eating). Neurotransmitter function in behavioral addictions is poorly understood, but has important implications in understanding its relationship with substance use disorders and underlying mechanisms of therapeutic efficacy. Here, we compare opioid and dopamine function between two behavioral addiction phenotypes: pathological gambling (PG) and binge eating disorder (BED). Thirty-nine participants (15 PG, 7 BED, and 17 controls) were scanned with [C]carfentanil and [F]fluorodopa positron emission tomography using a high-resolution scanner. Binding potentials relative to non-displaceable binding (BP) for [C]carfentanil and influx rate constant (K) values for [F]fluorodopa were analyzed with region-of-interest and whole-brain voxel-by-voxel analyses. BED subjects showed widespread reductions in [C]carfentanil BP in multiple subcortical and cortical brain regions and in striatal [F]fluorodopa K compared with controls. In PG patients, [C]carfentanil BP was reduced in the anterior cingulate with no differences in [F]fluorodopa K compared with controls. In the nucleus accumbens, a key region involved in reward processing, [C]Carfentanil BP was 30-34% lower and [F]fluorodopa K was 20% lower in BED compared with PG and controls (p<0.002). BED and PG are thus dissociable as a function of dopaminergic and opioidergic neurotransmission. Compared with PG, BED patients show widespread losses of mu-opioid receptor availability together with presynaptic dopaminergic defects. These findings highlight the heterogeneity underlying the subtypes of addiction and indicate differential mechanisms in the expression of pathological behaviors and responses to treatment.
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http://dx.doi.org/10.1038/npp.2016.265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357051PMC
April 2017

Ultrafast Click Chemistry with Fluorosydnones.

Angew Chem Int Ed Engl 2016 09 25;55(39):12073-7. Epub 2016 Aug 25.

Service de Chimie Bio-organique et Marquage (SCBM), IBITECS, CEA, Université Paris-Saclay, 91191, Gif-sur-Yvette, France.

We report the synthesis and reactivity of 4-fluorosydnones, a unique class of mesoionic dipoles displaying exquisite reactivity towards both copper-catalyzed and strain-promoted cycloaddition reactions with alkynes. Synthetic access to these new mesoionic compounds was granted by electrophilic fluorination of σ-sydnone Pd(II) precursors in the presence of Selectfluor. Their reactions with terminal and cyclic alkynes were found to proceed very rapidly and selectively, affording 5-fluoro-1,4-pyrazoles with bimolecular rate constants up to 10(4)  m(-1)  s(-1) , surpassing those documented in the literature with cycloalkynes. Kinetic studies were carried out to unravel the mechanism of the reaction, and the value of 4-fluorosydnones was further highlighted by successful radiolabeling with [(18) F]Selectfluor.
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http://dx.doi.org/10.1002/anie.201606495DOI Listing
September 2016

(18)F-labeling syntheses and preclinical evaluation of functionalized nanoliposomes for Alzheimer's disease.

Eur J Pharm Sci 2016 Jun 16;88:257-66. Epub 2016 Mar 16.

Turku PET Centre, Radiopharmaceutical Chemistry Laboratory, University of Turku, Turku, Finland; Turku PET Centre, Accelerator Laboratory, Åbo Akademi University, Turku, Finland; Department of Chemistry, University of Turku, Turku, Finland.

The aim of the present study was to synthesize functionalized (18)F-labeled NLs ((18)F-NLs) and evaluate their biological behavior in mouse models of Alzheimer's disease (AD) using positron emission tomography (PET) and ex vivo brain autoradiography. (18)F-fluorine was introduced to (18)F-NLs either by using a core forming (18)F-lipid or by encapsulating a (18)F-tracer, (18)F-treg-curcumin inside the NLs. Phosphatidic acid (PA) and curcumin derivative (Curc) functionalized (18)F-NLs with or without additional mApoE functionalization were produced using thin film hydration. The biodistribution and β-amyloid plaque-binding ability of (18)F-NLs were studied in wild type mice and AD mouse models using in vivo PET imaging and ex vivo brain autoradiography at 60min after (18)F-NL injection. Functionalized (18)F-NLs were successfully synthesized. The preclinical evaluation in mice showed that the functional group affected the biodistribution of (18)F-NLs. Further functionalization with mApoE increased the brain-to-blood ratio of (18)F-NLs but the overall brain uptake remained low with all functionalized (18)F-NLs. The liposomal encapsulation of (18)F-treg-curcumin was not successful and preclinical results of encapsulated (18)F-treg-curcumin and plain (18)F-treg-curcumin were identical. Although the studied functionalized (18)F-NLs were not suitable for PET imaging as such, the synthesis techniques introduced in this study can be utilized to modify the biological behavior of (18)F-labeled NLs.
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http://dx.doi.org/10.1016/j.ejps.2016.03.016DOI Listing
June 2016

Organomediated Enantioselective (18)F Fluorination for PET Applications.

Angew Chem Int Ed Engl 2015 Nov 11;54(45):13366-9. Epub 2015 Sep 11.

University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA (UK).

The first organomediated asymmetric (18)F fluorination has been accomplished using a chiral imidazolidinone and [(18)F]N-fluorobenzenesulfonimide. The method provides access to enantioenriched (18)F-labeled α-fluoroaldehydes (>90% ee), which are versatile chiral (18)F synthons for the synthesis of radiotracers. The utility of this process is demonstrated with the synthesis of the PET (positron emission tomography) tracer (2S,4S)-4-[(18)F]fluoroglutamic acid.
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http://dx.doi.org/10.1002/anie.201506035DOI Listing
November 2015

The Cannabinoid Receptor-1 Is an Imaging Biomarker of Brown Adipose Tissue.

J Nucl Med 2015 Dec 10;56(12):1937-41. Epub 2015 Sep 10.

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

Unlabelled: Recently, the existence of significant deposits of brown adipose tissue (BAT) in human adults was confirmed. Its role in the human metabolism is unknown but could be substantial. Inhibition of the cannabinoid receptor-1 (CB1) by the antagonist rimonabant (SR141716) has been associated with activation of BAT thermogenesis and weight loss in mice and rats. The role of peripheral and central CB1 in the activation of BAT merits further investigation. Here we developed a technique for quantifying CB1 in BAT by PET.

Methods: Sections of rat BAT and subcutaneous white adipose tissue (WAT) were stained for CB1 and uncoupling protein-1 by immunofluorescent staining. Binding of the radiolabeled CB1 antagonist (3R,5R)-5-(3-(18F-fluoromethoxy)phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)-phenyl)pyrrolidin-2-one ((18)F-FMPEP-d2) to BAT in vivo and in vitro was assessed in rats by PET.

Results: We found that CB1 was colocalized with uncoupling protein-1 in BAT, but neither protein was found in WAT. Binding of the radiotracer to BAT sections (but not WAT) in vitro was high and displaceable by pretreatment with rimonabant. Deposits of BAT in rats had significant binding of (18)F-FMPEP-d2 in vivo, indicating high CB1 density. WAT deposits were negative for (18)F-FMPEP-d2, consistent with the immunofluorescent staining and in vitro results.

Conclusion: (18)F-FMPEP-d2 PET can quantify CB1 density noninvasively in vivo in rats. CB1 is therefore a promising surrogate imaging biomarker for assessing the presence of BAT deposits as well as for elucidating the mechanism of CB1 antagonist-mediated weight loss.
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http://dx.doi.org/10.2967/jnumed.115.156422DOI Listing
December 2015

18F-fluorodihydroxyphenylalanine in the diagnosis of neuroendocrine tumors.

PET Clin 2014 Jan 2;9(1):27-36. Epub 2013 Oct 2.

Turku PET Centre, Turku University Hospital, PO Box 52, Turku 20521, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, PO Box 52, Turku 20521, Finland.

(18)F-fluorodihydroxyphenylalanine (FDOPA) is a powerful tool for the diagnosis and detection of neuroendocrine tumors when planning and monitoring surgical and oncologic therapies. Pheochromocytomas, paragangliomas, and medullary thyroid cancers especially are amenable to FDOPA imaging because of the high specific uptake of this amino acid analogue and excellent tumor-to-background contrast on PET/computed tomography.
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http://dx.doi.org/10.1016/j.cpet.2013.08.013DOI Listing
January 2014

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

Transl Oncol 2014 May 23. Epub 2014 May 23.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Catalytic decarboxylative fluorination for the synthesis of tri- and difluoromethyl arenes.

Org Lett 2013 Jun 20;15(11):2648-51. Epub 2013 May 20.

Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.

Treatment of readily available α,α-difluoro- and α-fluoroarylacetic acids with Selectfluor under Ag(I) catalysis led to decarboxylative fluorination. This operationally simple reaction gave access to tri- and difluoromethylarenes applying a late-stage fluorination strategy. Translation to [(18)F]labeling is demonstrated using [(18)F]Selectfluor bis(triflate), a reagent affording [(18)F]tri- and [(18)F]difluoromethylarenes not within reach with [(18)F]F2.
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http://dx.doi.org/10.1021/ol4009377DOI Listing
June 2013

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

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

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

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

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

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

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

[18F]fluorination of an arylboronic ester using [18F]selectfluor bis(triflate): application to 6-[18F]fluoro-L-DOPA.

Chem Commun (Camb) 2013 Feb;49(14):1386-8

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

The Ag-mediated electrophilic [(18)F]fluorination of an arylboronic ester is reported. This new radiochemical transformation uses [(18)F]selectfluor bis(triflate) in acetone. The process gave 6-[(18)F]fluoro-L-DOPA with a RCY of 19 ± 12% and a specific activity of 2.6 ± 0.3 GBq μmol(-1).
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http://dx.doi.org/10.1039/c2cc38646aDOI Listing
February 2013