Publications by authors named "Merja Haaparanta"

28 Publications

  • Page 1 of 1

19F/18F exchange synthesis for a novel [18F]S1P3-radiopharmaceutical.

J Labelled Comp Radiopharm 2013 Jun 5;56(8):385-91. Epub 2013 Jun 5.

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

(19)F/(18)F isotope exchange is a useful method to label drug molecules containing (19)F-fluorine with (18)F without modifying the drug molecule itself. Sphingosine-1-phosphate (S1P) is an important cellular mediator that functions by signaling through cell surface receptors. S1P is involved in several cell responses and may be related to many central nervous system disorders, including neural malfunction in Alzheimer's disease. In this study, [(18)F]1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(2-methoxyethoxy)-1H-indole-3-carboxamide, a novel (18)F-labeled positron emission tomography tracer for the S1P3 receptor, was successfully synthesized using the (19)F/(18)F isotope exchange reaction. Parameters of the reaction kinetics were studied, and correlations between the initial (18)F-activity, the amount of precursor, radiochemical yield and specific activity (SA) were determined. Contrary to expectations, high initial (18)F-activity decreased the radiochemical yield, and only a minor increase of SA occurred. This is most probably due to the complexity of the molecule and the subsequent susceptibility to radiolytic bond disruption. On the basis of the present results, a convenient condition for the (19)F/(18)F exchange reaction is the use of 2 µmol precursor with 20 GBq of (18)F-activity. This afforded a radiochemical yield of ~10% with an SA of 0.3 GBq/µmol. Results from this study are of interest for new tracer development where high initial (18)F-activity and (19)F/(18)F isotope exchange is used.
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http://dx.doi.org/10.1002/jlcr.3055DOI Listing
June 2013

Electrophilic addition of chlorine monofluoride for PET tracers.

Mol Imaging Biol 2013 Apr;15(2):131-5

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

Purpose: We have studied the utility of [(18)F]ClF electrophilic addition to the carbon-carbon double bond of analogues of a model positron emission tomography (PET) tracer, [(18)F]EF5. The consequence of simultaneous chlorine/fluorine addition on lipophilicity and biological activity of the molecule is evaluated.

Procedures: Post-target produced [(18)F]F2 was reacted with Cl2 to produce [(18)F]ClF, which was used in electrophilic addition.

Results: [(18)F]ClF was produced and used to label chlorinated analogues of [(18)F]EF5. The chlorinated analogues, [(18)F]EF4Cla and [(18)F]EF4Clb, were synthesized simultaneously. The in vivo uptake of the analogues compared well with [(18)F]EF5 uptake in tumor-bearing mice.

Conclusion: [(18)F]ClF is a suitable labeling reagent for electrophilic addition to double bonds of PET tracers. The results show that the modification of the pentafluoro group of [(18)F]EF5 by monofluorine-for-chlorine exchange affected the lipophilicity, but the hypoxia avidity of these molecules was not apparently altered.
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http://dx.doi.org/10.1007/s11307-012-0584-9DOI Listing
April 2013

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

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

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

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

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

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

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

Novel electrophilic synthesis of 6-[¹⁸F]fluorodopamine and comprehensive biological evaluation.

Eur J Nucl Med Mol Imaging 2012 May 10;39(5):800-10. Epub 2012 Jan 10.

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

Purpose: 6-[(18)F]Fluorodopamine (4-(2-aminoethyl)-5-[(18)F]fluorobenzene-1,2-diol, 6-[(18)F]FDA) is a tracer for imaging sympathetically innervated tissues. Previous electrophilic labelling methods produced 6-[(18)F]FDA with low specific radioactivity (SA) which has limited its wider use. Our aim was to employ electrophilic labelling and increase the SA to around 15 GBq/μmol. We also sought to determine an extensive biodistribution pattern for 6-[(18)F]FDA in rats in order to thoroughly identify tissues with dense sympathetic innervation that were specifically labelled with 6-[(18)F]FDA. In addition, to investigate the safety profile of 6-[(18)F]FDA in larger animals, we performed in vivo studies in pigs.

Methods: 6-[(18)F]FDA was synthesised using high SA electrophilic [(18)F]F(2) as the labelling reagent. Biodistribution and metabolism of 6-[(18)F]FDA was determined ex vivo in rats, and in vivo studies were done in pigs.

Results: 6-[(18)F]FDA was synthesised with 2.6 ± 1.1% radiochemical yield. The total amount of purified 6-[(18)F]FDA was 663 ± 291 MBq at the end of synthesis (EOS). SA, decay corrected to EOS, was 13.2 ± 2.7 GBq/μmol. Radiochemical purity exceeded 99.0%. Specific uptake of 6-[(18)F]FDA was demonstrated in heart, lung, pancreas, adrenal gland, lower large intestine (LLI), eye, thyroid gland, spleen and stomach tissue. 6-[(18)F]FDA in rat plasma declined rapidly, with a half-life of 2 min, indicating fast metabolism. In vivo PET studies in pigs confirmed the tracer could be used safely without pharmacological effects.

Conclusion: 6-[(18)F]FDA was synthesised with good radiopharmaceutical quality and yields high enough for several human PET studies. The SA of 6-[(18)F]FDA was improved by 50- to 500-fold compared to previous electrophilic methods. Uptake of 6-[(18)F]FDA was specific in various peripheral organs, indicating that 6-[(18)F]FDA PET can be used to investigate sympathoneural functions beyond cardiac studies when higher specific uptake is achieved.
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http://dx.doi.org/10.1007/s00259-011-2032-5DOI Listing
May 2012

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

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

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

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

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

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

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

α2-adrenoceptor regulation of blood glucose homeostasis.

Basic Clin Pharmacol Toxicol 2011 Jun 11;108(6):365-70. Epub 2011 Apr 11.

Turku PET Centre, University of Turku, Finland.

The α(2A)-adrenoceptor has been identified as an important regulator of blood glucose homeostasis. α(2A)-Adrenoceptors on pancreatic β-cells inhibit insulin secretion, and α(2A)-adrenoceptors on sympathetic nerves and on adrenomedullary chromaffin cells limit sympathoadrenal output. Recently, human α(2A)-adrenoceptor gene polymorphisms that influence α(2A)-adrenoceptor expression and function have been described. Increased α(2A)-adrenoceptor expression has been associated with impaired glucose-stimulated insulin secretion, elevated fasting blood glucose levels and an increased risk of type 2 diabetes. Accordingly, administration of α(2)-adrenoceptor agonists generally increases blood glucose levels, in spite of the ensuing sympatholysis that would be expected to lower blood glucose as a result of diminished α(1)- and β-adrenoceptor activation. α(2)-Adrenoceptor antagonists increase insulin secretion and reduce blood glucose levels by inhibiting tonically active α(2A)-adrenoceptors on pancreatic β-cells, but may also enhance sympathoadrenal output. In addition, α(2)-adrenoceptor antagonists potentiate the insulinotropic effect of sulphonylurea drugs, pointing to a potentially serious adverse drug interaction when the two classes of drugs are combined. The α(2)-adrenoceptor antagonist atipamezole is widely used in veterinary medicine, and sulphonylureas are prescribed for the treatment of type 2 diabetes in cats and dogs. Even if no dedicated α(2)-adrenoceptor antagonists are in clinical use in humans, some antipsychotic and antidepressant drugs are relatively potent α(2)-adrenoceptor antagonists. In the treatment of type 2 diabetes, α(2)-adrenoceptor agonists could possibly protect against sulphonylurea-induced hypoglycaemia, and α(2)-adrenoceptor antagonist drugs could improve insulin secretion. The potential usefulness of such drugs may vary between individuals, depending on α(2A)-adrenoceptor genetics, sympathetic tone and concomitant pathological conditions, such as cardiovascular disease and obesity.
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http://dx.doi.org/10.1111/j.1742-7843.2011.00699.xDOI Listing
June 2011

[(11)C]PIB-, [(18)F]FDG-PET and MRI imaging in patients with Parkinson's disease with and without dementia.

Parkinsonism Relat Disord 2010 Dec 25;16(10):666-70. Epub 2010 Sep 25.

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

The objective of this study was to identify possible group differences between PD patients with dementia and without dementia by combining different functional and structural imaging methods in vivo, which might provide an opportunity to disentangle the pathophysiological correlates of cognitive impairment and dementia in PD. We performed a neuropsychological evaluation, structural brain MRI, [(18)F]FDG PET and [(11)C]PIB PET in 19 PD patients [eight non-demented (PD), eleven demented (PDD)] and 24 healthy elderly volunteers. [(11)C]PIB region-to-cerebellum ratios did not differ significantly between the groups in any brain region (p > 0.05). PDD patients showed impaired glucose metabolism in cortical brain regions and this reduction was associated with the degree of cognitive impairment. PDD patients had more atrophy both in the hippocampus and the frontal cortex compared with PD patients and controls, and hippocampal atrophy was associated with impaired memory. This cross-sectional data suggests that development of dementia in PD is associated with extensive spread of hypometabolism beyond the occipital cortex, and with hippocampal and frontal atrophy but not beta-amyloid deposition consistent with a unique biological process related to PD rather than co-incidental development of AD in persons with PD.
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http://dx.doi.org/10.1016/j.parkreldis.2010.08.021DOI Listing
December 2010

Assessment of islet specificity of dihydrotetrabenazine radiotracer binding in rat pancreas and human pancreas.

J Nucl Med 2010 Sep 18;51(9):1439-46. Epub 2010 Aug 18.

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

Unlabelled: Vesicular monoamine transporter 2 (VMAT2) is a putative molecular target for the quantitative imaging of pancreatic beta-cell mass by PET. The VMAT2 PET tracer (11)C-dihydrotetrabenazine ((11)C-DTBZ) exhibits high pancreatic uptake that is reduced in type 1 diabetes. The aim of this study was to assess the islet and VMAT2 specificity of DTBZ binding in the pancreas.

Methods: The biodistribution of (11)C-DTBZ in rats was determined 10 and 60 min after injection. The localization of DTBZ radioactivity in rat and human pancreatic tissue sections was investigated by autoradiography. Saturation and competition binding assays were performed with (3)H-DTBZ and sections of rat pancreatic and control tissues. The binding of (11)C-DTBZ in pancreatic sections from rats with streptozotocin-induced diabetes was compared with that in control rats.

Results: The values for the pancreatic uptake of (11)C-DTBZ (percentage injected dose per gram of tissue) were 3.0 at 10 min and 2.7 at 60 min. At 10 min, pancreatic radioactivity was heterogeneously distributed, with higher levels toward the head of the pancreas (head-to-tail ratio, 1.7). No such gradient was observed in pancreatic sections incubated with (11)C-DTBZ and (3)H-DTBZ in vitro. In rats, (11)C-DTBZ and (3)H-DTBZ binding in pancreatic islets did not exceed binding in the exocrine pancreas. Saturable (3)H-DTBZ binding was observed in the rat brain striatum (dissociation constant [K(d)], 1.3 nM) and the bovine adrenal medulla (K(d), 3.3 nM), whereas in the rat pancreas, (3)H-DTBZ binding was nonsaturable. Competition binding with (3)H-DTBZ and VMAT2 antagonists also indicated that DTBZ binding in the rat pancreas was nonspecific and did not represent binding to VMAT2. Nonspecific pancreatic (11)C-DTBZ binding was lower in rats with streptozotocin-induced diabetes than in control rats. In sections of human pancreas, a subset of pancreatic islets were weakly but VMAT2-specifically labeled with (3)H-DTBZ.

Conclusion: The results showed that the pancreatic uptake of (11)C-DTBZ is mainly due to nonspecific binding in the exocrine pancreas and suggested that the reduction in pancreatic (11)C-DTBZ binding observed in type 1 diabetes is not specific for the loss of beta-cell mass.
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http://dx.doi.org/10.2967/jnumed.109.074492DOI Listing
September 2010

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

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

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

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

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

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

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

Higher free fatty acid uptake in visceral than in abdominal subcutaneous fat tissue in men.

Obesity (Silver Spring) 2010 Feb 20;18(2):261-5. Epub 2009 Aug 20.

Turku PET Centre, Turku, Finland.

Visceral adipose tissue has been shown to have high lipolytic activity. The aim of this study was to examine whether free fatty acid (FFA) uptake into visceral adipose tissue is enhanced compared to abdominal subcutaneous tissue in vivo. Abdominal adipose tissue FFA uptake was measured using positron emission tomography (PET) and [(18)F]-labeled 6-thia-hepta-decanoic acid ([(18)F]FTHA) and fat masses using magnetic resonance imaging (MRI) in 18 healthy young adult males. We found that FFA uptake was 30% higher in visceral compared to subcutaneous adipose tissue (0.0025 +/- 0.0018 vs. 0.0020 +/- 0.0016 micromol/g/min, P = 0.005). Visceral and subcutaneous adipose tissue FFA uptakes were strongly associated with each other (P < 0.001). When tissue FFA uptake per gram of fat was multiplied by the total tissue mass, total FFA uptake was almost 1.5 times higher in abdominal subcutaneous than in visceral adipose tissue. In conclusion, we observed enhanced FFA uptake in visceral compared to abdominal subcutaneous adipose tissue and, simultaneously, these metabolic rates were strongly associated with each other. The higher total tissue FFA uptake in subcutaneous than in visceral adipose tissue indicates that although visceral fat is active in extracting FFA, its overall contribution to systemic metabolism is limited in healthy lean males. Our results indicate that subcutaneous, rather than visceral fat storage plays a more direct role in systemic FFA availability. The recognized relationship between abdominal visceral fat mass and metabolic complications may be explained by direct effects of visceral fat on the liver.
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http://dx.doi.org/10.1038/oby.2009.267DOI Listing
February 2010

Autoradiographic characterization of alpha(2C)-adrenoceptors in the human striatum.

Synapse 2008 Jul;62(7):508-15

Turku PET Centre, Turku, Finland.

Indirect experimental evidence suggests that drugs acting on the alpha(2C)-adrenoceptor could be useful in the treatment of neuropsychiatric disorders such as depression and schizophrenia. In rodent brain, the highest levels of alpha(2C)-adrenoceptors are found in the striatum, with lower levels in cerebral cortex and hippocampus. In human brain, because of the poor subtype-selectivity of the available alpha(2)-adrenoceptor ligands, the localization of alpha(2C)-adrenoceptors has remained unknown. Recently, a selective alpha(2C)-adrenoceptor antagonist, JP-1302, was characterized, and to assess the presence of alpha(2C)-adrenoceptors in human brain, we performed competition binding in vitro receptor autoradiography with JP-1302 and the alpha(2)-adrenoceptor subtype nonselective antagonist [ethyl-(3)H]RS79948-197 on rat and human postmortem brain sections. In striatum of both species, JP-1302 vs. [ethyl-(3)H]RS79948-197 competition binding was biphasic, identifying high- and low-affinity binding sites, whereas in cortex and cerebellum, only low-affinity binding sites were detected. The results indicate that a significant portion of the alpha(2)-adrenoceptors in striatum is of the alpha(2C) subtype, whereas non-alpha(2C)-adreocneptors predominate in cortex and cerebellum. Because the alpha(2C)-adrenoceptor subtype distribution pattern appears to be conserved between rodents and humans, results obtained from studies on the role of the alpha(2C)-adrenoceptor in rodent models of neuropsychiatric disorders may be relevant also for human diseases.
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http://dx.doi.org/10.1002/syn.20520DOI Listing
July 2008

Ex vivo evaluation of N-(3-[18F]fluoropropyl)-2 beta-carbomethoxy-3 beta-(4-fluorophenyl)nortropane in rats.

Nucl Med Biol 2008 Feb;35(2):177-83

Laboratory of Radiochemistry, Department of Chemistry, University of Helsinki, PO Box 55, FI-00014 Helsinki, Finland.

Introduction: The dopamine transporter (DAT) ligand N-(3-fluoropropyl)-2 beta-carbomethoxy-3beta-(4-fluorophenyl)nortropane (beta-CFT-FP) was labeled with fluorine-18, and its biodistribution was evaluated in rats ex vivo.

Methods: The distribution of 18F radioactivity in the brain and peripheral organs and tissues was determined at several time points 5-120 min after intravenous injection of [18F]beta-CFT-FP.

Results: The highest brain uptake of [18F]beta-CFT-FP was localized in the striatum; limbic structures also exhibited high uptake. Low uptake was found in the cerebellum. The highest ratio of striatum-to-cerebellum uptake, already reached within 5 min, was 3.1. Pretreatment with the selective DAT inhibitor GBR12909 significantly decreased [18F]beta-CFT-FP uptake in the striatum. In most peripheral tissues, the highest uptake was found at 5 min, indicating fast washout of the radioligand. Some accumulation of (18)F radioactivity was seen in bone as a function of time, reflecting defluorination of the radioligand.

Conclusion: The results indicate that [18F]beta-CFT-FP is a potential radioligand for studying DAT in vivo with positron emission tomography.
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http://dx.doi.org/10.1016/j.nucmedbio.2007.09.006DOI Listing
February 2008

Increased physical activity decreases hepatic free fatty acid uptake: a study in human monozygotic twins.

J Physiol 2007 Jan 19;578(Pt 1):347-58. Epub 2006 Oct 19.

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

Exercise is considered to be beneficial for free fatty acid (FFA) metabolism, although reports of the effects of increased physical activity on FFA uptake and oxidation in different tissues in vivo in humans have been inconsistent. To investigate the heredity-independent effects of physical activity and fitness on FFA uptake in skeletal muscle, the myocardium, and liver we used positron emission tomography (PET) in nine healthy young male monozygotic twin pairs discordant for physical activity and fitness. The cotwins with higher physical activity constituting the more active group had a similar body mass index but less body fat and 18 +/- 10% higher (P < 0.001) compared to the less active brothers with lower physical activity. Low-intensity knee-extension exercise increased skeletal muscle FFA and oxygen uptake six to 10 times compared to resting values but no differences were observed between the groups at rest or during exercise. At rest the more active group had lower hepatic FFA uptake compared to the less active group (5.5 +/- 4.3 versus 9.0 +/- 6.1 micromol (100 ml)(-1) min(-1), P = 0.04). Hepatic FFA uptake associated significantly with body fat percentage (P = 0.05). Myocardial FFA uptake was similar between the groups. In conclusion, in the absence of the confounding effects of genetic factors, moderately increased physical activity and aerobic fitness decrease body adiposity even in normal-weighted healthy young adult men. Further, increased physical activity together with decreased intra-abdominal adiposity seems to decrease hepatic FFA uptake but has no effects on skeletal muscle or myocardial FFA uptake.
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http://dx.doi.org/10.1113/jphysiol.2006.121368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2075122PMC
January 2007

Analysis of 18F-labelled synthesis products on TLC plates: comparison of radioactivity scanning, film autoradiography, and a phosphoimaging technique.

Appl Radiat Isot 2006 Sep 24;64(9):1043-7. Epub 2006 Jul 24.

Division of Nuclear Medicine, Helsinki University Central Hospital, P.O. Box 340, FIN-00029 Helsinki, Finland.

We compared radioactivity scanning, film autoradiography, and digital photostimulated luminescence (PSL) autoradiography (phosphoimaging technique) in detection of radioactivity on thin-layer chromatography (TLC) plates. TLC combined with radioactivity detection is rapid, simple, and relatively flexible. Here, (18)F-labelled synthesis products were analyzed by TLC and the radioactivity distribution on the plates determined using the three techniques. Radioactivity scanning is appropriate only with good chromatographic resolution and previously validated scanning parameters. Film autoradiography exhibits poor linearity if radioactivity varies greatly. PSL provides high sensitivity and resolution and superior linearity compared with the other methods.
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http://dx.doi.org/10.1016/j.apradiso.2006.04.012DOI Listing
September 2006

Non-specific binding of [18F]FDG to calcifications in atherosclerotic plaques: experimental study of mouse and human arteries.

Eur J Nucl Med Mol Imaging 2006 Dec 15;33(12):1461-7. Epub 2006 Jul 15.

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

Purpose: [(18)F]FDG has been used as an inflammation marker and shown to accumulate in inflammatory atherosclerotic plaques. The aim of this study was to investigate the uptake and location of [(18)F]FDG in atherosclerotic plaque compartments.

Methods: The biodistribution of intravenously administered [(18)F]FDG was analysed in atherosclerotic LDLR/ApoB48 mice (n=11) and control mice (n=9). Digital autoradiography was used to detect the ex vivo distribution in frozen aortic sections. In vitro binding of [(18)F]FDG in human atherosclerotic arteries was also examined.

Results: The uptake of [(18)F]FDG was significantly higher in the aorta of atherosclerotic mice as compared with the control mice. Autoradiography of excised arteries showed higher [(18)F]FDG uptake in the plaques than in the healthy vessel wall (mean ratio +/-SD 2.7+/-1.1). The uptake of [(18)F]FDG in the necrotic, calcified sites of the advanced atherosclerotic lesions was 6.2+/-3.2 times higher than that in the healthy vessel wall. The in vitro studies of human arterial sections showed marked binding of [(18)F]FDG to the calcifications but not to other structures of the artery wall.

Conclusion: In agreement with previous studies, we observed [(18)F]FDG uptake in atherosclerotic plaques. However, prominent non-specific binding to calcified structures was found. This finding warrants further studies to clarify the significance of this non-specific binding in human plaques in vivo.
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http://dx.doi.org/10.1007/s00259-006-0159-6DOI Listing
December 2006

Planar chromatographic analysis and quantification of short-lived radioactive metabolites from microdialysis fractions.

J Chromatogr A 2006 Mar 30;1108(1):136-9. Epub 2006 Jan 30.

Turku PET Centre, Medicity Research Laboratory/PET Preclinical Imaging, Tykistokatu 6A, FI 20520 Turku, Finland.

A sensitive radiochromatographic method for the quantitative determination of compounds labelled with short-lived beta-emitting radionuclides in microdialysates is described. The method is well suited for microdialysis (MD) samples, which have small volumes and low concentrations of compounds. An 18F-labelled (beta+; T(1/2)=109.8 min) radiopharmaceutical, (1R,2S)-4-[18F]fluorometaraminol (FMR), was injected intravenously into rats, and microdialysis fractions were then collected from the blood at 15 min intervals. Fractions were analyzed for FMR and its radioactive metabolites by planar chromatography combined with digital photostimulated luminescence autoradiography. The lowest detectable 18F-radioactivity was 0.24 Bq/application and the limit of quantification was 0.31 Bq/application with 4-16 h exposure. The method was found to be highly sensitive and linear in the range of 0.1 Bq-2 kBq. This method thus allows the quantification of beta-emitting radiopharmaceuticals in sequential microdialysis fractions with good time-resolution.
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http://dx.doi.org/10.1016/j.chroma.2005.12.107DOI Listing
March 2006

Visualization and quantification of neurokinin-1 (NK1) receptors in the human brain.

Mol Imaging Biol 2005 Jul-Aug;7(4):262-72

Neuropsychiatric Imaging, Turku PET Centre, Turku University Central Hospital, Finland.

Purpose: This study was conducted to develop a new positron emission tomography (PET) method to visualize neurokinin-1 (NK(1)) receptor systems in the human brain in vivo in order to examine their neuroanatomical distribution and facilitate investigations of the role of substance P, NK(1) receptors, and NK(1) receptor antagonists in central nervous system (CNS) function and dysfunction.

Methods: PET studies were conducted in 10 healthy male volunteers using a novel selective, high-affinity NK(1) receptor antagonist labeled with fluorine-18 to very high specific radioactivity (up to 2000 GBq/micromol) [F-18]SPA-RQ. Data were collected in 3D mode for greatest sensitivity. Different modeling methods were compared and regional receptor distributions determined for comparison with in vitro autoradiographic studies using postmortem human brain slices with [F-18]SPA-RQ.

Results: The studies showed that the highest uptake of [F-18]SPA-RQ was observed in the caudate and putamen. Lower binding was found in globus pallidus and substantia nigra. [F-18]SPA-RQ uptake was also widespread throughout the neocortex and limbic cortex including amygdala and hippocampus. There was very low specific uptake of the tracer in the cerebellar cortex. The distribution pattern was confirmed using in vitro receptor autoradiography with [F-18]SPA-RQ on postmortem human brain slices. Kinetic modeling of the [F-18]SPA-RQ uptake data indicated a binding potential between 4 and 5 in the basal ganglia and between 1.5 and 2.5 in the cortical regions.

Conclusions: [F-18]SPA-RQ is a novel tool for exploration of the functions of NK(1) receptors in man. [F-18]SPA-RQ can be used to define receptor pharmacodynamics and focus dose selection of novel NK(1) receptor antagonists in clinical trials thereby ensuring adequate proof of concept testing particularly in therapeutic applications related to CNS dysfunction.
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http://dx.doi.org/10.1007/s11307-005-7001-6DOI Listing
March 2006

An autoradiographic study of [(18)F]FDG uptake to islets of Langerhans in NOD mouse.

Diabetes Res Clin Pract 2005 Dec 13;70(3):217-24. Epub 2005 Jun 13.

DIPP-project, Department of Pediatrics, University of Turku, Turku, Finland.

To evaluate the potential of in vivo imaging of accumulation of lymphocytes to islets of Langerhans (insulitis), we compared 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) uptake in the pancreas and pancreatic islets of healthy BALB/c mice, phenotypically healthy NOD mice with insulitis and diabetic NOD mice. [(18)F]FDG was injected i.v. to 14 female BALB/c mice (age 13+/-3 weeks, plasma glucose 8+/-2 mmol/l) and 21 age-matched female NOD mice (plasma glucose 8+/-4 mmol/l, p=0.06). The mice were killed 90-min post injection and distribution of radioactivity was analysed using digital autoradiography. There was no correlation of plasma glucose concentration with the [(18)F]FDG uptake values. Uptake of radioactivity in NOD mice to the islets affected by insulitis was up to 2.3 times higher (p=0.001) than that to unaffected islets in the same pancreas. Uptake to NOD islets with insulitis was also clearly enhanced (1.0-2.3 times higher) compared to the islets in the BALB/c mice. In conclusion, NOD mouse islets with insulitis accumulate [(18)F]FDG markedly more than islets without insulitis or BALB/c islets. However, the relatively small difference in the [(18)F]FDG intensity between healthy and diseased islets, combined with the limited resolution ability of the positron emission tomography (PET), probably prevent the use of [(18)F]FDG in PET studies aiming at in vivo documentation of onset and progression of insulitis and prediabetes in mouse and man.
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http://dx.doi.org/10.1016/j.diabres.2005.04.008DOI Listing
December 2005

The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L-amino acid decarboxylase in healthy subjects.

Pharmacogenet Genomics 2005 Jun;15(6):387-91

Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku University Central Hospital, Turku, Finland.

The A1 allele of the TaqI restriction fragment length polymorphism (RFLP) of the human dopamine D2 receptor gene (DRD2) is associated with a low density of D2 dopamine receptors in the striatum. Because of the important role of D2 autoreceptors in regulating dopamine synthesis, we aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain. We also studied the effects of two other DRD2 polymorphisms, C957 T and--141C Ins/Del, which have been suggested to affect D2 receptor levels in brain. The relationships between the TaqIA RFLP, C957 T and--141C Ins/Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers were studied using positron emission tomography and [18F]fluorodopa ([18F]FDOPA), a radiolabelled analog of the dopamine precursor L-DOPA. Heterozygous carriers of the A1 allele (A1/A2; 10 subjects) had significantly higher (18%) [18F]FDOPA uptake in the putamen than subjects without the A1 allele (A2/A2; 23 subjects). C957 T and--141C Ins/Del polymorphisms did not significantly affect [18F]FDOPA Ki values. These results demonstrate that the A1 allele of DRD2 gene is associated with increased striatal activity of aromatic L-amino acid decarboxylase, the final enzyme in the biosynthesis of dopamine and the rate-limiting enzyme for trace amine (e.g. beta-phenylethylamine) synthesis. The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function, and suggests that dopamine and/or trace amine synthesis rate is increased in the brains of A1 allele carriers.
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http://dx.doi.org/10.1097/01213011-200506000-00003DOI Listing
June 2005

Synthesis and characterization of a potent, selective, radiolabeled substance-P antagonist for NK1 receptor quantitation: ([18F]SPA-RQ).

Mol Imaging Biol 2004 Nov-Dec;6(6):373-84

Turku PET Centre, Turku, Finland.

Purpose: To develop and characterize a radiolabelled Substance-P antagonist useful for quantitation of neurokinin-1 receptors in the brain via PET imaging.

Procedure: [18F]SPA-RQ (Substance-P antagonist - receptor quantifier) was synthesized in good yield and high specific activity by alkylation of a BOC protected phenolate anion using [18F]bromofluoromethane. Removal of the BOC protecting group with trifluoroacetic acid gave [18F]SPA-RQ.

Results: SPA-RQ has high affinity for human, rhesus monkey and guinea pig NK1 receptors (h-IC50=67 pM) and has a log P value of 1.8. Biodistribution studies in guinea pig showed that this tracer penetrates the blood-brain barrier and selectively labels NK1 receptors in the striatum and cortex.

Conclusion: [18F]SPA-RQ is a potent, high affinity Substance-P antagonist that can be conveniently labeled with high specific activity using [18F]fluoromethylbromide. This tracer is a useful tool for noninvasive imaging of central NK1 receptors.
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http://dx.doi.org/10.1016/j.mibio.2004.08.001DOI Listing
May 2005

Altered glucose homeostasis in alpha2A-adrenoceptor knockout mice.

Eur J Pharmacol 2004 Nov;505(1-3):243-52

Department of Pharmacology and Clinical Pharmacology, University of Turku, Itäinen Pitkäkatu 4B, FI-20520 Turku, Finland.

To elucidate the functions of alpha2-adrenoceptor subtypes in metabolic regulation, we determined plasma glucose and insulin levels and tissue uptake of the glucose analogue 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) in C57Bl/6J wild-type (WT) and alpha2A-adrenoceptor knockout (alpha2A-KO) mice at baseline and following alpha2-adrenoceptor agonist ((+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (dexmedetomidine)) and antagonist (4-[2-ethyl-2,3-dihydro-1H-inden-2-yl]-1H-imidazole (atipamezole)) administration. Basal glucose levels were 30% lower in alpha2A-KO mice than in WT mice. In WT mice, dexmedetomidine lowered insulin and elevated glucose levels, and atipamezole reduced glucose levels. In alpha2A-KO mice, neither drug affected the glucose or insulin levels. [18F]FDG uptake was investigated in plasma, heart, liver, kidney, pancreas, lung, fat, and skeletal muscle. Cardiac [18F]FDG uptake was a sensitive indicator of sympathetic function. Liver [18F]FDG uptake conformed to the plasma glucose levels. In alpha2A-KO mice, drug effects on [18F]FDG tissue uptake were absent. Thus, the alpha2A-adrenoceptor is the alpha2-adrenoceptor subtype primarily involved in the regulation of blood glucose homeostasis in vivo.
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http://dx.doi.org/10.1016/j.ejphar.2004.10.023DOI Listing
November 2004

In vivo sampling for pharmacokinetic studies in small experimental animals: a combination of microdialysis, planar chromatography and digital autoradiography.

Mol Imaging Biol 2004 Jan-Feb;6(1):27-33

Turku PET Centre, Medicity Research Laboratory/PET, Turku, Finland.

Purpose: We describe a method for measuring the pharmacokinetics of positron emission tomography (PET) tracers during rat studies using microdialysis (MD) in combination with planar chromatography and digital autoradiography with a phosphoimager plate (DAR).

Procedures: An MD probe was inserted into the jugular vein of the rat and perfused with physiological buffer solution (n>/=3). An (18)F-labeled radiopharmaceutical was injected intravenously, and dialysate fractions were collected, measured for radioactivity, and applied on a chromatography plate. This plate was exposed with an imaging plate for radioactivity imaging.

Results: Time activity curves for unbound, unchanged tracer and metabolites were determined. The amount of unchanged tracer in the last MD fraction was compared with the amount in the plasma sample collected after sacrifice of the animal.

Conclusion: MD continuously samples and monitors the amount of unbound tracer in the blood from one single experimental animal. MD combined with planar chromatography and DAR is a highly sensitive and linear method for simultaneous analysis of PET tracers and their metabolites in blood.
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http://dx.doi.org/10.1016/j.mibio.2003.12.005DOI Listing
November 2004

A novel electrophilic synthesis and evaluation of medium specific radioactivity (1R,2S)-4-[18F]fluorometaraminol, a tracer for the assessment of cardiac sympathetic nerve integrity with PET.

Nucl Med Biol 2004 Jan;31(1):103-10

Turku PET Centre, Radiopharmaceutical Chemistry Laboratory and Accelerator Laboratory, Porthaninkatu 3, FIN 20500, Turku, Finland.

(1R,2S)-4-[18F]fluorometaraminol (4-[18F]FMR), a tracer for cardiac sympathetic innervation, was synthesized by electrophilic aromatic substitution. A trimethylstannyl precursor, protected with tert-butoxycarbonyl protecting groups, was radiofluorinated with high specific radioactivity [18F]F2. Specific radioactivity of 4-[18F]FMR, in average 11.8 +/-3.3 GBq/micromol, was improved 40-800-fold in comparison to the previous electrophilic fluorinations. The biodistribution of 4-[18F]FMR in rat was in accordance with the known distribution of sympathetic innervation. 4-[18F]FMR showed no metabolic degradation in left ventricle of rat heart, where the uptake was high, rapid and specific.
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http://dx.doi.org/10.1016/s0969-8051(03)00098-2DOI Listing
January 2004

Comparison of the biodistribution of two hypoxia markers [18F]FETNIM and [18F]FMISO in an experimental mammary carcinoma.

Eur J Nucl Med Mol Imaging 2004 Apr 14;31(4):513-20. Epub 2004 Jan 14.

Medicity Research Laboratory, Turku PET Centre, Tykistökatu 6 A, 20520 Turku, Finland.

The first aim of this study was to compare the hypoxia imaging ability of fluorine-18 fluoroerythronitroimidazole ([18F]FETNIM) with that of fluorine-18 fluoromisonimidazole ([18F]FMISO) in murine tumours of different sizes under two different oxygenation conditions. Secondly, we wanted to assess the biodistribution of the markers in normal tissues under similar conditions. Female CDF1 mice with a C3H mammary carcinoma grown on their backs were used. Tumours were size matched and animals breathed either normal air (21% O(2)) or carbogen gas (95% O(2) + 5% CO(2)). The gassing procedure was begun 5 min before the intravenous injection of either [18F]FETNIM or [18F]FMISO and continued until the mice were sacrificed at 120 min. Blood, tumour, muscle, heart, lung, liver, kidney and fat were removed, counted for radioactivity and weighed. The tumour and muscle were frozen and cut with a cryomicrotome into sections. The spatial distribution of radioactivity from the tissue sections was determined with digital autoradiography. Estimation of the necrotic fraction was made on sections from formalin-fixed tumours. Digital autoradiography showed that the whole tumour-to-muscle radioactivity uptake ratios were significantly higher in normal air-breathing mice than in carbogen-treated mice for both [18F]FETNIM (4.9+/-2.6 vs 1.8+/-0.5; P<0.01) and [18F]FMISO (4.4+/-1.0 vs 1.5+/-0.4; P<0.01). The carbogen treatment had only slight effects on the biodistribution of either marker in normal tissues. The necrotic fraction determined in tumours did not correlate with the tumour volume or with the tumour-to-muscle radioactivity uptake ratio. This study shows that the uptake of both [18F]FETNIM and [18F]FMISO correlates with the oxygenation status in tumours. In addition, our data show no significant difference in the intratumoral uptake between the two markers. However, significantly higher radioactivity uptake values were measured for [18F]FMISO than for [18F]FETNIM in normal tissues.
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http://dx.doi.org/10.1007/s00259-003-1404-xDOI Listing
April 2004

Uptake of 6-[18F]fluoro-L-dopa and [18F]CFT reflect nigral neuronal loss in a rat model of Parkinson's disease.

Synapse 2004 Feb;51(2):119-27

MediCity PET, Turku PET Centre, FIN 20520 Turku, Finland.

In order to characterize the sensitivity of an analog of levodopa and a dopamine transporter ligand to detect defects in nigrostriatal function, the uptake of [(18)F]FDOPA and [(18)F]CFT was studied ex vivo in a rat model of Parkinson's disease. The brains of these rats were unilaterally lesioned with an intranigral injection of 6-hydroxydopamine. The lesioned animals were divided into three groups subject to their behavior after pharmacological challenges. Circling behavior was recorded after amphetamine, apomorphine, and L-DOPA challenge in order to predict lesion size. The spatial distribution of radioactivity after [(18)F]FDOPA or [(18)F]CFT injection in brain sections was determined with digital autoradiography. Regions of interest were left/right striatum, left/right substantia nigra, and cerebellum. The degree of unilateral lesion for each animal was confirmed by counting of nigral tyrosine hydroxylase-positive cell bodies. With both tracers the uptake in the lesioned side was lower than in the intact side in the striatum and in the substantia nigra. In conclusion, both tracers clearly demonstrated nigrostriatal dopaminergic hypofunction and correlated with the number of nigral dopaminergic neurons. However, [(18)F]FDOPA showed a much higher unspecific uptake of radioactivity, due to extensive metabolism; therefore, this tracer was less sensitive than the transporter tracer [(18)F]CFT to detect these defects.
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http://dx.doi.org/10.1002/syn.10293DOI Listing
February 2004

Microdialysis and 2-[18F]fluoro-2-deoxy-D-glucose (FDG): a study on insulin action on FDG transport, uptake and metabolism in rat muscle, liver and adipose tissue.

Life Sci 2003 Aug;73(11):1437-51

Turku PET Centre, Medicity Research Laboratory/PET, Tykistokatu 6 A, FIN 20520 Turku, Finland.

A combination of microdialysis (MD) and 2-[18F ]fluoro-2-deoxy-D-glucose (FDG) was used to assess FDG uptake, phosphorylation and the glucose metabolic index (Rg') in certain tissues of fed and fasting anesthetized Sprague-Dawley rats which received an i.v. bolus injection of insulin or saline during the course of the study. The relative recovery for FDG for the MD probes was also measured as a function of flow rate and temperature. The elimination half-life (T(1/2 FDG)) of FDG from the plasma and the extracellular fluid of muscle and liver was studied with MD. The phosphorylation of FDG in muscle, liver, subcutaneous fat and mesenteric fat from homogenates of these tissues was analyzed by a radioHPLC-method and the Rg' was calculated. The results show that the nutritional status does not affect the T(1/2 FDG), the total uptake of FDG 6-phosphate or the Rg' values in the studied tissues at ambient glucose. Insulin stimulation decreased T(1/2 FDG), and increased the total FDG 6-P accumulation and Rg' in the muscle of fed and fasted rats. In adipose tissues the insulin stimulation enhanced the phosphorylation but in muscle the proportion of FDG 6-P remained unchanged. Rg' in adipose tissue was higher after insulin administration in fed rats than without insulin but with fasted rats there were no differences in Rg' values with or without insulin, although the proportion of FDG 6-P did increase. The Rg' values for the livers were unaffected by any of the manipulations, but fasted rats accumulated proportionately more FDG 6-P after insulin administration than did fed rats. These results indicate that the combination of MD and FDG is a valuable and reliable tool when studying glucose metabolism in physiological and pathological models in vivo.
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http://dx.doi.org/10.1016/s0024-3205(03)00470-3DOI Listing
August 2003

S-[18F]fluoromethyl-(+)-McN5652, a PET tracer for the serotonin transporter: evaluation in rats.

Synapse 2003 Jan;47(1):45-53

MediCity PET Laboratory, Turku PET Centre, Turku, Finland.

The [(18)F]fluoromethyl analog of (+)-McN5652 ([(18)F]FMe-McN) for imaging serotonin transporter (SERT) with positron emission tomography (PET) has recently been synthesized. We describe here the biological evaluation of [(18)F]FMe-McN in rats. Biodistribution studies of [(18)F]FMe-McN in rat brain ex vivo after an intravenous injection showed a high accumulation of radioactivity in the regions rich in SERT, such as raphe nuclei, hypothalamus, thalamus, substantia nigra, locus coeruleus, and amygdala. Region-to-cerebellum ratios reached a maximum value of 9 in raphe nuclei within 3.5 h after administration. The specificity and selectivity of [(18)F]FMe-McN binding to SERT was studied by preinjecting blocking doses of serotonin, norepinephrine, and dopamine transporter inhibitors. Fluoxetine, a specific inhibitor for SERT, decreased the specific binding of [(18)F]FMe-McN in raphe nuclei by 91 +/- 4%; in other regions rich in SERT, similar results were obtained. GBR12909 and nisoxetine, selective inhibitors for dopamine transporter (DAT) and norepinephrine transporter (NET), respectively, showed no significant effects on the uptake of [(18)F]FMe-McN. Our studies show that [(18)F]FMe-McN has a clear potential as a tracer for studies with PET of SERT function in humans.
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http://dx.doi.org/10.1002/syn.10150DOI Listing
January 2003

Sex differences in striatal presynaptic dopamine synthesis capacity in healthy subjects.

Biol Psychiatry 2002 Oct;52(7):759-63

Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland.

Background: There are sex differences in the clinical features of several neuropsychiatric illnesses associated with dopamine dysfunction. The effects of sex on brain dopaminergic function have been sparsely studied in human subjects using modern imaging techniques. We have previously reported that the apparent affinity of [(11)C]raclopride for striatal D(2) dopamine receptors in vivo is lower in women than in men, whereas D(2) receptor density is not different. This finding indirectly suggests that women have a higher synaptic concentration of dopamine in the striatum. We explored further the basis of this phenomenon in an independent study and hypothesized that striatal presynaptic dopamine synthesis capacity would also be elevated in women.

Methods: A total of 23 healthy men and 12 healthy women (age range 20-60 years) were studied using positron emission tomography and [(18)F]fluorodopa.

Results: Women had significantly higher striatal [(18)F]fluorodopa uptake (Ki values) than men. The difference was more marked in the caudate (+26%) than in the putamen (+12%). In addition, there was a negative correlation between striatal [(18)F]fluorodopa Ki values and age in men but not in women.

Conclusions: The results further substantiate sex differences in striatal dopaminergic function in humans. This finding may be associated with sex differences in vulnerability and clinical course of neuropsychiatric disorders with dopaminergic dysregulation, e.g., schizophrenia, alcohol dependence, and Parkinson's disease.
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http://dx.doi.org/10.1016/s0006-3223(02)01369-0DOI Listing
October 2002