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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. [ABSTRACT FROM AUTHOR]

Background: Fatty acid uptake can be measured using PET and 14-(R,S)-[ 18 F]fluoro-6-thia-heptadecanoic acid ([ 18 F]FTHA). However, the relatively rapid rate of [ 18 F]FTHA metabolism significantly affects kinetic modeling of tissue uptake. Thus, there is a need for accurate chromatographic methods to analyze the unmetabolized [ 18 F]FTHA (parent fraction). Here we present a new radiometabolite analysis (RMA) method, with comparison to a previous method for parent fraction analysis, and its use in a test-retest clinical study under fasting and postprandial conditions. We developed a new thin-layer chromatography (TLC) RMA method for analysis of [ 18 F]FTHA parent fraction and its radiometabolites from plasma, by testing stationary phases and eluent combinations. Next, we analyzed [ 18 F]FTHA, its radiometabolites, and plasma radioactivity from subjects participating in a clinical study. A total of 17 obese or overweight participants were dosed with [ 18 F]FTHA twice under fasting, and twice under postprandial conditions and plasma samples were obtained between 14 min (mean of first sample) and 72 min (mean of last sample) post-injection. Aliquots of 70 plasma samples were analyzed using both methods, enabling head-to-head comparisons. We performed test-retest and group comparisons of the parent fraction and plasma radioactivity., Results: The new TLC method separated seven [ 18 F]FTHA radiometabolite peaks, while the previous method separated three. The new method revealed at least one radiometabolite that was not previously separable from [ 18 F]FTHA. From the plasma samples, the mean parent fraction value was on average 7.2 percentage points lower with the new method, compared to the previous method. Repeated [ 18 F]FTHA investigations on the same subject revealed reproducible plasma SUV and parent fractions, with different kinetics between the fasted and postprandial conditions., Conclusions: The newly developed improved radio-TLC method for [ 18 F]FTHA RMA enables accurate parent fraction correction, which is required to obtain quantitative data for modelling [ 18 F]FTHA PET data. Our test-retest study of fasted and postprandial conditions showed robust reproducibility, and revealed clear differences in the [ 18 F]FTHA metabolic rate under different study settings., Trial Registration: EudraCT No: 2020-005211-48, 04Feb2021; and Clinical Trials registry NCT05132335, 29Oct2021, URL: https://classic., Clinicaltrials: gov/ct2/show/NCT05132335 ., (© 2024. The Author(s).)

Hypoxic-ischemic encephalopathy due to insufficient oxygen delivery to brain tissue is a leading cause of death or severe morbidity in neonates. The early recognition of the most severely affected individuals remains a clinical challenge. We hypothesized that hypoxic-ischemic injury can be detected using PET radiotracers for hypoxia ([ 18 F]EF5), glucose metabolism ([ 18 F]FDG), and inflammation ([ 18 F]F-DPA)., Methods: A preclinical model of neonatal hypoxic-ischemic brain injury was made in 9-d-old rat pups by permanent ligation of the left common carotid artery followed by hypoxia (8% oxygen and 92% nitrogen) for 120 min. In vivo PET imaging was performed immediately after injury induction or at different timepoints up to 21 d later. After imaging, ex vivo brain autoradiography was performed. Brain sections were stained with cresyl violet to evaluate the extent of the brain injury and to correlate it with [ 18 F]FDG uptake., Results: PET imaging revealed that all three of the radiotracers tested had significant uptake in the injured brain hemisphere. Ex vivo autoradiography revealed high [ 18 F]EF5 uptake in the hypoxic hemisphere immediately after the injury (P < 0.0001), decreasing to baseline even 1 d postinjury. [ 18 F]FDG uptake was highest in the injured hemisphere on the day of injury (P < 0.0001), whereas [ 18 F]F-DPA uptake was evident after 4 d (P = 0.029), peaking 7 d postinjury (P < 0.0001), and remained significant 21 d after the injury. Targeted evaluation demonstrated that [ 18 F]FDG uptake measured by in vivo imaging 1 d postinjury correlated positively with the brain volume loss detected 21 d later (r = 0.72, P = 0.028)., Conclusion: Neonatal hypoxic-ischemic brain injury can be detected using PET imaging. Different types of radiotracers illustrate distinct phases of hypoxic brain damage. PET may be a new useful technique, worthy of being explored for clinical use, to predict and evaluate the course of the injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In the development of new 18 F-labelled tracers, it is important to assess the amount of released [ 18 F]fluoride taken up in the bones of experimental animals because all 18 F-labelled PET-tracers are prone, to lesser or higher degree, to undergo defluorination, with subsequent release of [ 18 F]fluoride during scanning. However, the pharmacokinetics of [ 18 F]fluoride in bones and other organs of healthy rats have not been well documented in a comprehensive manner. We aimed to study pharmacokinetics of [ 18 F]NaF in rats in order to increase our understanding of the biodistribution of [ 18 F]fluoride originating from defluorination of 18 F-labelled tracers. We studied [ 18 F]fluoride uptake in Sprague Dawley rat bones, including the epiphyseal parts of the tibia and radius, the mandible, ilium, lumbar vertebrae, costochondral joints, tibia, radius, and ribs, with 60-min in vivo PET/CT imaging. Kinetic parameters, K 1 , K i , K i /K 1 , and k 3 were calculated with a three-compartment model. In addition, separate groups of male and female rats were studied with ex vivo bone and soft tissue harvesting and gamma counting over a 6-h period., Results: [ 18 F]fluoride perfusion and uptake varied among the different bones. [ 18 F]fluoride uptake was higher in trabecular bones, due to high perfusion and osteoblastic activity, compared to cortical bones. In soft tissues, the organ-to-blood uptake ratios increased over time in the eyes, lungs, brain, testes, and ovaries during the 6 h study period., Conclusion: Understanding the pharmacokinetics of [ 18 F]fluoride in various bones and soft tissues is highly useful for assessing 18 F-labelled radiotracers that release [ 18 F]fluoride., (© 2023. The Author(s).)

Introduction: [ 18 F]FMTEB, along with other tracers, was developed as a promising PET radioligand for imaging metabotropic glutamate receptor subtype 5 (mGluR5). Despite favorable preliminary results, it has not been used further for studies of mGluR5. This paper presents an in-depth preclinical evaluation of [ 18 F]FMTEB in healthy Sprague Dawley rats., Methods: [ 18 F]FMTEB was synthesized from a boronic ester precursor using copper-mediated fluorination. In vivo PET imaging was performed on six rats, of which three were pre-treated with a high affinity mGluR5 receptor antagonist. An additional 18 rats were used for ex vivo experiments for metabolite analyses in plasma, brain and urine, and for biodistribution and ex vivo brain autoradiography at different time points., Results: [ 18 F]FMTEB was synthesized in adequate radiochemical yield and a molar activity of 154 ± 64 GBq/μmol. Both in vivo imaging and ex vivo brain autoradiography showed high specificity for mGluR5, and the blocking experiments showed a clear decrease in radioactivity in mGluR5-rich brain areas. Metabolite analyses confirmed fast metabolism of the tracer in plasma. The percentage of parent compound in brain tissue exceeded 90 % up to 90 min after injection., Conclusion: [ 18 F]FMTEB produced via copper-mediated 18 F-fluorination fulfilled the requirements for preclinical evaluation in rats. The absence of specific uptake in cerebellum and absence of defluorination of the tracer allowed cerebellum to be used as a reference tissue. Due to the fast kinetics in rats, the region-to-cerebellum ratios equilibrated within 30 min. These results prove [ 18 F]FMTEB to be a good candidate for mapping mGluR5 in rat brain and a suitable alternative to [ 18 F]FPEB., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could appear to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

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, [ 18 F]fluorodopa (FDOPA), [ 11 C]MADAM and [ 11 C]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 [ 11 C]carfentanil binding and risk-taking to losses positively correlated with [ 11 C]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.

Radiometabolites of PET tracers interfere with imaging and need to be taken into account when modeling PET data. Various tracer and radiometabolite characteristics affect the uptake rate into tissue. In this study, we investigated two such factors, lipophilicity and protein-free fraction. A novel rapid method was developed using thin-layer chromatography with digital autoradiography (radioTLC) and ultrafiltration for analyzing the protein-free fractions of an exemplar PET tracer, [ 11 C]SMW139 (f P, free parent tracer over all radioactivity), and its radiometabolites (f M , free radiometabolites over all radioactivity). Detailed understanding of the uptake of radiometabolites into extravascular cells requires analyzing f M , which has not previously been performed for PET tracers. Mice were injected with [ 11 C]SMW139, and time-activity curves from plasma and brain coupled with the parent fraction and free fraction data were analyzed to demonstrate the true levels of protein-free and protein-bound [ 11 C]SMW139 and its radiometabolites in plasma. The ultrafiltration method included separate membrane correction factors for the parent tracer and its radiometabolites for analysis of unbiased f P and f M . Metabolism of [ 11 C]SMW139 was rapid, and after 45 min, the parent fraction was 0.33 in plasma and 0.28 in brain. Ultrafiltration membrane correction had a significant effect on the f P but not the f M . From 10-45 min, the f P decreased from 0.032 to 0.007, while f M remained between 0.52 and 0.35. The much higher f M in plasma could explain why the less lipophilic radiometabolites enter the brain efficiently. This detailed understanding of f P and f M from rodents can be used in translational studies to explain the behavior of the tracer in humans. Similar parent fraction and plasma protein binding methods can be used for human in vivo analysis., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Rationale: 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. Methods: Spinal cord inflammation after intravenous OEC transplantation was detected in vivo and ex vivo by translocator protein PET tracer [ 18 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 [ 18 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 in vitro gene knocking down experiments and OECs/microglia co-culture experiment. Results: 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. In vitro 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. Conclusion: 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 via the secretion of IL-1Ra to reduce neuroinflammation., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Rationale: Evaluation of the feasibility of [ 18 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 [ 18 F]EF5 and [ 18 F]FDG-PET/CT preoperatively. The distribution of [ 18 F]EF5-uptake, total intraabdominal metabolic tumor volume (TMTV), and hypoxic subvolume (HSV) were assessed., Results: [ 18 F]EF5-PET/CT suggested hypoxia in 47% (7/15) patients. The median HSV was 87 cm 3 (31% of TMTV). The [ 18 F]EF5-uptake was detected in primary tumors and in four patients also in intra-abdominal metastases. The [ 18 F]EF5-uptake in cancer tissue was low compared to physiological excretory pathways, complicating the interpretation of PET/CT images., Conclusions: [ 18 F]EF5-PET/CT is not feasible in ovarian cancer imaging in clinical setting due to physiological intra-abdominal [ 18 F]EF5-accumulation. However, it may be useful when used complementarily to FDG-PET/CT.

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 2 ) and LET. To demonstrate model performance, calculations were done with spread-out Bragg peaks (SOBP) in water phantoms with pO 2 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 2 estimated voxel-by-voxel using [ 18 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 2 . 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 1.1 -weighted doses., Conclusion: We realized a Monte Carlo based tool for calculating the ROWD. Read-in of patient pO 2 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., (Copyright © 2020 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Here, we describe the development of an in-house-built device for the fully automated multistep synthesis of the cannabinoid CB 1 receptor imaging tracer (3R,5R)-5-(3-([ 18 F]fluoromethoxy-d 2 )phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one ([ 18 F]FMPEP-d 2 ), 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 18 F-fluorination of an alkylating agent and its GC purification, the subsequent 18 F-fluoroalkylation of a precursor molecule, the semipreparative HPLC purification of the 18 F-fluoroalkylated product, and its formulation for injection. We have optimized the duration and temperature of the 18 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., (© 2020 The Authors. Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons Ltd.)

[ 18 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 m 's). In certain cases, low A m 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 [ 18 F]F-DPA resulting in high A m (990 ± 150 GBq/µmol) and performed in vivo comparison with low A m (9.0 ± 2.9 GBq/µmol) [ 18 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 m 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 m [ 18 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 m [ 18 F]F-DPA. The differences between APP/PS1-21 and wild-type animals showed higher significance when high A m was used.

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 [ 18 F]FDOPA, [ 11 C]MADAM and [ 11 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 [ 11 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.

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 [ 18 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 [ 18 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 [ 18 F]SPA-RQ, whereas the tracer uptake in peripheral tissues was similar to that seen in guinea pigs. We conclude that [ 18 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.

Purpose: The α 2 -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 2A and α 2C are found in the brain in significant amounts. Subtype-selective positron emission tomography (PET) imaging of α 2 -adrenoceptors has been limited to the α 2C subtype. Here, we report the synthesis of 6-[ 18 F]fluoro-marsanidine, a subtype-selective PET tracer candidate for α 2A -adrenoceptors, and its preclinical evaluation in rats and mice., Procedures: 6-[ 18 F]Fluoro-marsanidine was synthesized using electrophilic F-18 fluorination with [ 18 F]Selectfluor bis(triflate). The tracer was evaluated in Sprague Dawley rats and in α 2A -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 2 -agonist medetomidine. The peripheral biodistribution and extent of metabolism of 6-[ 18 F]fluoro-marsanidine were also analyzed., Results: 6-[ 18 F]Fluoro-marsanidine was synthesized with [ 18 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 2A -KO mice compared to WT mice. The results for selectivity were confirmed by ex vivo brain autoradiography. Blocking studies revealed reduced uptake in α 2A -adrenoceptor-rich brain regions in pretreated animals, demonstrating the specificity of the tracer. Metabolite analyses revealed very rapid metabolism of 6-[ 18 F]fluoro-marsanidine with blood-brain barrier-permeable metabolites in both rats and mice., Conclusion: 6-[ 18 F]Fluoro-marsanidine was synthesized and evaluated as a PET tracer candidate for brain α 2A -adrenoceptors. However, rapid metabolism, extensive presence of labeled metabolites in the brain, and high non-specific uptake in mouse and rat brain make 6-[ 18 F]fluoro-marsanidine unsuitable for α 2A -adrenoceptor targeting in rodents in vivo.

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 [ 18 F]NS12137 and to demonstrate the ability of [ 18 F]NS12137 to quantify changes in NET expression. Methods: We applied an 18 F-radiolabeling method in which a brominated precursor was debrominated by nucleophilic 18 F-fluorination in dimethyl sulfoxide. Radiolabeling was followed by a deprotection step, purification, and formulation of the radiotracer . The [ 18 F]NS12137 brain uptake and distribution were studied with in vivo PET/CT and ex vivo 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. Results: [ 18 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 in vivo [ 18 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, in vivo 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. Ex vivo 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 [ 18 F]NS12137 was dramatically reduced both in vivo and ex vivo by pretreatment with nisoxetine, demonstrating the specificity of binding. Conclusions: [ 18 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., Competing Interests: Competing Interests: Authors, Francisco R. López-Picón, Anna K. Kirjavainen, Sarita Forsback, Jatta S. Takkinen, Merja Haaparanta-Solin, and Olof Solin declare that they do not have competing interests. DanPET AB (100% owned by Dan Peters, CEO ) is the registered owner of the US patent US7407970 covering the chemical structure of NS12137.

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-[ 18 F]fluoro-l-dopa and [ 11 C]carfentanil. The specificity of the findings was further investigated by including a serotonin transporter ligand, [ 11 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 [ 11 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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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 [ 18 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: [ 18 F]F-DPA was synthesised by the previously reported electrophilic 18 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 [ 18 F]F-DPA were analysed and the specificity of [ 18 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 [ 18 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 [ 18 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 [ 18 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 [ 18 F]F-DPA can be used to visualise activated microglia at an early stage of AD pathology., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

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 m ), 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 m 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 m for the [ 18 F]fluoride was determined and compared with the A m of [ 18 F]fluciclatide, synthesized from the same [ 18 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 m can be increased by using non-fluorinated transport tubing. Of all the tubing materials studied PP is preferred., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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 2 ), 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., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

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 [ 18 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 [ 18 F]EF5 a median of 7 days apart and one with [ 18 F]FDG. Metabolically active primary tumour volumes were defined in [ 18 F]FDG images and transferred to co-registered [ 18 F]EF5 images for repeatability analysis. A tumour-to-muscle uptake ratio (TMR) of 1.5 at 3 h from injection of [ 18 F]EF5 was used as a threshold representing hypoxic tissue., Results: In 10 paired [ 18 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 [ 18 F]EF5 PET/CT within one week shows high repeatability and is feasible for the guiding of hypoxia-targeted treatment interventions in HNC.

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-[ 18 F]fluoro-2-pyridyl)oxy]-8-azabicyclo[3.2.1]-octane ([ 18 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 [ 18 F]F 2 , and (2) labeling with [ 18 F]Selectfluor, a derivative of [ 18 F]F 2 , using post-target produced [ 18 F]F 2 . The time-dependent distribution of [ 18 F]NS12137 in brain tissue of healthy, adult Sprague-Dawley rats was determined by ex vivo autoradiography. The specificity of [ 18 F]NS12137 binding was demonstrated on the basis of competitive binding by nisoxetine, a known NET antagonist of high specificity., Results: [ 18 F]NS12137 was successfully synthesized with radiochemical yields of 3.9% ± 0.3% when labeled with [ 18 F]F 2 and 10.2% ± 2.7% when labeled with [ 18 F]Selectfluor. The molar activity of radiotracer was 8.8 ± 0.7 GBq/μmol with [ 18 F]F 2 labeling and 6.9 ± 0.4 GBq/μmol with [ 18 F]Selectfluor labeling at the end of synthesis of [ 18 F]NS12137. Uptake of [ 18 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 [ 18 F]NS12137 in the LCoe. Analyses of whole brain samples for radiometabolites showed only the parent compound [ 18 F]NS12137. Uptake of 18 F-radioactivity in bone increased with time., Conclusions: The two electrophilic 18 F-labeling methods proved to be suitable for synthesis of [ 18 F]NS12137 with the [ 18 F]Selectfluor method providing an approximate three-fold higher yield than the [ 18 F]F 2 method. As an electrostatically neutral radiotracer [ 18 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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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 i  = 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 [ 18 F]F-DPA using [ 18 F]Selectfluor bis(triflate) and the preliminary evaluation of [ 18 F]F-DPA in healthy rats. Its metabolic profile and biodistribution in rats are compared with that of [ 18 F]DPA-714, a closely related structure., Procedures: [ 18 F]F-DPA was synthesized by electrophilic fluorination using [ 18 F]Selectfluor bis(triflate), [ 18 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 [ 18 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 [ 18 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 [ 18 F]F-DPA and [ 18 F]DPA-714 account for 28.3 ± 6.4 and 11.1 ± 2.6 % of the remaining radioactivity, respectively. In the brain, unchanged [ 18 F]F-DPA accounts for 93.5 ± 2.8 % of the radioactivity; whereas for [ 18 F]DPA-714, this value is 53.6 ± 1.6 %., Conclusions: [ 18 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 [ 18 F]DPA-714 with regard to in vivo metabolism. [ 18 F]F-DPA is a promising new radiotracer and warrants further investigation in animal models of disease.

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 [ 11 C]carfentanil and [ 18 F]fluorodopa positron emission tomography using a high-resolution scanner. Binding potentials relative to non-displaceable binding (BP ND ) for [ 11 C]carfentanil and influx rate constant (K i ) values for [ 18 F]fluorodopa were analyzed with region-of-interest and whole-brain voxel-by-voxel analyses. BED subjects showed widespread reductions in [ 11 C]carfentanil BP ND in multiple subcortical and cortical brain regions and in striatal [ 18 F]fluorodopa K i compared with controls. In PG patients, [ 11 C]carfentanil BP ND was reduced in the anterior cingulate with no differences in [ 18 F]fluorodopa K i compared with controls. In the nucleus accumbens, a key region involved in reward processing, [ 11 C]Carfentanil BP ND was 30-34% lower and [ 18 F]fluorodopa K i 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.

The chemistry of F 2 and its derivatives are amenable to facile aliphatic or aromatic substitution, as well as electrophilic addition. The main limitation in the use of [ 18 F]F 2 for radiopharmaceutical synthesis is the low specific activity achieved by the traditional methods of production. The highest specific activities, 55 GBq/μmol, for [ 18 F]F 2 have been achieved so far by using electrical discharge in the post-target production of [ 18 F]F 2 gas from [ 18 F]CH 3 F. We demonstrate that [ 18 F]F 2 is produced by illuminating a gas mixture of neon/F 2 /[ 18 F]CH 3 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 [ 18 F]F - , amount of carrier F 2 , and number of 193-nm laser pulses at constant power were evaluated regarding radiochemical yield and specific activity. The specific activity attained for [ 18 F]F 2 -derived [ 18 F]NFSi was 10.3 ± 0.9 GBq/μmol, and the average radiochemical yield over a wide range of conditions was 6.7% from [ 18 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., (Copyright © 2017 The Authors. Journal of Labelled Compounds and Radiopharmaceuticals Published by John Wiley & Sons, Ltd.)

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., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.

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.

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 ([ 18 F]EF5) and 2-deoxy-2-[ 18 F]fluoro-d-glucose ([ 18 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 [ 18 F]EF5 uptake was seen in xenografts expressing high levels of CA IX, Glut-1, and Hif-1α, whereas low [ 18 F]EF5 uptake was detected in xenografts expressing low amounts of CA IX and Hif-1α. The uptake of [ 18 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 [ 18 F]FDG during hypoxia., Conclusions: The UT-SCC cell lines studied differed with respect to their hypoxic phenotypes, and these variations were detectable with [ 18 F]EF5. Acute hypoxia increases [ 18 F]FDG uptake in vitro, whereas a high [ 18 F]EF5 uptake reflects a more complex phenotype associated with hypoxia and an aggressive growth pattern., (Copyright © 2014 Elsevier Inc. All rights reserved.)

(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., (Copyright © 2014 Elsevier Inc. All rights reserved.)