Anna Kirjavainen

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

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

Radiosynthesis and Evaluation of [18F]Selectfluor bis(triflate)†

Positron (b) emission tomography (PET) is a noninvasive molecular imaging technique that allows for the in vivo investigation of physiological processes. As a radioisotope, fluorine-18 benefits from an advantageous half-life (109.7 min), a clean decay process (97% b emission), and a short b trajectory, which is a property that enables the acquisition of high-resolution images. The global use of the radiotracer [F]-2-fluoro-2-deoxy-d-glucose has generated a vast amount of invaluable clinical data and has stimulated a worldwide interest in PET and F radiochemistry. For applications other than radiolabeling, nucleophilic and electrophilic fluorination are complementary processes that are used indiscriminately; the method of choice depends on the reactivity profile of the precursor to be fluorinated. A similar degree of synthetic flexibility would facilitate significantly the production and evaluation of new F radiotracers but to date, this is far from the reality because the range of reactions suitable for F labeling remains limited in comparison with the number of transformations available to access nonlabeled fluorinated material. Electrophilic F-fluorination suffers from well-recognized drawbacks. The carrieradded method employed for the production of [F]F2 gas gives labeled products with low specific activity (SA). In addition, [F]F2, a reagent that requires specialist equipment for its handling, can react unselectively and lead to a mixture of products. This complication lowers the radiochemical yield (RCY) and may lead to problematic and time-consuming purification processes. Despite these limitations, clinical doses of the radiotracers [F]-2-fluoro-l-tyrosine and [F]-6-fluoro3,4-dihydroxy-l-phenylalanine are currently prepared relying on an electrophilic fluorodestannylation reaction using [F]F2. [4]

Hyperthyroidism Increases Brown Fat Metabolism in Humans

CONTEXT Thyroid hormones are important regulators of brown adipose tissue (BAT) development and function. In rodents, BAT metabolism is up-regulated by thyroid hormones. OBJECTIVE The purpose of this article was to investigate the impact of hyperthyroidism on BAT metabolism in humans. DESIGN This was a follow-up study using positron emission tomography imaging. MAIN OUTCOME MEASURES Glucose uptake (GU) and perfusion of BAT, white adipose tissue, skeletal muscle, and thyroid gland were measured using [18F]2-fluoro-2-deoxy-D-glucose and [15O]H2O and positron emission tomography in 10 patients with overt hyperthyroidism and in 8 healthy participants. Five of the hyperthyroid patients were restudied after restoration of euthyroidism. Supraclavicular BAT was quantified with magnetic resonance imaging or computed tomography and energy expenditure (EE) with indirect calorimetry. RESULTS Compared with healthy participants, hyperthyroid participants had 3-fold higher BAT GU (2.7±2.3 vs 0.9±0.1 μmol/100 g/min, P=.0013), 90% higher skeletal muscle GU (P<.005), 45% higher EE (P<.005), and a 70% higher lipid oxidation rate (P=.001). These changes were reversible after restoration of euthyroidism. During hyperthyroidism, serum free T4 and free T3 were strongly associated with EE and lipid oxidation rates (P<.001). TSH correlated inversely with BAT and skeletal muscle glucose metabolism (P<.001). Hyperthyroidism had no effect on BAT perfusion, whereas it stimulated skeletal muscle perfusion (P=.04). Thyroid gland GU did not differ between hyperthyroid and euthyroid study subjects. CONCLUSIONS Hyperthyroidism increases GU in BAT independently of BAT perfusion. Hyperthyroid patients are characterized by increased skeletal muscle metabolism and lipid oxidation rates.

Effect of the myeloperoxidase inhibitor AZD3241 on microglia: a PET study in Parkinson’s disease

Impaired mitochondrial function, oxidative stress and formation of excessive levels of reactive oxygen species play a key role in neurodegeneration in Parkinsons disease. Myeloperoxidase is a reactive oxygen generating enzyme and is expressed by microglia. The novel compound AZD3241 is a selective and irreversible inhibitor of myeloperoxidase. The hypothesized mechanism of action of AZD3241 involves reduction of oxidative stress leading to reduction of sustained neuroinflammation. The purpose of this phase 2a randomized placebo controlled multicentre positron emission tomography study was to examine the effect of 8 weeks treatment with AZD3241 on microglia in patients with Parkinsons disease. Parkinson patients received either AZD3241 600 mg orally twice a day or placebo (in 3:1 ratio) for 8 weeks. The binding of (11)C-PBR28 to the microglia marker 18 kDa translocator protein, was examined using positron emission tomography at baseline, 4 weeks and 8 weeks. The outcome measure was the total distribution volume, estimated with the invasive Logan graphical analysis. The primary statistical analysis examined changes in total distribution volume after treatment with AZD3241 compared to baseline. Assessments of safety and tolerability of AZD3241 included records of adverse events, vital signs, electrocardiogram, and laboratory tests. The patients had a mean age of 62 (standard deviation = 6) years; 21 were male, three female and mean Unified Parkinsons Disease Rating Scale III score (motor examination) ranged between 6 and 29. In the AD3241 treatment group (n = 18) the total distribution volume of (11)C-PBR28 binding to translocator protein was significantly reduced compared to baseline both at 4 and 8 weeks (P < 0.05). The distribution volume reduction across nigrostriatal regions at 8 weeks ranged from 13-16%, with an effect size equal to 0.5-0.6. There was no overall change in total distribution volume in the placebo group (n = 6). AZD3241 was safe and well tolerated. The reduction of (11)C-PBR28 binding to translocator protein in the brain of patients with Parkinsons disease after treatment with AZD3241 supports the hypothesis that inhibition of myeloperoxidase has an effect on microglia. The results of the present study provide support for proof of mechanism of AZD3241 and warrant extended studies on the efficacy of AZD3241 in neurodegenerative disorders.

Muscle-specific glucose and free fatty acid uptake after sprint interval and moderate-intensity training in healthy middle-aged men

We tested the hypothesis that sprint interval training (SIT) causes larger improvements in glucose and free fatty acid uptake (FFAU) in lower and upper body muscles than moderate-intensity training (MIT). Twenty-eight healthy, untrained, middle-aged men were randomized into SIT (n = 14, 4-6 × 30 s of all-out cycling/4 min recovery) and MIT groups [n = 14, 40-60 min cycling at 60% of peak O2 uptake (V̇o2 peak)] and completed six training sessions within 2 wk. Pre- and postmeasurements included V̇o2 peak, whole body (M-value), muscle-specific insulin-stimulated glucose uptake (GU), and fasting FFAU measured with positron emission tomography in thigh [quadriceps femoris (QF) and hamstrings] and upper body (deltoids, biceps, and triceps brachii) muscles. V̇o2 peak and M-value improved significantly by 6 and 12% in SIT, and 3 and 8% in MIT, respectively,. GU increased significantly only in the QF, and there was no statistically significant difference between the training modes. GU increased in all four heads of QF in response to SIT, but only in the vasti muscles in response to MIT, whereas in rectus femoris the response was completely lacking. Training response in FFAU in QF was smaller and nonsignificant, but it also differed between the training modes in the rectus femoris. In conclusion, SIT and MIT increased insulin-stimulated GU only in the main working muscle QF and not in the upper body muscles. In addition, the biarticular rectus femoris did not respond to moderate-intensity training, reflecting most probably poor activation of it during moderate-intensity cycling.

Organomediated Enantioselective 18 F Fluorination for PET Applications

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.

Differential contributions of ankle plantarflexors during submaximal isometric muscle action: A PET and EMG study

The objective of this study was to investigate the relative contributions of superficial and deep ankle plantarflexors during repetitive submaximal isometric contractions using surface electromyography (SEMG) and positron emission tomography (PET). Myoelectric signals were obtained from twelve healthy volunteers (27.3±4.2yrs). A tracer ([(18)F]-FDG) was injected during the exercise and PET scanning was done immediately afterwards. The examined muscles included soleus (Sol), medial gastrocnemius (MG), lateral gastrocnemius (LG), and flexor hallucis longus (FHL). It was found that isometric maximal voluntary contraction (MVC) force, muscle glucose uptake (GU) rate, and SEMG of various plantarflexors were comparable bilaterally. In terms of %EMG MVC, FHL and MG displayed the highest activity (∼34%), while LG (∼21%) had the lowest activity. Cumulative SEMG from all parts of the triceps surae (TS) muscle accounted for ∼70% of the combined EMG signal of all four plantarflexors. As for GU, the highest quantity was observed in MG (2.4±0.8μmol*100g(-1)*min(-1)), whereas FHL (1.8±0.6μmol*100g(-1)*min(-1)) had the lowest uptake. Cumulative GU of TS constituted nearly 80% of the combined GU. The findings of this study provide valuable reference for studies where individual muscle contributions are estimated using models and simulations.

Vacuum ultraviolet ‐ photon mediated production of [18F]F2

The chemistry of F2 and its derivatives are amenable to facile aliphatic or aromatic substitution, as well as electrophilic addition. The main limitation in the use of [18F]F2 for radiopharmaceutical synthesis is the low specific activity achieved by the traditional methods of production. The highest specific activities, 55 GBq/μmol, for [18F]F2 have been achieved so far by using electrical discharge in the post‐target production of [18F]F2 gas from [18F]CH3F. We demonstrate that [18F]F2 is produced by illuminating a gas mixture of neon/F2/[18F]CH3F with vacuum ultraviolet photons generated by an excimer laser. We tested several illumination chambers and production conditions. The effects of the initial amount of [18F]F‐, amount of carrier F2, and number of 193‐nm laser pulses at constant power were evaluated regarding radiochemical yield and specific activity. The specific activity attained for [18F]F2‐derived [18F]NFSi was 10.3 ± 0.9 GBq/μmol, and the average radiochemical yield over a wide range of conditions was 6.7% from [18F]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.

Influence of triple disease modifying anti-rheumatic drug therapy on carotid artery inflammation in drug-naive patients with recent onset of rheumatoid arthritis

OBJECTIVE Increased atherosclerosis in RA is not fully explained by the ordinary risk factors, but it may be related to vascular inflammation. The aim of this study was to investigate the degree of carotid artery inflammation in drug-naive patients with early RA before and after DMARD triple therapy. METHODS Fifteen non-diabetic patients with recently diagnosed RA [age 51 (16) years, 6 males] were examined before and at 2 and 4 weeks after the initiation of combination therapy with MTX, SSZ, HCQ and ⩽10 mg/day oral prednisolone. Eight healthy males aged 49 (6) years were examined once as controls. Inflammation in the carotid artery was quantified, using [(18)F]fluorodeoxyglucose ((18)F-FDG)-PET/CT, as the maximum standardized uptake value (SUVmax) and the maximum target-to-background ratio (TBRmax). RESULTS Before the treatment, patients with RA had significantly higher carotid artery (18)F-FDG uptake, as compared with healthy controls [TBRmax 1.78 (0.07) vs 1.51 (0.08), P = 0.03]. The 4-week DMARD therapy reduced the TBRmax to the level of healthy controls [1.53 (0.05), P = 0.84]. Compared with the baseline, the TBRmax decreased by 12.4 (16.8)% (P = 0.01) during 4-week DMARD therapy. At baseline, the SUVmax correlated with ESR (r = 0.52, P = 0.02) and CRP (r = 0.65, P = 0.01). Change in SUVmax correlated with changes in ESR and CRP after 4 weeks of treatment, as did the changes in TBRmax and SUVmax with DAS at 12 weeks of treatment. CONCLUSION (18)F-FDG-PET/CT revealed that drug-naive patients with early RA show carotid artery inflammation that can be efficiently reduced by 1-month DMARD triple therapy.

Electrophilic Addition of Chlorine Monofluoride for PET tracers

PurposeWe have studied the utility of [18F]ClF electrophilic addition to the carbon–carbon double bond of analogues of a model positron emission tomography (PET) tracer, [18F]EF5. The consequence of simultaneous chlorine/fluorine addition on lipophilicity and biological activity of the molecule is evaluated.ProceduresPost-target produced [18F]F2 was reacted with Cl2 to produce [18F]ClF, which was used in electrophilic addition.Results[18F]ClF was produced and used to label chlorinated analogues of [18F]EF5. The chlorinated analogues, [18F]EF4Cla and [18F]EF4Clb, were synthesized simultaneously. The in vivo uptake of the analogues compared well with [18F]EF5 uptake in tumor-bearing mice.Conclusion[18F]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 [18F]EF5 by monofluorine-for-chlorine exchange affected the lipophilicity, but the hypoxia avidity of these molecules was not apparently altered.