Fully automated one-pot synthesis of [18F]fluoromisonidazole

A (18)F-labeled fluoromisonidazole (1H-1-(3-[(18)F]fluoro-2-hydroxypropyl)-2-nitroimidazole, [(18)F]FMISO) was prepared via a one-pot, two-step synthesis procedure using a modified commercial Tracerlab FX(F-N) synthesis module. Nucleophilic fluorination of the precursor molecule 1-(2'-nitro-1'-imidazolyl)-2-O-tetrahydropyranyl-3-O-toluenesulphonylpropanediol using no-carrier-added [(18)F]fluoride, followed by hydrolysis of the protecting group with 1 mol/L HCl and purification with Sep-Paks instead of HPLC, gave [(18)F]FMISO. The overall radiochemical yield with no decay correction was greater than 40%, the whole synthesis time was less than 40 min and the radiochemical purity was greater than 95%. The new automated synthesis procedure can be applied to the fully automated synthesis of [(18)F]FMISO using a commercial FDG synthesis module.     

Fully automated synthesis of [18F]fluoromisonidazole using a conventional [18F]FDG module

We developed a new fully automated method for the synthesis of [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) by modifying a commercial FDG synthesizer and its disposable fluid pathway. A three-step procedure was used to prepare the tosylate precursor, 1-(2′-nitro-1′-imidazolyl)-2-O-tetrahydrofuranyl-3-O-toluenesulfonylpropanediol. Using glycerol as the starting material, the precursor was synthesized with a yield of 21%. The optimal labeling conditions for the automated synthesis of [¹⁸F]FMISO was 10 mg of precursor in acetonitrile (2 ml heated at 105°C for 360 s, followed by heating at 75°C for 280 s and hydrolysis with 1 N HCl at 105°C for 300 s. Using 3.7 GBq of [¹⁸F]F⁻ as a starting activity, [¹⁸F]FMISO was obtained with high end-of-synthesis (EOS) radiochemical yields of 58.5±3.5% for 60.0±5.2 min with high-performance liquid chromatography (HPLC) purification. When solid-phase purification steps were added, the EOS radiochemical yields were 54.5±2.8% (337±25 GBq/μmol) for 70.0±3.8 min (n=10 for each group, decay-corrected). With a high starting radioactivity of 37.0 GBq, we obtained radiochemical yields of 54.4±2.9% and 52.8±4.2%, respectively (n=3). The solid-phase purification removed unreacted [¹⁸F]fluoride and polar impurities before the HPLC procedure. Long-term tests showed a good stability of 98.2±1.5%. This new automated synthesis procedure combines high and reproducible yields with the advantage of using a disposable cassette system.     

A high yield robotic synthesis of 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG) and 9-[3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine([18F] FHPG) for gene expression imaging.

The aim of this study was to develop an automated synthesis of 9-(4-[(18)F]-fluoro-3-hydroxymethylbutyl)guanine ([(18)F]FHBG) and 9-[(3-[(18)F]fluoro-1-hydroxy-2-propoxy)methyl]guanine ([(18)F]FHPG) using a Scanditronix Anatech RB III robotic system. [(18)F]HF was produced via (18)O(p, n)(18)F using a Scanditronix MC17F cyclotron. On average, a typical run produced [(18)F]FHBG and [(18)F]FHPG with an uncorrected radiochemical yield of 19% and 16%, respectively, at end of synthesis (EOS) from irradiation of 95% enriched [(18)O]water. The total synthesis time was 80 min. The retention time of [(18)F]FHBG and [(18)F]FHPG (the radio-peak) was 3.9 and 4.0 min, respectively, which was consistent with the [(19)F]FHBG and [(19)F]FHPG ultraviolet peak. The radiochemical purity was greater than 97%. A robotic, automated method for [(18)F]FHBG and [(18)F]FHPG radiosynthesis is therefore feasible. The radiation burden for the operator can be reduced as much as possible. Sufficient radioactivities of [(18)F]FHBG and [(18)F]FHPG could be obtained for non-invasive monitoring the expression of transfected gene in vivo with positron emission tomography (PET).     

Long-circulating liposomes radiolabeled with [18F]fluorodipalmitin ([18F]FDP)

Synthesis of a radiolabeled diglyceride, 3-[(18)F]fluoro-1,2-dipalmitoylglycerol [[(18)F]fluorodipalmitin ([(18)F]FDP)], and its potential as a reagent for radiolabeling long-circulating liposomes were investigated. The incorporation of (18)F into the lipid molecule was accomplished by nucleophilic substitution of the p-toluenesulfonyl moiety with a decay-corrected yield of 43+/-10% (n=12). Radiolabeled, long-circulating polyethylene-glycol-coated liposomes were prepared using a mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] ammonium salt (61:30:9) and [(18)F]FDP with a decay-corrected yield of 70+/-8% (n=4). PET imaging and biodistribution studies were performed with free [(18)F]FDP and liposome-incorporated [(18)F]FDP. Freely injected [(18)F]FDP had the highest uptake in the liver, spleen and lungs. Liposomal [(18)F]FDP remained in blood circulation at near-constant levels for at least 90 min, with a peak concentration near 2.5%ID/cc. Since [(18)F]FDP was incorporated into the phospholipid bilayer, it could potentially be used for radiolabeling a variety of lipid-based drug carriers.     

NanoPET imaging of [18F]fluoromisonidazole uptake in experimental mouse tumours

Purpose The purpose of this study was to assess the potential and utility of ultra-high-resolution hypoxia imaging in various murine tumour models using the established hypoxia PET tracer [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO).Methods [¹⁸F]FMISO PET imaging was performed with the dedicated small-animal PET scanner NanoPET (Oxford Positron Systems) and ten different human tumour xenografts in nude mice as well as B16 melanoma tumours in syngeneic Balb/c mice. For comparison, [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) PET scans were also performed in the mice bearing human tumour xenografts.Results In 10 out of 11 experimental tumour models, [¹⁸F]FMISO PET imaging allowed clear-cut visualisation of the tumours. Inter- and intratumoural heterogeneity of tracer uptake was evident. In addition to average TMRR (tumour-to-muscle retention ratio including all voxels in a volume of interest (VOI)), the parameters TMRR_75% and TMRR₅ (tumour-to-muscle retention ratio including voxels of 75% or more of the maximum radioactivity in a VOI and the five hottest pixels, respectively) also served as measures for quantifying the heterogeneous [¹⁸F]FMISO uptake in the tumours. The variability observed in [¹⁸F]FMISO uptake was related neither to tumour size nor to the injected mass of the radiotracer. The pattern of normoxic and hypoxic regions within the human tumour xenografts, however, correlated with glucose metabolism as revealed by comparison of [¹⁸F]FDG and [¹⁸F]FMISO images.Conclusion This study demonstrates the feasibility and utility of [¹⁸F]FMISO for imaging murine tumour models using NanoPET.     

Biodistribution,pharmacokinetics and PET Imaging of [18F]FMISO, [18F]FDG and [18F]FAc in a sarcoma- and inflammation-bearing mouse model

2-Deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG), [¹⁸F]fluoroacetate ([¹⁸F]FAc) and [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) were all considered to be positron emission tomography (PET) probes for tumor diagnosis, though based on different rationale of tissue uptake. This study compared the biodistribution, pharmacokinetics and imaging of these three tracers in a sarcoma- and inflammation-bearing mouse model.MethodsC3H mice were inoculated with 2×10⁵ KHT sarcoma cells in the right thigh on Day 0. Turpentine oil (0.1 ml) was injected in the left thigh on Day 11 to induce inflammatory lesion. Biodistribution, pharmacokinetics and microPET imaging of [¹⁸F]FMISO, [¹⁸F]FDG and [¹⁸F]FAc were performed on Day 14 after tumor inoculation.ResultsThe inflammatory lesions were clearly visualized by [¹⁸F]FDG/microPET and autoradiography at 3 days after turpentine oil injection. The tumor-to-muscle and inflammatory lesion-to-muscle ratios derived from microPET imaging were 6.79 and 1.48 for [¹⁸F]FMISO, 8.12 and 4.69 for [¹⁸F]FDG and 3.72 and 3.19 for [¹⁸F]FAc at 4 h post injection, respectively. Among these, the tumor-to-inflammation ratio was the highest (4.57) for [¹⁸F]FMISO compared with that of [¹⁸F]FDG (1.73) and [¹⁸F]FAc (1.17), whereas [¹⁸F]FAc has the highest bioavailability (area under concentration of radiotracer vs. time curve, 116.2 h×percentage of injected dose per gram of tissue).ConclusionsMicroPET images and biodistribution studies showed that the accumulation of [¹⁸F]FMISO in the tumor is significantly higher than that in inflammatory lesion at 4 h post injection. [¹⁸F]FDG and [¹⁸F]FAc delineated both tumor and inflammatory lesions. Our results demonstrated the potential of [¹⁸F]FMISO/PET in distinguishing tumor from inflammatory lesion.     

A simplified one-pot synthesis of 9-[(3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine([18F]FHPG) and 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG) for gene therapy

9-[(3-[18F]Fluoro-1-hydroxy-2-propoxy)methyl]guanine ([18F]FHPG, 2) has been synthesized by nucleophilic substitution of N(2)-(p-anisyldiphenylmethyl)-9-[[1-(p-anisyldiphenylmethoxy)-3-toluenesulfonyloxy-2-propoxy]methyl]guanine (1) with potassium [18F]fluoride/Kryptofix 2.2.2 followed by deprotection with 1 N HCl and purification with different methods in variable yields. When both the nucleophilic substitution and deprotection were carried out at 90 degrees C and the product was purified by HPLC (method A), the yield of compound 2 was 5-10% and the synthesis time was 90 min from EOB. However, if both the nucleophilic substitution and deprotection were carried out at 120 degrees C and the product was purified by HPLC, the yield of compound 2 decreased to 2%. When compound 2 was synthesized at 90 degrees C and purified by Silica Sep-Pak (method B), the yield increased to 10-15% and the synthesis time was 60 min from EOB. Similarly, 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG, 4) was synthesized with method A and method B in 9% and 10-15% yield, respectively, in a synthesis time of 90 and 60 min, respectively, from EOB. Compound 2 was relatively unstable in acidic medium at 120 degrees C while compound 4 was stable under the same condition. Both compound 2 and compound 4 had low lipid/water partition coefficient (0.126 +/- 0.022, n=5 and 0.165 +/- 0.023, n=5, respectively). Although it contains non-radioactive ganciclovir ( approximately 5-30 microg) as a chemical by-product, compound 2 synthesized by method B has a similar uptake in 9L glioma cells as that synthesized by method A, and is a potential tracer for imaging herpes simplex virus thymidine kinase gene expression in tumors using PET. Similarly, compound 4 synthesized by method B contains approximately 10-25 microg of penciclovir as a chemical by-product. Thus, the simplified one pot synthesis (method B) is a useful method for synthesizing both compound 2 and compound 4 in good yield for routine clinical use, and the method is readily amenable for automation.     

The synthesis of [18F]Xenon difluoride from [18F]fluoride gas

A convenient procedure for the rapid synthesis of ¹⁸F labelled XeF₂ was developed. Neon gas with 0.087 to 5% carrier fluorine was irradiated with 15 MeV deuterons to produce [¹⁸F]F₂ with a yield of 17 mCi/μAh, EOB. It was, in turn, reacted with excess of xenon in a high pressure nickel vessel at 390°C for 40 min. The isolated reaction product was XeF₂ exclusively. The production yield was 11 mCi/μAh at EOB and the specific activity was 450mCi/mmol. [¹⁸F]XeF₂ has been shown to be a versatile intermediate for the syntheses of ¹⁸F-labelled radiopharmaceuticals, for example, [¹⁸F]2-fluoro-2-deoxy-D-glucose and L-[¹⁸F]6-fluorodopa.     

Regioselective radiofluorodestannylation with [18F]F2 and [18F]CH3COOF: A high yield synthesis of 6-[18F]fluoro-l-dopa

A protected 6-trimethylstannyl dopa derivative 6 has been synthesized for the first time as a precursor for the preparation of 6-[¹⁸F]fluoro-l-dopa. The tin derivative 6 readily reacted with electrophilic radiofluorinating agents such as [¹⁸F]F₂ and [¹⁸F]AcOF. The [¹⁸F]fluoro intermediate 7 was easily hydrolyzed with HBr and the product 6-[¹⁸F]fluoro-l-dopa was isolated after HPLC purification in a maximum radiochemical yield of 25%, ready for human use. The various intermediates, the stannyl precursor 6 and the final product (after ¹⁸F decay) were all fully characterized by ¹H, ¹³C, ¹⁹F and ¹¹⁹Sn NMR as well as high resolution mass spectroscopy.     

Increased [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) yield with recycled target [18O]water: factors affecting the [18F]FDG yield.

The reuse of [18O] water after being purified by distillation has been reported to give lower [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) yields, probably due to the presence of organic impurities. In our routine production of [18F]FDG, however, we observed increased [18F]FDG yields with recycled [18O]water. Thus, factors affecting [18F]FDG yield were examined using as-purchased (virgin) and recycled (by photochemical combustion and distillation) [18O]water. [18F]FDG was synthesized by nucleophilic 18F-fluorination on a quaternary 4-aminopyridinium resin. The recycled [18O]water gave an [18F]FDG yield significantly higher than did the virgin water, without any significant difference in the [18F]fluoride yield. Levels of several ionic impurities including Cl- and Ca2+ were significantly higher in the virgin [18O]water than in the recycled water, while significantly larger amounts of organic impurities were detected in the former. Hence, trace amounts of organic impurities were not responsible for the lower [18F]FDG yield. Chloride anion in the [18O]water may compete with [18F]fluoride to lower the [18F]FDG yield.     

Radiochemical synthesis of [18F]fluororaclopride

The radiochemical synthesis of [¹⁸F]Fluororaclopride (S-3,5-dichloro-6-methoxy-N-(1-(2-[¹⁸F]fluoro-ethyl)-2-pyrrolidinylmethyl)salicylamide) is accomplished via a two step synthesis. [¹⁸F]Fluoroethyltriflate is prepared by [¹⁸F]fluoride displacement on the bis triflate of ethylene glycol. [¹⁸F]Fluoroethyl triflate is then allowed to alkylate a secondary amine precursor to yield [¹⁸F]fluororaclopride. Purification of the radiopharmaceutical involves use of a short silica BONDELUT column and subsequent reverse-phase HPLC. The final product is obtained with a radiochemical yield of approximately 15% (corrected for decay) in a synthesis time of approximately 50 min. Fluororaclopride displays a 3- to 4-fold lower affinity for the D₂ receptor than does raclopride.     

Imaging and quantitation of the hypoxic cell fraction of viable tumor in an animal model of intracerebral high grade glioma using [18F]fluoromisonidazole (FMISO)

We have demonstrated that FMISO uptake is significantly higher in tumor tissue in the C6 intracerebral glioma rat model compared to normal brain, and that there is persisting hypoxia in gliomas independent of tumor size. FMISO uptake was observed homogeneously throughout viable glioma tissue in tumor sizes ranging from 2mm to almost 1cm. Quantitation of uptake of FMISO showed a tumor/brain ratio of 1.9 and a tumor/blood ratio of 2.6 at 2 hours post injection.     

Kinetic Evaluation of the Hypoxia Radiotracers [18F]FMISO and [18F]FAZA in Dogs with Spontaneous Tumors Using Dynamic PET/CT Imaging

PurposeWe evaluated the kinetics of the hypoxia PET radiotracers, [18F]fluoromisonidazole ([18F]FMISO) and [18F]fluoroazomycin-arabinoside ([18F]FAZA), for tumor hypoxia detection and to assess the correlation of hypoxic kinetic parameters with static imaging measures in canine spontaneous tumors.MethodsSixteen dogs with spontaneous tumors underwent a 150-min dynamic PET scan using either [18F]FMISO or [18F]FAZA. The maximum tumor-to-muscle ratio (TMR_max) > 1.4 on the last image frame was used as the standard threshold to determine tumor hypoxia. The tumor time-activity curves were analyzed using irreversible and reversible two-tissue compartment models and graphical methods. TMR_max was compared with radiotracer trapping rate (k₃), influx rate (K_i), and distribution volume (V_T).ResultsTumor hypoxia was detected in 7/8 tumors in the [18F]FMISO group and 4/8 tumors in the [18F]FAZA group. All hypoxic tumors were detected at > 120 min with [18F]FMISO and at > 60 min with [18F]FAZA. [18F]FAZA showed better fit with the reversible model. TMR_max was strongly correlated with the irreversible parameters (k₃ and K_i) for [18F]FMISO at > 90 min and with the reversible parameter (V_T) for [18F]FAZA at > 120 min.ConclusionsOur results showed that [18F]FAZA provided a promising alternative radiotracer to [18F]FMISO with detecting the presence of tumor hypoxia at an earlier time (60 min), consistent with its favorable faster kinetics. The strong correlation between TMR_max over the 90–150 min and 120–150 min timeframes with [18F]FMISO and [18F]FAZA, respectively, with kinetic parameters associated with tumor hypoxia for each radiotracer, suggests that a static scan measurement (TMR_max) is a good alternative to quantify tumor hypoxia.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13139-022-00780-4.     

Automated synthesis of 18F analogue of paclitaxel (PAC): [18F]Paclitaxel (FPAC).

A positron-emitting paclitaxel (PAC) derivative could allow in vivo measurement of multidrug resistance in tumors and, therefore, predict a potential chemotherapeutic benefit to patients. [18F]Paclitaxel was produced using a 2-reaction vessel automated synthesizer followed by HPLC purification. Optimized reaction conditions resulted in radiochemical yields of 21.2+/-9.6% at end of bombardment, radiochemical purity >99%, and specific activity of 159+/-43 G Bq/micromol. [18F]Paclitaxel activities of 1.33+/-0.729 G Bq (n=7) were obtained in sterile, pyrogen-free solution for IV administration.     

Synthesis and preclinical evaluation of the choline transport tracer deshydroxy-[18F]fluorocholine ([18F]dOC)

11C-labeled choline ([11C]CHO) and 18F-fluorinated choline analogues have been demonstrated to be valuable tracers for in vivo imaging of neoplasms by means of positron emission tomography (PET). The objective of the present study was to evaluate whether deshydroxy-[18F]fluorocholine, ([18F]dOC), a non-metabolizable [18F]fluorinated choline analogue, can serve as a surrogate for cholines that are able to be phosphorylated and thus allow PET-imaging solely by addressing the choline transport system. The specificity of uptake of [18F]dOC was compared with that of [11C]choline ([11C]CHO) in cultured rat pancreatic carcinoma and PC-3 human prostate cancer cells in vitro. In addition, biodistribution of [18F]dOC and [11C]CHO was compared in AR42J- and PC-3 tumor bearing mice. The in vitro studies revealed that membrane transport of both compounds can be inhibited in a concentration dependent manner by similar concentrations of cold choline (IC50 [18F]dOC= 11 microM; IC50 [11C]CHO=13 microM. In vitro studies with PC-3 and AR42J cells revealed that the internalized fraction of [18F]dOC after 5 min incubation time is comparable to that of [11C]CHO, whereas the uptake of [11C]CHO was superior after 20 min incubation time. As for [11C]CHO, kidney and liver were also the primary sites of uptake for [18F]dOC in vivo. Biodistribution data after simultaneous injection of both tracers into AR42J tumor bearing mice revealed slightly higher tumor uptake for [18F]dOC at 10 min post-injection, whereas [11C]CHO uptake was higher at later time points. In conclusion, [18F]dOC is taken up into AR42J rat pancreatic carcinoma and PC-3 human prostate cancer cells by a choline specific transport system. Similar transport rates of [18F]dOC and [11C]CHO result in comparable cellular uptake levels at early time points. In contrast to [18F]dOC, which is transported but not intracellularly trapped, the choline kinase substrate [11C]CHO is transported into tumor cells and retained. Thus, the signal obtained by imaging early after injection is mainly reflecting transport, whereas a valid quantification of choline kinase activity needs imaging at later time points. Further studies have to clarify whether quantification of the transport capacity or the choline kinase activity result in a better pathophysiological correlate and thus is the more useful process for tumor characterization.     

Synthesis of 2-(1,1-dicyanopropen-2-yl)-6-(2-[18F]-fluoroethyl)-methylamino-naphthalene ([18F]FDDNP).

2-(1,1-dicyanopropen-2-yl)-6-(2-[18F]-fluoroethyl)-methylamino-naphthalene ([18F]FDDNP) was synthesized in a single step labeling procedure. The precursor, 2-(1,1-dicyanopropen-2-yl)-6-(2-tosyloxyoethyl)-methylamino-naphthalene, was fluorinated with 18F in acetonitrile. After 15 min the reaction mixture was subjected to preparative HPLC purification. The product was isolated from the HPLC eluent with solid-phase extraction, and formulated in an ascorbic acid solution to prevent formation of side products during formulation. Quantitative sticking to tubing and filters was overcome by the addition of polysorbatum-80. This formulation yielded an isotonic, pyrogen-free and sterile solution of [18F]FDDNP. The overall decay-corrected radiochemical yield was 41+/-11% (n=22). Radiochemical purity was >98% and the specific activity was 102+/-56 GBq/micromol at the end of synthesis.     

Simple,column purification technique for the fully automated radiosynthesis of [18F]fluoroazomycinarabinoside ([18F]FAZA)

A novel fully automated radiosynthesis procedure for the fluorine-18 analog of 1-α-D-(5′-deoxy-5′-fluoro-(1S,2R,3S,4S) arabinofuranosyl)-2-nitroimidazole ([¹⁸F]FAZA) using a commercially available combination column – Chromabond^® Set V (FDG-base-hydrolysis) – for purification was developed. [¹⁸F]FAZA was prepared via a one-pot, two-step synthesis using a nuclear interface nucleophilic synthesis module. Nucleophilic fluorination of the precursor molecule, 1-(2,3-di-O-acetyl-5-O-tosyl-α-D-arabinofuranosyl)-2-nitroimidazole, with no-carrier added [¹⁸F]fluoride followed by hydrolysis of the protecting groups with 0.3 M NaOH was performed. Purification was carried out using the Chromabond^® Set V column without any modifications. The overall radiochemical yield obtained was 21.98±1.40% (n=5, without decay correction) within a total synthesis period of 51±1 min. The radiochemical purity was greater than 95% and devoid of any other chemical impurities. The reported method can easily be adapted in any commercial FDG synthesis module.     

Correlation of [18F]FMISO autoradiography and pimonodazole immunohistochemistry in human head and neck carcinoma xenografts

Purpose  Tumour cell hypoxia is a common feature in solid tumours adversely affecting radiosensitivity and chemosensitivity in head and neck squamous cell carcinomas. Positron emission tomography (PET) using the tracer [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) is most frequently used for non-invasive evaluation of hypoxia in human tumours. A series of ten human head and neck xenograft tumour lines was used to validate [¹⁸F]FMISO as hypoxia marker at the microregional level. Methods  Autoradiography after injection of [¹⁸F]FMISO was compared with immunohistochemical staining for the hypoxic cell marker pimonidazole in the same tumour sections of ten different human head and neck xenograft tumour lines. The methods were compared: first, qualitatively considering the microarchitecture; second, by obtaining a pixel-by-pixel correlation of both markers at the microregional level; third, by measuring the signal intensity of both images; and fourth, by calculating the hypoxic fractions by pimonidazole labelling. Results  The pattern of [¹⁸F]FMISO signal was dependent on the distribution of hypoxia at the microregional level. The comparison of [¹⁸F]FMISO autoradiography and pimonidazole immunohistochemistry by pixel-by-pixel analysis revealed moderate correlations. In five tumour lines, a significant correlation between the mean [¹⁸F]FMISO and pimonidazole signal intensity was found (range, r ² = 0.91 to r ² = 0.99). Comparison of the tumour lines with respect to the microregional distribution pattern of hypoxia revealed that the correlation between the mean signal intensities strongly depended on the microarchitecture. Overall, a weak but significant correlation between hypoxic fractions based on pimonidazole labeling and the mean [¹⁸F]FMISO signal intensity was observed (r ² = 0.18, p = 0.02). For the three tumour models with a ribbon-like microregional distribution pattern of hypoxia, the correlation between the hypoxic fraction and the mean [¹⁸F]FMISO signal intensity was much stronger and more significant (r ² = 0.73, p < 0.001) than for the tumours with a more homogenous, patchy, microregional distribution pattern of hypoxia. Conclusion  Different patterns of [¹⁸F]FMISO accumulation dependent on the underlying microregional distribution of hypoxia were found in ten head and neck xenograft tumours. A weak albeit significant correlation was found between the mean [¹⁸F]FMISO signal intensity and the hypoxic fraction of the tumours. In larger clinical tumours, [¹⁸F]FMISO–PET provides information on the tumour oxygenation status on a global level, facilitating dose painting in radiation treatment planning. However, caution must be taken when studying small tumour subvolumes as accumulation of the tracer depends on the presence of hypoxia and on the tumour microarchitecture. An erratum to this article can be found at     

Assessment of radionuclidic impurities in 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) routine production.

In this paper, radionuclidic impurities generated during the bombardment of [18 O]water in the routine production of 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) were studied. In order to assess such impurities and the efficacy of purification methods through the different steps of the synthesis, samples of the target filters, purification columns, [18 O]water recovered after the synthesis, and the final solution was collected and their activities measured and analyzed by means of a gamma-ray spectrometry system. The data demonstrated that purification methods adopted for the synthesis provide the [18F]FDG radionuclidically pure, as requested by the EU Pharmacopeia.