Correction: Fast and reliable generation of [18F]triflyl fluoride, a gaseous [18F]fluoride source.

Correction for 'Fast and reliable generation of [18F]triflyl fluoride, a gaseous [18F]fluoride source' by A. Pees et al., Chem. Commun., 2018, 54, 10179-10182.

Fast and reliable generation of [18F]triflyl fluoride, a gaseous [18F]fluoride source.

A novel strategy for the production of reactive [18F]fluoride has been developed, omitting time consuming azeotropic drying procedures. Gaseous [18F]triflyl fluoride is formed instantaneously at room temperature from hydrated [18F]fluoride, followed by distillation in less than 5 minutes into a dry aprotic solvent, in which dry [18F]fluoride is released in presence of base with >90% radiochemical yield. The reactivity of the [18F]fluoride has been confirmed by reaction with several model compounds and by the synthesis of the PET tracers [18F]fluoroestradiol ([18F]FES) and O-2-[18F]fluoroethyl-l-tyrosine ([18F]FET), providing good isolated radiochemical yields and molar activities of up to 123 GBq µmol-1.

The Cu(+)-assisted radioiodination Kit: Mechanistic study of unexplored parameters concerning the acidity and redox properties of the reaction medium.

Nucleophilic Cu(+)-assisted radioiodination can be optimally performed at pH approximately 2.3 by using conventional reducing agents such as gentisic acid and SnSO(4), mixed or separately. A mechanistic overview of the Cu(+)-radioiodination method is presented in the extended pH-range of 1-4.4. At lower pH, these usual reducing agents show a distinct behaviour. Oxidizing acids (HSO(4)(-), H(3)PO(4)) must be avoided, where as redox neutral acids (trifluoroacetic acid or methanesulfonic acid) or reducing acids (H(2)SO(3), H(3)PO(2)) are well tolerated. The presence of reducing acids makes the use of the usual reducing agents redundant.

Synthesis and biodistribution of [11C]R107474, a new radiolabeled alpha2-adrenoceptor antagonist.

R107474, 2-methyl-3-[2-(1,2,3,4-tetrahydrobenzo[4,5]furo[3,2-c]pyridin-2-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one, was investigated using in vitro and in vivo receptor assays and proved to be a potent and relatively selective alpha(2)-adrenoceptor antagonist. Performed assays in vitro were inhibition of binding to a large number of neurotransmitter receptor sites, drug receptor binding sites, ion channel binding sites, peptide receptor binding sites, and the monoamine transporters in membrane preparations of brain tissue or of cells expressing the cloned human receptors. The compound has subnanomolar affinity for halpha(2A)- and halpha(2C)-adrenoceptors (K(i) = 0.13 and 0.15 nM, respectively) and showed nanomolar affinity for the halpha(2B)-adrenoceptors and 5-hydroxytryptamine(7) (h5-HT(7)) receptors (K(i) = 1 and 5 nM, respectively). R107474 interacted weakly (K(i) values ranging between 81 and 920 nM) with dopamine-hD(2L), -hD(3) and -hD(4), h5-HT(1D)-, h5-HT(1F)-, h5-HT(2A)-, h5-HT(2C)-, and h5-HT(5A) receptors. The compound, tested up to 10 microM, interacted only at micromolar concentrations or not at all with any of the other receptor or transporter binding sites tested in this study. In vivo alpha(2A)- and alpha(2C)-adrenoceptor occupancy was measured by ex vivo autoradiography 1h after subcutaneous (sc) administration of R107474. It was found that R107474 occupies the alpha(2A)- and alpha(2C)-adrenoceptors with an ED(50) (95% confidence limits) of 0.014 mg/kg sc (0.009-0.019) and 0.026 mg/kg sc (0.022-0.030), respectively. Radiolabeled 2-methyl-3-[2-([1-(11)C]-1,2,3,4-tetrahydrobenzo[4,5]furo[3,2-c]pyridin-2-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one ([(11)C]R107474) was prepared and evaluated as a potential positron emission tomography (PET) ligand for studying central alpha(2)-adrenoceptors. [(11)C]R107474 was obtained via a Pictet-Spengler reaction with [(11)C]formaldehyde in 33 +/- 4% overall decay-corrected radiochemical yield. The total synthesis time was 55 min and the specific activity was 24-28 GBq/micromol. The biodistribution of [(11)C]R107474 in rats revealed that the uptake of [(11)C]R107474 after in vivo intravenous administration is very rapid; in most tissues (including the brain) it reaches maximum concentration at 5 min after tracer injection. In agreement with the known distribution of alpha(2)-adrenoceptors in the brain, highest uptake of radioactivity was observed in septum (3.54 +/- 0.52 ID/g, 5 min pi) and entorhinal cortex (1.57 +/- 0.10 ID/g, 5 min pi). Tissue/cerebellum concentration ratios for septum (5.38 +/- 0.45, 30 min pi) and entorhinal cortex (3.43+/-0.24, 30 min pi) increased with time due to rapid uptake followed by a slow washout. In vivo blocking experiments using the non-selective alpha(2)-adrenoceptor antagonist mirtazapine demonstrated specific inhibition of [(11)C]R107474 binding in selective brain areas. The receptor binding profile of mirtazapine is reported and the selectivity of inhibition of binding is discussed. These results suggest that [(11)C]R107474 deserves further investigation as a potential radioligand for studying alpha(2)-adrenoceptors using PET.

Synthesis and biodistribution of [(11)C]R116301, a promising PET ligand for central NK(1) receptors.

N1-(2,6-Dimethylphenyl)-2-(4-{(2R,4S)-2-benzyl-1-[3,5-di(trifluoromethyl)[carbonyl-(11)C]benzoyl]hexahydro-4-pyridinyl}piperazino)acetamide ([(11)C]R116301) was prepared and evaluated as a potential positron emission tomography (PET) ligand for investigation of central neurokinin(1) (NK(1)) receptors. 1-Bromo-3,5-di(trifluoromethyl)benzene was converted in three steps into 3,5-di(trifluoromethyl)[carbonyl-(11)C]benzoyl chloride, which was reacted with N1-(2,6-dimethylphenyl)-2-{4-[(2R,4S)-2-benzylhexahydro-4-pyridinyl]piperazino}acetamide providing [(11)C]R116301 in 45-57% decay-corrected radiochemical yield. The total synthesis time, from end of bombardment (EOB) to the formulated product, was 35 min. Specific activity (SA) was 82-172 GBq/micromol (n=10) at the end of synthesis. N1-([4-(3)H]-2,6-Dimethylphenyl)-2-(4-{(2R,4S)-2-benzyl-1-[3,5-di(trifluoromethyl)benzoyl]hexahydro-4-pyridinyl}piperazino)acetamide ([(3)H]R116301) was also synthesized (SA: 467 GBq/mmol). The B(max) for [(3)H]R116301 measured in vitro on Chinese hamster ovary cell membranes stably transfected with the human NK(1) receptor was 19.10+/-1.02 pmol/mg protein with an apparent dissociation constant of 0.08+/-0.01 nM. Ex vivo, in vivo and in vitro autoradiography studies with [(3)H]R116301 in gerbils demonstrated a preferential accumulation of the radioactivity in the striatum, olfactory tubercule, olfactory bulb and locus coeruleus. In vivo, the biodistribution of [(11)C]R116301 in gerbils revealed that the highest initial uptake is in the lung, followed by the liver and kidney. In the brain, maximum accumulation was found in the olfactory tubercules (1.10+/-0.08 injected dose (ID)/g 20 min post injection (p.i.)) and the nucleus accumbens (1.00+/-0.12ID/g 10 min p.i.). Tissue/cerebellum concentration ratios for striatum and nucleus accumbens increased with time due to rapid uptake followed by a slow wash out (1.29 and 1.64, respectively, 30 min p.i.). A tissue to cerebellum ratio of 1.33 and 1.62 was also observed for olfactory bulb and olfactory tubercules, respectively (20 min p.i.). In summary, [(11)C]R116301 appears to be a promising radioligand suitable for the visualization of NK(1) receptors in vivo using PET.

Adsorption of radioiodine on platinum: a fast and simple column method to obtain concentrated and pure radioiodide in either water or anhydrous solvents.

Radioiodine can be adsorbed on a small column filled with platinum powder from an acidified aqueous solution. The adsorption is nearly quantitative, irrespective of the oxidation state of the iodine used. With an alternated flow of hydrogen gas and solvent, the iodine can be desorbed from the platinum into an aqueous or organic solvent. Depending on the solvent used, the desorption process is also nearly quantitative, and the eluate obtained contains almost pure radioiodide. Using this method, labelling reactions with radioiodide are no longer restricted to water-stable substrates and catalysts.

Feasibility of planar myocardial carbon 11-acetate imaging.

BACKGROUND: Myocardial oxygen consumption can be determined by using carbon 11-acetate (11C-acetate) and positron emission tomography (PET). The aim of this study was to validate planar 11C-acetate scintigraphy in healthy individuals by relating the myocardial clearance rate of dynamic 11C-acetate scintigraphy with the rate-pressure product, which is used as a measure of cardiac work. Also, the optimal curve-fitting procedure of the time-activity curve and the intraobserver and interobserver variation of determining the clearance rates were assessed. METHODS AND RESULTS: Six subjects were studied at rest, and seven subjects were studied during dobutamine stimulation. Imaging was performed with a planar camera equipped with high-energy collimators for 45 minutes after the injection of 185 MBq of 11C-acetate. Myocardial time-activity curves were corrected for decay. During the study, heart rates and blood pressures were measured to calculate the rate-pressure product. Myocardial time-activity curves showed a clear biphasic pattern. Clearance rates were expressed in k values. The best fitting procedure, as assessed by means of the lowest error of k and the best correlation with the rate-pressure product, proved to be a monoexponential fit on the first part of the time-activity curve (kmono). Subjects studied during dobutamine infusion had significantly higher rate-pressure product (15.0 +/- 2.1*10(3) vs 8.6 +/- 1.2*10(3), P < .001) and 11C-acetate clearance rates (kmono = 0.0657 +/- 0.0110 vs 0.0313 +/- 0.0056, P < .0001) than subjects studied at rest. There was low intraobserver and interobserver variation in determining kmono values. A significant correlation between the rate-pressure product and the monoexponential clearance rate was found (kmono = 5.11*10(-6)*RPP-0.012; r = 0.94, P < .001). CONCLUSIONS: The estimation of myocardial oxygen consumption is feasible with planar 11C-acetate scintigraphy. Clearance rates and the relation with the rate-pressure product are similar to those reported in PET studies. This technique may be used for the assessment and follow-up of global myocardial metabolic abnormalities, eg, in patients with hypertensive heart disease, cardiomyopathy, myocarditis, and valvular disease.

Characterization of the binding site of the histamine H(3) receptor. 2. Synthesis, in vitro pharmacology, and QSAR of a series of monosubstituted benzyl analogues of thioperamide.

A series of monosubstituted benzyl analogues of the histamine H(3) receptor antagonist thioperamide were synthesized and evaluated for their histamine H(3) receptor activity on the guinea pig jejunum. Incorporation of Cl, Br, and I at the ortho position of the benzyl moiety led to an increase of the pA(2) value, whereas the same substituents at the para position led to a decrease. However, a fluorine substituent gave a strong decrease in pA(2), regardless of the position. Molecular modeling revealed a QSAR with a correlation (r = 0.93) between the pA(2) and the dihedral angle between the thiourea and the benzyl moiety and the calculated electron density on the substituted carbon atom. To verify whether this QSAR model had a predictive value, the ortho tert-butyl and methyl analogues were synthesized and evaluated. Indeed it was shown that the predicted pA(2) values of these two compounds were in accordance with the measured pA(2) values.

Radiosynthesis and biodistribution of 123I-labeled antagonists of the histamine H3 receptor as potential SPECT ligands.

We have synthesized three 123I-labeled histamine H3 receptor ligands, i.e., [123I]GR 190028, [123I]FUB 271, and [123I]iodoproxyfan, in moderate to good radiochemical yields via a Cu+-assisted I-for-123I exchange method. Biodistribution in the rat of these compounds revealed high hepatic and pulmonary uptake. Brain uptake was moderate, but for [123I]iodoproxyfan, brain uptake was high enough for a pilot single photon emission computed tomography (SPECT) study in the rabbit. However, for this compound, the cerebral uptake could not be blocked by a pretreatment with [R]-alpha-methylhistamine, a selective, high-affinity histamine H3 receptor agonist, both in the SPECT study in the rabbit and in the biodistribution study in the rat. Apparently, [123I]iodoproxyfan is binding to a non-H3 receptor binding site. None of the three investigated compounds is suitable for use as a SPECT ligand for the H3 receptor in the brain.

Evaluation of [18F]VUF 5000 as a potential PET ligand for brain imaging of the histamine H3 receptor.

[18F]VUF 5000 was evaluated as a potential PET ligand for the histamine H3 receptor. In the rat a high uptake of [18F]VUF 5000 was observed in liver, lung and kidney and a low uptake in the brain. In order to explain these findings we determined the LogD(oct,7.2) of [18F]VUF 5000, studied the biodistribution in the presence of carrier VUF 5000, modified [18F]VUF 5000 chemically and studied the binding of [18F]VUF 5000 to human serum albumin. From the results of these experiments it was concluded that [18F]VUF 5000 is not suitable as a PET ligand for brain imaging of the histamine H3 receptor, since [18F]VUF 5000 hardly penetrates into the brain.

Zirconium-labeled monoclonal antibodies and their distribution in tumor-bearing nude mice.

UNLABELLED: A method to label monoclonal antibodies (MAbs) with 88Zr and 89Zr has been developed and tested on the MAbs 323/A3 and E48. METHODS: The bifunctional chelating agent desferal (Df) was linked through a thioether bond to the MAbs. Labeling was accomplished by addition of the premodified antibodies to isolated Zr. The retention of the in vivo behavior of the MAbs was determined by comparing the biodistribution of 88Zr-labeled MAbs with those of 123I and 99mTc in mice bearing tumor xenografts. RESULTS: The labeling was simple and the yields were high (above 90%). The obtained conjugates retained their immunoreactivity (> 80%). The blood clearance and biodistribution of Zr-labeled MAbs resembled those of the reference conjugates. The Zr-Df-MAb conjugates showed a specific tumor accumulation. Zirconium-89-labeled 323/A3 could be visualized with a PET camera. The absence of large amounts of Zr present in the bone pointed to a good in vivo stability of the Zr-Df-MAb conjugates. CONCLUSION: This method is well suited for labeling MAbs with Zr isotopes. Using 89Zr, the biodistribution of the radioimmunoconjugate can easily be visualized with a PET camera.

Vesamicol and some of its derivatives: questionable ligands for selectively labelling acetylcholine transporters in rat brain.

Presynaptic cholinergic markers could be used for estimating the integrity of the cholinergic systems in the human brain with brain imaging techniques such as Single-photon emission computed tomography (SPECT). Vesamicol, an inhibitor of the vesicular acetylcholine transporter, and some of its derivatives have been suggested as potential ligands for this purpose. However, vesamicol binds not only to acetylcholine transporters but also to sigma binding sites. In the present study, we estimated the contribution of sigma site labelling to [3H](-)-vesamicol binding in different rat brain regions by selectively labelling the acetylcholine transporter, using [3H](-)-vesamicol in the presence of the sigma-ligand 1,3-di(2-tolyl)guanidine to occlude the sigma binding sites. The contribution of sigma site labelling was substantial in all brain regions and ranged from 25% in the striatum to 60% in the medulla. In addition, we investigated, in various experimental set ups, the affinities of several vesamicol derivatives for acetylcholine transporters and sigma binding sites. All vesamicol derivatives used displayed a higher affinity for the sigma1 site than for the acetylcholine transporter and also displayed a high sigma2 site affinity. This poor selectivity limits the usefulness of these compounds as selective cholinergic markers for brain imaging studies.

Biodistribution of 123I-labeled 4-hydroxytamoxifen derivatives in rats with dimethylbenzanthracene-induced mammary carcinomas.

A 123I-labeled tamoxifen derivative with a high affinity for the antiestrogen-binding site (AEBS) has been prepared. Biodistribution studies in rats showed a good linear correlation between the AEBS contents of tissue in fmol/g and the accumulated amount of radioactivity in percent dose per gram at 24 h.

A facile method for the labeling of proteins with zirconium isotopes.

To label proteins with positron emitters with a half-life in the order of days, a method has been developed to label proteins with zirconium (Zr)-isotopes. Therefore, the bifunctional chelating agent desferal (Df) was coupled to albumins via a thioether bond. Labeling of the premodified proteins was easily performed by addition of these proteins to freeze-dried Zr-oxalate. This labeling was efficient (> 90%) and accomplished in several minutes. The conjugates showed a high in vitro stability. Biodistribution studies were performed with 88Zr-citrate, 88Zr-Df, and 88Zr-labeled mouse serum albumin (88Zr-Df-MSA), modified with different amounts of chelating groups. Whereas Zr-citrate was found to accumulate in bone, Zr-Df was cleared very fast by glomerular filtration. The 88Zr-Df-MSA showed similar blood clearance as did 123I-labeled MSA. The biodistribution pattern of 88Zr-Df-MSA differed only from 123I-MSA in that a higher accumulation of Zr in liver, kidney, and spleen was found. The absence of large amounts of 88Zr in bone indicated that in vivo the conjugates are also reasonably stable.

18F-radiopharmacokinetics of [18F]-5-fluorouracil in a mouse bearing two colon tumors with a different 5-fluorouracil sensitivity: a study for a correlation with oncological results.

The tissue distribution and biodynamics of 18F-labelled 5-fluorouracil (FU) are described and studied for correlation with its in vivo antitumor activity. The in vivo model consisted of Balb/c mice bearing a FU sensitive (Colon 26-10 carcinoma) tumor in the left and a less responsive (Colon 26 carcinoma) tumor in the right abdominal side of the animal. Distribution and efflux of 18F-label from tumor, blood, and other tissues were determined by obduction at 0.5, 1, 2, 4, and 6 h postintravenous injection. For a comparison, the 18F-labeled 5-fluoro-6-hydroxy and cis-5-fluoro-6-ethoxy uracil adducts were studied in the same in vivo model. For 18F-FU it was found that the 18F-label tumor kinetics rapidly fell into a biphasic mode: a relatively short 18F beta phase (18F t1/2 beta 21 +/- 3 min), linked with the total body metabolic capacity and clearance of the animal, and a longer 18F gamma phase, linked with the intrinsic intratumoral FU metabolism (Colon 26-10: 18F t1/2 gamma 10.3 h; Colon 26: 18F t1/2 gamma 5.6 h). It is proposed that the observed faster 18F efflux of the less responsive Colon 26 corresponds to an enhanced breakdown of 5-fluoronucleotides to 5-fluoronucleosides and subsequent elimination from the tumor cells. It is concluded that on PET scanning, measurement of the dynamic 18F t1/2 gamma and 18F t1/2 beta parameter is of prime importance for an insight in the in vivo tumor biology of a patient.

A simple and efficient method to remove free radioiodide from *I-radiopharmaceuticals.

Removal of free radioiodide from *I-radiopharmaceuticals was easily performed by using a pure metallic silver membrane, placed in a screwable holder. Well-known radiopharmaceuticals such as 3-iodobenzylguanidine, Hippuran, iomazenil and fatty acids were treated successfully, and gave reproducible results. Only a trace of free radioiodide (< or = 1%) was left after passing the silver membrane, while rest activity due to retention of the radiopharmaceutical on the membrane was negligible (2%-5%). This simple and reliable method offers the possibility of application as a last purification step in routine productions, in research or in a nuclear medicine department's pharmacy.

Labeling of monoclonal antibodies with rhenium-186 using the MAG3 chelate for radioimmunotherapy of cancer: a technical protocol.

A detailed technical protocol is provided for reproducible and aseptical production of stable 186Re-monoclonal antibody conjugates. Labeled Mab E48 IgG and its F(ab')2 fragment which are promising candidates for radioimmunotherapy of squamous cell carcinoma of the head and neck were used for evaluation. S-benzoylmercaptoacetyltriglycine (S-benzoyl-MAG3) was used as a precursor. Rhenium-186-MAG3 was prepared via a unique solid-phase synthesis, after which known strategies for esterification and conjugation to Mab IgG/F(ab')2 were applied. The biodistribution of 186Re-E48 F(ab')2 in tumor-bearing nude mice was found to be comparable to that of analogously labeled 99mTc-E48 F(ab')2 or 131I-E48 F(ab')2, indicating that the intrinsic behavior of the antibody remains preserved when using this labeling technique. Radiolytic decomposition of 186Re-E48 IgG/F(ab')2 solutions of 10 mCi.ml-1 was effectively reduced by the antioxidant ascorbic acid. Upon increase of the Re-MAG3 molar amount, a conjugation of seven to eight Re-MAG3 molecules per Mab molecule was generally the maximum ratio that could chemically be obtained. Such a ratio did not impair the immunoreactivity or alter the in vivo biodistribution characteristics of the immunoconjugate, making this labeling procedure suitable for general clinical application.

Comparison of uptake, oxidation and lipid distribution of 17-iodoheptadecanoic acid, 15-(p-iodophenyl)pentadecanoic acid and 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid in normal canine myocardium.

The kinetics of 17-[123I]iodoheptadecanoic acid (IHDA), 15-(p-[125I]iodophenyl)pentadecanoic acid (pIPPA) and 15-(p-[131I]iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPPA) were investigated in normal canine myocardium. After simultaneous intravenous injection, myocardial biopsy specimens and samples of arterial blood were taken over 80 min. IHDA showed the highest myocardial uptake (995 +/- 248 dpm/mg.mCi versus pIPPA: 785 +/- 197 dpm/mg.mCi, ns) and the largest size of oxidation (74% +/- 4% versus pIPPA: 65% +/- 5%, p < 0.05). Myocardial activity of IHDA decreased with a half-time value of 11.2 min (pIPPA: 13.2 min). Phospholipids were the main lipid fraction into which IHDA was incorporated, whereas pIPPA was predominantly incorporated into triacylglycerols. DMIPPA myocardial activity remained constant during the assay period and instead of being oxidized, DMIPPA was mainly incorporated into triacylglycerols (55% +/- 12%). The myocardium-to-blood ratios of DMIPPA were greater than 10:1. The ratios at peak for IHDA and pIPPA were 4.1:1 and 3.9:1, respectively (both p < 0.0001 versus DMIPPA). In conclusion, differences have been found in the myocardial uptake, oxidation and lipid distribution of IHDA, pIPPA and DMIPPA. DMIPPA is a promising tracer for fatty acid uptake studies with single-photon emission computerized tomography because of its prolonged retention and high myocardium-to-blood ratios.

Evaluation of desferal as a bifunctional chelating agent for labeling antibodies with Zr-89.

Zirconium-desferal was prepared and analysed by TLC, NMR and u.v.-spectroscopy. The stoichiometry of the complex was found to be 1:1. Chelation of desferal, coupled to resin, with 88Zr appeared to be fast and almost quantitative in various buffer systems in a broad pH-range (4-7). A high in vitro stability of the zirconium-desferal complex was observed; less than 0.2% zirconium was lost within 24 h in plasma-solutions.

Tissue distribution of [18F]-5-fluorouracil in mice: effects of route of administration, strain, tumour and dose.

In a study investigating the usefulness of 5-fluorouracil labelled with fluorine 18 [( 18F]-5-FU) in cancer chemotherapy, the tissue distribution of the radiolabel was determined in mice at 2, 4 and 6 h after administration by varying several parameters such as the mode of administration, the strain of mouse, the presence of a tumour and the total dose of 5-FU. The tissue distribution of fluorine 18 after i.p. injection pointed to an altered behaviour of the drug and/or its metabolites when compared with values obtained after i.v. injection, but no difference was found in the accumulation of radiolabel in the tumour. A comparison of non-tumour-bearing BALB/c and C57Bl/6 mice revealed that the latter showed a higher radiolabel accumulation of the drug and its metabolites in the liver, kidney, intestines and coecum (P less than 0.05 at 2 and 4 h). In tumour-bearing mice, especially at 2 h, the tissue accumulation of radiolabel was found to be significantly higher than in non-tumour-bearing controls (in BALB/c mice bearing colon 26 carcinoma, P less than 0.05 for all tissues; in C57Bl/6 mice bearing colon 38 carcinoma, P less than 0.05 for the blood, lung, liver, kidney, large intestines, coecum and muscle). Finally, a comparison of injections of a tracer dose of [18F]-5-FU (2.5 mg/kg) vs a therapeutic dose (100 mg/kg) revealed only small differences in the accumulation of fluorine 18 in the liver and kidney.