This document is meant to complement Part B of the EANM Guidelines on current good radiopharmacy practice (cGRPP) in the preparation of radiopharmaceuticals issued by the Radiopharmacy Committee of the European Association of Nuclear Medicine, covering small-scale in-house preparation of radiopharmaceuticals with automated modules. The aim is to provide more detailed and practice-oriented guidance to those who are involved in the small-scale preparation of radiopharmaceuticals, which are not intended for commercial purposes or distribution.

The development of positron emission tomography (PET) from being an exclusive and expensive research tool at major research institutes to a clinically useful modality found at most major hospitals around the world is largely dependent on radiochemistry and synthesis technology achievements by a few pioneer researchers starting their PET careers 40 to 50years ago. Especially, the introduction of [C-11]methyl iodide resulted in a quantum jump in the history of PET tracer development enabling the smooth labelling of a multitude of useful tracers. A more recent and still challenging methodological improvement is transition metal mediated C-11-carbonylations, having a large synthetic potential that has, however, not yet been realized in the clinical setting. This mini-review focuses on the history of carbon-11 radiochemistry and related technology developments and the role this played in PET tracer developments, especially emphasizing radiolabelling of endogenous compounds. A few examples will be presented of how the use of radiolabelled endogenous substances have provided fundamental information of in vivo biochemistry using the concept of position-specific labelling in different positions in the same molecule.

Rhodium-mediated carbonylation reaction was applied to synthesize diethyl [carbonyl-C-11]malonate using [C-11]carbon monoxide at low concentration. The synthesis was performed starting with ethyl diazoacetate, ethanol and the rhodium complex being made in situ by chloro(1,5-cyclooctadiene)rhodium(l) dimer ([Rh(cod)Cl](2)) and 1,2-bis(diphenylphosphino)ethane (dppe), and the reaction is assumed to proceed via a ketene intermediate. The isolated radiochemical yield was 20% (75% analytical radiochemical yield) and the trapping efficiency of [C-11]carbon monoxide in the order of 85%. The specific radioactivity of this compound was measured at 127 GBq/mu mol (7.28 nmol total mass) after 8 mu Ah bombardment and 35 min synthesis. The corresponding C-13-labelled compound was synthesized using (C-13)carbon monoxide to confirm the position of the carbonyl-labelled atom by C-13-NMR. Diethyl [carbonyl-C-11]malonate was further used in subsequent alkylation step using ethyl iodide and tetrabutylammonium fluoride to obtain diethyl diethyl [carbonyl-C-11]malonate in 50% analytical radiochemical yield.

[¹¹C]Hydroxyurea has been successfully labelled using [¹¹C]carbon monoxide at low concentration. The decay-corrected radiochemical yield was 38±3%, and the trapping efficiency of [¹¹C]carbon monoxide in the order of 90±5%. This synthesis was performed by a rhodium-mediated carbonylation reaction starting with azidotrimethylsilane and the rhodium complex being made in situ by chloro(1,5-cyclooctadiene)rhodium(I) dimer ([Rh(cod)Cl]₂) and 1,2-bis(diphenylphosphino)ethane (dppe). (¹³C)Hydroxyurea was synthesized using this method and the position of the labelling was confirmed by ¹³C-NMR. In order to perform accurate LC–MS identification, the derivative 1-hydroxy-3-phenyl[¹¹C]urea was synthesized in a 35±4% decay-corrected radiochemical yield. After 13 µA h bombardment and 21 min synthesis, 1.6 GBq of pure 1-hydroxy-3-phenyl[¹¹C]urea was collected starting from 6.75 GBq of [¹¹C]carbon monoxide and the specific radioactivity of this compound was in the order of 686 GBq/µmol (3.47 nmol total mass). [¹¹C]Hydroxyurea could be used in conjunction with PET to evaluate the uptake of this anticancer agent into tumour tissue in individual patients.

The cholinergic system is involved in neurodegenerative diseases, and visualization of cholinergic innervations with positron emission tomography (PET) would be a useful tool in understanding these diseases. A ligand for the vesicular acetylcholine transporter (VAChT), acknowledged as a marker for cholinergic neurons, could serve as such a PET tracer. The aim was to find a VAChT PET tracer using a library concept to create a small but diverse library of labeled compounds. From the same precursor and commercially available aryl iodides 6a-f, six potential VAChT PET tracers, [C-11]-(+/-)5a-f, were C-11-labeled by a palladium (0)-mediated aminocarbonylation, utilizing a standard protocol. The labeled compounds [C-11]-(+/-)5a-f were obtained in radiochemical purities >95% with decay-corrected radiochemical yields and specific radioactivities between 4-25% and 124-597 GBq/mu mol, respectively. Autoradiography studies were then conducted to assess the compounds binding selectivity for VAChT. Labeled compounds [C-11]-(+/-)5d and [C-11]-(+/-)5e showed specific binding but not enough to permit further preclinical studies. To conclude, a general method for a facile synthesis and labeling of a small piperazine-based library of potential PET tracers for imaging of VAChT was shown, and in upcoming work, another scaffold will be explored using this approach.

A one-step ¹⁸F-labeling strategy was used to prepare three labeled analogues of the vitamin biotin, which can be a useful tracer because of its high affinity for avidin. The labeled compounds were obtained in decay-corrected yields of up to 35%, and specific radioactivity of 320 ± 60 GBq/mmol. When evaluated in situ, the analogues showed good affinity for avidin: 60–75% of the radiolabeled compounds were bound to avidin within 5 min. The binding was site-specific, as shown by blocking experiments with native biotin.

A one-step ¹⁸F-labelling strategy was used to prepare four ¹⁸F-labelled analogues of 7-methoxy-1-methyl-9H-β-carboline (harmine): 7-(2-[¹⁸F]fluoroethoxy)-1-methyl-9H-β-carboline (5), 7-(3-[¹⁸F]fluoro-propoxy)-1-methyl-9H-β-carboline (6), 7-[2-(2-[¹⁸F]fluoroethoxy)ethoxy]-1-methyl-9H-β-carboline (7), and 7-{2-[2-(2-[¹⁸F]fluoroethoxy)ethoxy]-ethoxy}-1-methyl-9H-β-carboline (8). These were synthesized as potential PET ligands for monoamine oxidase A. A solution of pure labelled compound in buffer was obtained in < 70 min from end of radionuclide production, with a decay-corrected yield of up to 23%. The average specific binding to MAO-A in rat brain, determined by autoradiography experiments, was highest for compounds 7 and 8 (89 ± 2 and 96 ± 1% respectively), which was obtained at < 1 nM radioligand concentration.

Exchange of [F-18]fluoride with F-19 in various organofluorine compounds in concentrations ranging from 0.06 to 56 mM was explored. We aimed to explore whether exchange reactions can be a potential useful labelling strategy, when there are no requirement of high specific radioactivity. Parameters such as solvents, temperature, conventional vs microwave heating, and the degree of fluorine load in some aromatic and alkyl compounds were investigated with regard to radiochemical yield and specific radioactivity. A series of fluorobenzophenones (1-6), 1-(4-fluorophenyl)ethanone (7), various activated and deactivated fluoro benzenes (8-16), N-(pentafluorophenyl)benzamide (17), (pentafluorophenyl)formamide (18), (tridecafluorohexyl) benzene (19) and tetradecafluorohexane (20) were subjected to [F-18]/F-19 exchange. To test this strategy to label biologically active molecules containing fluorine atoms in an aryl group, two analogues of WAY-100635 (21-22), Lapatinib (23), 2,5,6,7,8-pentafluoro-3-methyinaphthoquinone (24) and 1-(2,4-difluorophenyl)-3-(4-fluorophenyl)propan-l-one (25) were investigated. The multi-fluorinated molecules containing an electron-withdrawing group were successfully labelled at room temperature, whereas the monofluorinated, as well as those containing an electron-donating group, required heating for the exchange reaction to take place.

Substrates with leaving groups that contained perfluoro moieties were investigated in labelling chemistry in order to exploit their properties to improve reactivity and purification. [F-18] (Fluoromethyl) benzene was used as the model target compound. Precursors containing perfluoroalkyl and perfluoroaryl sulfonate moieties were subjected to nucleophilic F-18-fluorination, and the impact of perfluoro groups on the substitution reaction and product purification was investigated. [F-18]Fluoride interacted with perfluoroalkyl chains, precluding nucleophilic substitution. When perfluoroaryl groups were used, the substitution proceeded, and the separation of product was explored. The radiolabelled product was obtained in 32% analytical yield and the radiochemical purity was increased to approximately 77% using fluorous solid phase extraction purification.

Vascular endothelial growth factor (VEGF) signaling via vascular endothelial growth factor receptor 2 (VEGFR-2) on tumor endothelial cells is a critical driver of tumor angiogenesis. Novel anti-angiogenic drugs target VEGF/VEGFR-2 signaling and induce changes in VEGFR-2 prevalence. To monitor VEGFR-2 prevalence in the course of treatment, we are evaluating (68)Ga positron emission tomography imaging agents based on macrocyclic chelators, site-specifically conjugated via polyethylene glycol (PEG) linkers to engineered VEGFR-2 ligand, single-chain (sc) VEGF. The (68)Ga-labeling was performed at room temperature with NOTA (2,2', 2 ''-(1,4,7-triazonane-1,4,7-triyl) triacetic acid) conjugates or at 90 degrees C by using either conventional or microwave heating with NOTA and DOTA (2,2', 2 '', 2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl) tetraacetic acid) conjugates. The fastest (similar to 2min) and the highest incorporation (>90%) of (68)Ga into conjugate that resulted in the highest specific radioactivity (similar to 400MBq/nmol) was obtained with microwave heating of the conjugates. The bioactivity of the NOTA-and DOTA-containing tracers was validated in 3-D tissue culture model of 293/KDR cells engineered to express high levels of VEGFR-2. The NOTA-containing tracer also displayed a rapid accumulation (similar to 20s after intravenous injection) to steady-state level in xenograft tumor models. A combination of high specific radioactivity and maintenance of functional activity suggests that scVEGF-PEG-[(68)Ga] NOTA and scVEGF-PEG-[(68)Ga] DOTA might be promising tracers for monitoring VEGFR-2 prevalence and should be further explored.

A method to prepare [1-C-11]propyl iodide and [1-C-11]butyl iodide from [C-11]carbon monoxide via a three step reaction sequence is presented. Palladium mediated formylation of ethene with [C-11]carbon monoxide and hydrogen gave [1-C-11]propionaldehyde and [1-C-11]propionic acid. The carbonylation products were reduced and subsequently converted to [1-C-11]propyl iodide. Labelled propyl iodide was obtained in 58 +/- 4% decay corrected radiochemical yield and with a specific radioactivity of 270 +/- 33 GBq/mu mol within 15 min from approximately 12 GBq of [C-11]carbon monoxide. The position of the label was confirmed by C-13-labelling and C-13-NMR analysis. [1-C-11]Butyl iodide was obtained correspondingly from propene and approximately 8 GBq of [C-11]carbon monoxide, in 34 +/- 2% decay corrected radiochemical yield and with a specific radioactivity of 146 +/- 20 GBq/mu mol. The alkyl iodides were used in model reactions to synthesize [O-propyl-1-C-11]propyl and [O-butyl-1-C-11]butyl benzoate. Propyl and butyl analogues of etomidate, a (beta-11-hydroxylase inhibitor, were also synthesized.

A method and an apparatus for preparing [C-11]methyl iodide from [C-11]methane and iodine in a single pass through a non-thermal plasma reactor has been developed. The plasma was created by applying high voltage (400 V/31 kHz) to electrodes in a stream of helium gas at reduced pressure. The [C-11]methane used in the experiments was produced from [C-11]carbon dioxide via reduction with hydrogen over nickel. [C-11]methyl iodide was obtained with a specific radioactivity of 412 +/- 32 GBq/mu mol within 6 min from approximately 24 GBq of [C-11]carbon dioxide. The decay corrected radiochemical yield was 13 +/- 3% based on [C-11]carbon dioxide at start of synthesis. [C-11]Flumazenil was synthesized via a N-alkylation with the prepared [C-11]methyl iodide.

Transition metal mediated carbonylation with [11C]CO has proven a useful method to label a wide array of compounds in the carbonyl position. However, the general use in radiopharmaceutical synthesis has been hampered by the low solubility of carbon monoxide in most solvents and the resulting challenge to confine [11C]CO in low volume reaction vessels. This paper introduces a method that utilises xenon to transfer pre-concentrated [11C]CO to a sealed disposable glass vial containing carbonylation reagents. The high solubility of xenon in the organic solvent made it possible to confine the [11C]CO without utilising a pressure autoclave or chemical trapping additives. The utility of the method in 11C-carbonylation was investigated by conducting three model reactions, where [11C-carbonyl]N-benzylbenzamide, [11C-carbonyl]triclocarban and [11C-carbonyl]methyl nicotinate were afforded in decay corrected radiochemical yields of 71?+/-?6%, 42?+/-?15% and 29?+/-?10%, respectively. These promising results and the straight forward technical implementation suggest that 11C-cabonylation can become a viable mean to provide labelled carbonyl functionalities in routine radiopharmaceutical synthesis. Compounds labelled with short lived positron emitters are used in Positron Emission Tomography, a molecular imaging technology with applications in clinical diagnostics, clinical research and basic biomedical research.

Temozolomide is a chemotherapeutic drug that is mainly used in the treatment of primary glioblastoma multiforme and recurrent high-grade glioma. Here, we report an efficient good manufacturing practice compliant method for the synthesis of [3-N-11C-methyl]temozolomide from 3-N-hydroxymethyl temozolomide that cleaves off formaldehyde in situ and becomes activated towards alkylation with [11C]methyl iodide. The labelling method was developed for an on-going patient study in which the predictive value of [3-N-11C-methyl]temozolomide and positron emission tomography on the outcome of temozolomide treatment is being investigated. The precursor was reacted with [11C]methyl iodide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in acetonitrile, heated at stepwise increasing temperature. Purification by semipreparative HPLC with pharmaceutical grade eluent and filtration gave approximately 10 mL sterile product solution ready for injection containing 1.55 ± 0.38 GBq (n = 5), the specific activity was 88 ± 25 GBq/μmol and the radiochemical purity was 98.5 ± 1.9%.13C-NMR spectroscopy confirmed the labelled position after colabelling with 11C and 13C.

Many ortho-/meta-/para-closo-carborane derivatives have been proposed for boron neutron capture therapy. However, it is difficult to follow their pharmacokinetics in patients, which creates a risk of suboptimal treatment. Adding a radioactive label to closo-carboranes may simplify pharmacokinetic studies. This paper reports on a study of the feasibility of palladium-catalyzed isotopic exchange of iodinated closo-carborane with radioisotopes of iodine. 2-iodo-para-carborane was selected as a model compound. It was shown that such isotopic exchange is possible and provides a high yield (83±4.2%) after 40 min of reaction time. The reaction conditions were optimized, and it was demonstrated that the presence of tetra n-butylammonium hydrogensulfate is important in order to stabilize the catalyst and to give reproducibility of the labeling.

By replacing the alkyl chain in a metomidate ester with F-18-labelled   di- or tri(ethylene glycol) chains, two F-18-labelled PET tracers, i.e.  2-(2-[F-18]fluoroethoxy)ethyl 1-[(1R)-1-phenylethyll-1   H-imidazole-5-carboxylate (1) and   2-[2-(2-[F-18]fluoroethoxy)-ethoxylethyl   1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (2), were   synthesized. Two precursors, 2-(2-bromoethoxy)ethyl  1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate and   2-[2-(2-chloroethoxy)ethoxylethyl  1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate, were prepared and   used in one-step nucleophilic [F-18]fluorination reactions using   conventional and microwave heating. Organ distribution, frozen section   autoradiography and metabolite analysis were performed. The   decay-corrected radiochemical yields of 1 and 2 were 26 +/- 8 and 23   +/- 8%, respectively, when they were prepared using conventional   heating. By performing microwave heating, the reaction time could be   decreased and the yields of analogues 1 and 2 could be increased to 57   +/- 12 and 51 +/- 18%, respectively. Organ distribution studies in the   rat showed considerable uptake in the lungs, adrenals and liver. Both   compounds bound with low nonspecific binding (1: approx. 20-30%; 2:   2.9% or lower) to tissue from pig and human normal and pathologic   adrenals. Metabolite analyses were performed in rats after 5 and 30 min   for tracer 1 (20 +/- 6 and 2 +/- 1 %) and tracer 2 (27 +/- 5 and 6 +/-   4%). Both compounds are interesting candidates for the detection of   different types of adrenal disorders.

One- and two-step syntheses for the F-18-labelling of 6-[(S)-(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1-(2-[F-18]fluoroe thyl)-1H-benzotriazole, [F-18]FVOZ, 1 and 6-[(S)-(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1-[2-(2-[18F]fluor oethoxy)ethyl]-1H-benzotriazole, [F-18]FVOO, 2 were developed. In the two-step synthesis, the nucleophilic fluorination step was performed by reacting (S)-6-[(4-chlorophenyl)-(1H-1,2,4-triazol-1-yl)methyl]-1H-benzotriazole (VOZ) with either the F-18-labelled ethane-1,2-diyl bis(4-methylbenzenesulfonate) or the oxydiethane-2,1-diyl bis(4-methylbenzenesulfonate). The radiochemical yields were in the range of 9-13% after the 110-120 min total syntheses and the specific radioactivities were 175 +/- 7 GBq/mu mol and 56 GBq/mu mol for compounds 1 and 2, respectively. In the one-step synthesis, the precursor 2-{6-[(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1H-1,2,3-benzotriaz ol-1-yl}ethyl 4-methylbenzenesulfonate (7) or 1-[2-(2-bromoethoxy)ethyl]-6-[(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)met hyl]-1H-benzotriazole (8) was directly labelled via, an 18F nucleophilic substitution to give the corresponding tracer. The labelled compounds were obtained in 36-99% radioichemical yield after 75-min syntheses. The specific radioactivities are 100 GBq/mu mol for compound 1 and 80 GBq/pmol for compound 2. In vitro autoradiography using frozen rat brains illustrated specific binding in the medial amygdala, the bed nucleus of stria terminalis and the preoptic area, all of which corresponded well to the result of C-11-labelled vorozole.

Innovation in basic and applied science has brought radiotracers to fruition as diagnostics. Non-invasive, longitudinal, and quantifiable molecular imaging is the key to diagnosing and monitoring numerous illnesses, with more to come from characterization of the clinical relevance of findings from genomics research. Radiotracers enable real-time in vivo studies of the effects of drug candidates on receptors, pathways, pharmacodynamics, and clinically relevant endpoints, thereby providing both early detection of pathophysiology to enable early intervention, and then monitoring of treatment responses to enable individualization of treatment regimens. We review developments which have translated imaging from bench to bedside, or biomarkers to diagnostics. Notable developments include (1) synthesis methods for rapid ¹¹C labeling of biomolecules to high specific radioactivity; (2) ligand-binding assays for screening molecular imaging agents rather than drugs; (3) in vivo imaging of radiotracers in animals; (4) discovering the imaging advantages of ^99mTc, ¹¹C, and ¹⁸F; (5) co-registration and automated quantitative assessment of high spatial resolution CT and MR images with molecular images from PET for longitudinal studies of treatment effect.

We have labeled proinsulin connecting peptide (C-peptide) with fluorine-18 (t(1/2) = 109.7min) in order to perform in vivo biodistribution and pharmacokinetic studies with position emission tomography (PET). This study reports the optimization of the conjugation labeling in the N-terminal with N-succinimidyl-4-[F-18]fluorobenzoate ([F-18]SFB). In preparative runs N-4-[F-18]fluorobenzoyl-C-peptide ([F-18]FB-C-peptide) was produced in 8-12% decay-corrected yields, counted from resolubilized [F-18]F-, in less than 5h. The specific radioactivity of [F-18]FB-C-peptide, determined using ELISA for one of the preparations, was around 70 GBq/mu mol at end of synthesis.

Huisgen cycloaddition is attractive to label peptide because of its rapidity and bioorthogonality. However, for larger tracers, the physico-chemical differences between the precursor and the tracer are usually insufficient to allow their separation by HPLC, reducing the specific activity. This is of importance for peptidic tracers because the combination of their high-affinity receptor with low specific activity results in the precursor saturating the receptors, causing non-specific tracer binding. Here, we report a fast, one-pot, general strategy to circumvent this issue, yielding a tracer of improved specific activity. It consists in adding a lipophilic azide after the labeling step to scavenge unreacted precursor into a more lipophilic species that does not co-elute with the tracer. We applied this strategy to a new fluorinated cyclopentapeptidic CXCR4 antagonist for the PET imaging of cancer, CCIC15, for which we managed to reduce the apparent peptide concentration by a factor of 34 in 10min. This tracer was radiolabeled by click chemistry with 2-[F-18]fluoroethylazide, yielding the tracer in 18 +/- 6% (n=5) end-of-synthesis radiochemical yields (EOS-RCY) in 1.5h from [F-18]fluoride with a specific activity of 19.4GBq mu mol(-1). Preliminary biological evaluation of the probe confirmed potency and specificity for CXCR4; further biological evaluation is underway.

Derivatives of nido-carborate have potential use in tumour targeting as hydrophilic boron-rich compounds for boron neutron capture therapy (BNCT) and as pendant groups for attachment of radiohalogens to tumour-seeking molecules. For this purpose, functionalized derivatives of nido-carborates that can be conjugated to biomolecules should be synthesized and evaluated. In this study, racemic 1, 7-(3′-ammoniopropyl)-7,8-dicarba-nido-undecaborate(-1) (acronym ANC) was obtained by degradation of the corresponding aminopropyl-o-carborane, which was synthesized in three steps from 1-tert-butyldimethylsilyl-2-(3-bromopropyl)-o-carborane, with sodium hydroxide in absolute ethanol. The racemate 1 was radioiodinated (¹²⁵I) using the Chloramine-T method. Radio-TLC results showed that radiolabelling with ¹²⁵I was achieved in a yield greater than 95%.

Two F-18-labeled analogs of vorozole ([F-18]FVOZ and [F-18]FVOO) have been developed as potential tools for the in vivo characterization of aromatase. The pharmacologicalproperties of these radioligands were evaluated using in vitro binding and in vivo distribution studies in the rat and primate. Saturation binding studies using rat ovary gave K-D and B-max values of 0.21 +/- 0.1 nM and 210 +/- 20 fmol/mg, respectively, for [F-18]FVOZ, and 7.6 +/- 1nMand 293 +/- 12fmol/mg, respectively, for [F-18]FVOO. Organ distribution studies in rats showed the highest accumulation in the adrenal glands, with standardized uptake values (SUVs) of 15 to 20, followed by ovaries and liver with SUVs of approximately 5. Ex vivo and in vitro autoradiography of the rat brain showed specific binding of both [F-18]FVOZ and [F-18]FVOO mainly in the amygdala. Positron emission tomography (PET) studies were performed in the Rhesus monkey, and these showed displaceable binding in the amygdala and the hypothalamus preoptic area. The PET images were also analyzed using masked volume-wise principal component analysis. These studies suggest that [F-18]FVOZ might be a suitable tracer for the study of aromatase in vitro and in vivo, and could be an alternative to [C-11]vorozole in human PET studies.

Primary aldosteronism (PA) is the leading secondary cause of hypertension. Determining whether one (unilateral) or both (bilateral) adrenal glands are the source of PA in a patient remains challenging, and yet it is a critical step in the decision whether to recommend potentially curative surgery (adrenalectomy) or lifelong medical therapy (typically requiring multiple drugs). Recently, we have developed a fluorine-18 radiopharmaceutical [(18) F]CETO to permit greater access to PA molecular imaging. Herein, we report an automated synthesis of this radiotracer. To manufacture the radiopharmaceutical routinely for clinical PET studies, we implemented an automated radiosynthesis method on a Synthra RNplus (c) synthesiser for which Cl-tosyletomidate was used as the precursor for radiolabelling via nucleophilic [(18) F]fluorination. [(18) F]CETO was produced with 35 +/- 1% (n = 7), decay corrected and 25 +/- 4% (n = 7) non-decay corrected radiochemical yield with molar activities ranging from 150 to 400 GBq/mu mol. The GMP compliant manufacturing process produces a sterile formulated [(18) F]CETO injectable solution for human use as demonstrated by the results of quality control. Automation of the radiosynthesis of [(18) F]CETO should facilitate uptake by other adrenal centres and increase access to molecular imaging in PA.

As part of our ongoing investigation into the imaging of angiogenic processes, a small library of eight vascular endothelial growth factor receptor-2 (VEGFR-2)/platelet-derived growth factor receptor beta dual inhibitors based on the N-phenyl-N'-4-(4-quinolyloxy)-phenyl-urea was labelled with C-11 (beta(+), t(1/2) = 20.4 min) in the urea carbonyl position via rhodium-mediated carbonylative cross-coupling of an aryl azide and different anilines. The decay-corrected radiochemical yields of the isolated products were in the range of 38-81% calculated from [C-11]carbon monoxide. Starting with 10.7+/-0.5 GBq of [C-11]carbon monoxide, 1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-3-(4-fluoro-phenyl)-[C-11]-urea (2.1 GBq) was isolated after total reaction time of 45 min with a specific activity of 92+/-4 GBq mu mol(-1).

Clinical findings using [C-11]methyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate ([C-11]MTO, 1) show high uptake in lesions of adrenocortical origin, including adenomas, but low uptake in lesions of non-adrenocortical origin. In this paper the synthesis and preclinical evaluation of two new C-11-labelled analogues of MTO, [C-11]methyl 1-[(1R)-1-(4-chlorophenyl)ethyl]-1H-imidazole-5-carboxylate ([C-11]CLM, 2) and [C-11]methyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate ([C-11]BRM, 3), using frozen-section autoradiography, organ distribution and a metabolic study are presented.

In the article, the strategy and synthesis of some endogenous compounds labeled mainly with 11C are presented. There are some examples illustrating how endogenous labeled compounds in connection with positron emission tomography have unique properties to describe various biological processes, and a few examples of the use of tracers labeled with 13N and 15O are also discussed. Labeled endogenous compounds may be an important asset to describe the conditions and the status of biological systems and might therefore be a key for the future search of individualized medicine.

In this review the recent progress in the development of suitable precursors for ¹¹C-labelling is discussed. Especially the last few years' advancement of the use of [¹¹C] carbon monoxide as a versatile and useful precursor in labelling chemistry is presented. The development is set in perspective of its potential in applying molecular imaging tools in drug and tracer development.The possibility of exploring small tracer libraries utilizing the microdosing concept is explored.

A method for the preparation of [3'-3H]-4-(2'-chloro-6'- hydroxyphenyl)-2-thioxo-3,4-dihydro-1H-indeno[1,2-d]pyrimidin-5 (2H)-one (1), a TRPA1 inhibitor, was developed for the evaluation of imaging properties of a class of TRPA1 inhibitors. 1 was prepared via tritiation of a protected benzaldehyde followed by a tetrachlorosilane catalyzed multicomponent one-step fusion and was obtained at a specific activity of 0.9 TBq/mmol. A 3H-NMR spectrum on 13.5MBq at 75 μM was recorded.

The use of kinetic isotope effects (KIEs) for the short-lived radionuclides ¹¹C and ¹⁸F in the study of reaction mechanisms is described using some examples. Leaving group fluorine KIEs (k ¹⁸/k¹⁹) have been utilized to determine the rate-limiting step for nucleophilic aromatic substitution reactions (S_NAr). The fluorine KIE was also used to probe the effect of changing solvent and nucleophile steric hindrance on rate-limiting step. The mechanism for a base promoted elimination reaction was determined to be stepwise (E1cB) by a multiple KIE study including the leaving group fluorine KIE. The transition state structures for aliphatic nucleophilic substitution reactions (S_N2) have been investigated by multiple KIE studies for cases where the substrate substitution, leaving group or solvent has been varied. Carbon KIEs for labelled α-carbon atom in the substrate are large, k¹¹/k¹⁴ = 1.189-1.220. For labelled nucleophile cyanide ion. k¹¹/k ¹⁴ = 0.99951-1.0119.

The radiosynthesis and GMP validation of [¹¹ C]AMT for human use are described. Three consecutive batches were produced giving 940-3790 MBq (4%-17% RCY, decay corrected, based on [¹¹ C]CO₂ ) of the tracer. The molar activity at the end of synthesis was 19 to 35 GBq/μmol, the radiochemical purity was ≥98%, and the enantiomeric purity was >99%. While the synthesis method was automated using a new generation of synthesis equipment, tracer production system developed in house, the method should be readily applicable to other synthesis platforms with minor modifications.

Synthetic routes for the synthesis of [¹⁴C] sarin and related nerve agents are described. Triethyl phosphite and [¹⁴C] methyl iodide are reacted in the Michaelis-Arbusov reaction to produce diethyl methyl phosphonate which is converted to methylphosphonic acid by hydrolysis. After chlorination and subsequent fluorination the final product is formed by reaction with the appropriate alcohol.