Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

BACKGROUND: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. MAIN BODY: This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. CONCLUSION: Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field in many aspects.

Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon-11 Labeled Endogenous and Natural Exogenous Compounds.

The presence of positron emission tomography (PET) centers at most major hospitals worldwide, along with the improvement of PET scanner sensitivity and the introduction of total body PET systems, has increased the interest in the PET tracer development using the short-lived radionuclides carbon-11. In the last few decades, methodological improvements and fully automated modules have allowed the development of carbon-11 tracers for clinical use. Radiolabeling natural compounds with carbon-11 by substituting one of the backbone carbons with the radionuclide has provided important information on the biochemistry of the authentic compounds and increased the understanding of their in vivo behavior in healthy and diseased states. The number of endogenous and natural compounds essential for human life is staggering, ranging from simple alcohols to vitamins and peptides. This review collates all the carbon-11 radiolabeled endogenous and natural exogenous compounds synthesised to date, including essential information on their radiochemistry methodologies and preclinical and clinical studies in healthy subjects.

Rapid 'on-column' preparation of hydrogen [11C]cyanide from [11C]methyl iodide via [11C]formaldehyde.

Hydrogen [11C]cyanide ([11C]HCN) is a versatile 11C-labelling agent for the production of 11C-labelled compounds used for positron emission tomography (PET). However, the traditional method for [11C]HCN production requires a dedicated infrastructure, limiting accessibility to [11C]HCN. Herein, we report a simple and efficient [11C]HCN production method that can be easily implemented in 11C production facilities. The immediate production of [11C]HCN was achieved by passing gaseous [11C]methyl iodide ([11C]CH3I) through a small two-layered reaction column. The first layer contained an N-oxide and a sulfoxide for conversion of [11C]CH3I to [11C]formaldehyde ([11C]CH2O). The [11C]CH2O produced was subsequently converted to [11C]HCN in a second layer containing hydroxylamine-O-sulfonic acid. The yield of [11C]HCN produced by the current method was comparable to that of [11C]HCN produced by the traditional method. The use of oxymatrine and diphenyl sulfoxide for [11C]CH2O production prevented deterioration of the molar activity of [11C]HCN. Using this method, compounds labelled with [11C]HCN are now made easily accessible for PET synthesis applications using readily available labware, without the need for the 'traditional' dedicated cyanide synthesis infrastructure.

Production of copper-64 using a hospital cyclotron: targetry, purification and quality analysis.

OBJECTIVES: To construct and evaluate a 64Cu production system that minimises the amount of costly 64Ni, radionuclidic impurities and nonradioactive metal contamination and maximises radiochemical and radionuclidic purity and molar activity; and to report analytical and quality control methods that can be used within typical PET radiochemistry production facilities to measure metal ion concentrations and radiometal molar activities. METHODS: Low volume was ensured by dissolving the irradiated nickel in a low volume of hydrochloric acid (<1 mL) using the concave gold target backing as a reaction vessel in a custom-built target holder. Removal of contaminating 55Co and nonradioactive trace metals was ensured by adding an intermediate hydrochloric acid concentration step during the conventional ion-exchange elution process. The radionuclidic purity of the product was determined by half-life measurements, gamma spectroscopy and ion radiochromatography. Trace metal contamination and molar activity were determined by ion chromatography. RESULTS AND CONCLUSIONS: On a small scale, suitable for preclinical research, the process produced typically 3.2 GBq 64Cu in 2 mL solution from 9.4 ± 2.1 mg nickel-64 electroplated onto a gold target backing. The product had high molar activity (121.5 GBq/µmol), was free of trace metal contamination detectable by ion chromatography and has been used for many preclinical and clinical PET imaging applications.

Silicon compounds in carbon-11 radiochemistry: present use and future perspectives.

Positron emission tomography (PET) is a powerful functional imaging technique that requires the use of positron emitting nuclides. Carbon-11 (11C) radionuclide has several advantages related to the ubiquity of carbon atoms in biomolecules and the conservation of pharmacological properties of the molecule upon isotopic exchange of carbon-12 with carbon-11. However, due to the short half-life of 11C (20.4 minutes) and the low scale with which it is produced by the cyclotron (sub-nanomolar concentrations), quick, robust and chemospecific radiolabelling strategies are required to minimise activity loss during incorporation of the 11C nuclide into the final product. To address some of the constraints of working with 11C, the use of silicon-based chemistry for 11C-labelling was proposed as a rapid and effective route for radiopharmaceutical production due to the broad applicability and high efficiency showed in organic chemistry. In the past years several organic chemistry methodologies have been successfully applied to 11C-chemistry. In this short review, we examine silicon-based 11C-chemistry, with a particular emphasis on the radiotracers that have been successfully produced and potential improvements to further expand the applicability of silicon in radiochemistry.

The Hantzsch reaction for nitrogen-13 PET: preparation of [13N]nifedipine and derivatives.

Nitrogen-13 is an attractive but under-used PET radionuclide for labelling molecules of biological and pharmaceutical interest, complementing other PET radionuclides. Its short half-life (t1/2 = 9.97 min) imposes synthetic challenges, but we have expanded the hitherto limited pool of 13N labelling strategies and tracers by adapting the multicomponent Hantzsch condensation reaction to prepare a library of 13N-labelled 1,4-dihydropyridines from [13N]ammonia, including the widely-used drug nifedipine. This represents a key advance in 13N PET radiochemistry, and will serve to underpin the renewed interest in clinical opportunities offered by short-lived PET tracers.

Carbon-11 carboxylation of terminal alkynes with [11 C]CO2.

A copper-catalysed radiosynthesis of carbon-11 radiolabelled carboxylic acids was developed by reacting terminal alkynes and cyclotron-produced carbon-11 carbon dioxide ([11 C]CO2 ) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). A small library of 11 C-labelled propiolic acid derivatives were obtained with a total synthesis time of 15 min from end of bombardment (EOB) with a (non-isolated) radiochemical yield ranging from 7% to 28%.

Rapid one-pot radiosynthesis of [carbonyl-11C]formamides from primary amines and [11C]CO2.

BACKGROUND: Formamides are common motifs of biologically-active compounds (e.g. formylated peptides) and are frequently employed as intermediates to yield a number of other functional groups. A rapid, simple and reliable route to [carbonyl-11C]formamides would enable access to this important class of compounds as in vivo PET imaging agents. RESULTS: A novel radiolabelling strategy for the synthesis of carbon-11 radiolabelled formamides ([11C]formamides) is presented. The reaction proceeded with the conversion of a primary amine to the corresponding [11C]isocyanate using cyclotron-produced [11C]CO2, a phosphazene base (2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine, BEMP) and phosphoryl chloride (POCl3). The [11C]isocyanate was subsequently reduced to [11C]formamide using sodium borohydride (NaBH4). [11C]Benzyl formamide was obtained with a radiochemical yield (RCY) of 80% in 15 min from end of cyclotron target bombardment and with an activity yield of 12%. This novel method was applied to the radiolabeling of aromatic and aliphatic formamides and the chemotactic amino acid [11C]formyl methionine (RCY = 48%). CONCLUSIONS: This study demonstrates the feasibility of 11C-formylation of primary amines with the primary synthon [11C]CO2. The reactivity is proportional to the nucleophilicity of the precursor amine. This novel method can be used for the production of biomolecules containing a radiolabelled formyl group.

Radionuclide Imaging for Neuroscience: Current Opinion and Future Directions.

This meeting report summarizes a Consultants Meeting that was held at International Atomic Energy Agency headquarters in Vienna to provide an update on radionuclide imaging for neuroscience applications.

Carbon-11 carboxylation of trialkoxysilane and trimethylsilane derivatives using [11C]CO2.

A novel carboxylation radiosynthesis methodology is described starting from cyclotron-produced [11C]CO2 and fluoride-activated silane derivatives. Six carbon-11 labelled carboxylic acids were obtained from their corresponding trimethylsilyl and trialkoxysilyl precursors in a one-pot labelling methodology. The radiochemical yields ranged from 19% to 93% within 12 minutes post [11C]CO2 delivery with a trapping efficiency of 21-89%.

Radiolabeling of [11C]FPS-ZM1, a receptor for advanced glycation end products-targeting positron emission tomography radiotracer, using a [11C]CO2-to-[11C]CO chemical conversion.

Aim: The receptor for advanced glycation end products (RAGE) is a viable target for early Alzheimer's disease (AD) diagnosis using positron emission tomography (PET) as RAGE overexpression precedes Aß plaque formation. The development of a carbon-11 analog of FPS-ZM1 (N-benzyl-4-chloro-N-cyclohexylbenzamide, [11C]FPS-ZM1), possessing nanomolar affinity for RAGE, may enable the imaging of RAGE for early AD detection. Methodology & results: Herein we report an optimized [11C]CO2-to-[11C]CO chemical conversion for the synthesis of [11C]FPS-ZM1 and in vitro brain autoradiography. The [11C]CO2-to-[11C]CO conversion via 11C-silanecarboxylate derivatives was achieved with a 57% yield within 30 s from end of [11C]CO2 delivery. [11C]FPS-ZM1 was obtained with a decay-corrected isolated radiochemical yield of 9.5%. Conclusion: [11C]FPS-ZM1 distribution in brain tissues of wild-type versus transgenic AD model mice showed no statistically significant difference and high nondisplaceable binding.

Guidelines for the content and format of PET brain data in publications and archives: A consensus paper.

It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis.

Chemical biology tools for probing transcytosis at the blood-brain barrier.

Absorptive- and receptor-mediated transcytosis (AMT/RMT) are widely studied strategies to deliver therapeutics across the blood-brain barrier (BBB). However, an improved understanding of the mechanism surrounding trafficking is required that could promote delivery. Accordingly, we designed a flexible platform that merged AMT and RMT motifs on a single scaffold to probe various parameters (ligand, affinity, valency, position) in a screening campaign. During this process we adapted an in vitro BBB model to reliably rank transcytosis of the vehicle library. Our results demonstrate heightened uptake and trafficking for the shuttles, with a structure-activity relationship for transcytosis emerging. Notably, due to their small size, the majority of shuttles demonstrated increased permeation compared to transferrin, with the highest performing shuttle affording a 4.9-fold increase. Consequently, we have identified novel peptide conjugates that have the capacity to act as promising brain shuttles.

Development of [18F]FAMTO: A novel fluorine-18 labelled positron emission tomography (PET) radiotracer for imaging CYP11B1 and CYP11B2 enzymes in adrenal glands.

INTRODUCTION: Primary aldosteronism accounts for 6-15% of hypertension cases, the single biggest contributor to global morbidity and mortality. Whilst ~50% of these patients have unilateral aldosterone-producing adenomas, only a minority of these have curative surgery as the current diagnosis of unilateral disease is poor. Carbon-11 radiolabelled metomidate ([11C]MTO) is a positron emission tomography (PET) radiotracer able to selectively identify CYP11B1/2 expressing adrenocortical lesions of the adrenal gland. However, the use of [11C]MTO is limited to PET centres equipped with on-site cyclotrons due to its short half-life of 20.4 min. Radiolabelling a fluorometomidate derivative with fluorine-18 (radioactive half life 109.8 min) in the para-aromatic position ([18F]FAMTO) has the potential to overcome this disadvantage and allow it to be transported to non-cyclotron-based imaging centres. METHODS: Two strategies for the one-step radio-synthesis of [18F]FAMTO were developed. [18F]FAMTO was obtained via radiofluorination via use of sulfonium salt (1) and boronic ester (2) precursors. [18F]FAMTO was evaluated in vitro by autoradiography of pig adrenal tissues and in vivo by determining its biodistribution in rodents. Rat plasma and urine were analysed to determine [18F]FAMTO metabolites. RESULTS: [18F]FAMTO is obtained from sulfonium salt (1) and boronic ester (2) precursors in 7% and 32% non-isolated radiochemical yield (RCY), respectively. Formulated [18F]FAMTO was obtained with >99% radiochemical and enantiomeric purity with a synthesis time of 140 min from the trapping of [18F]fluoride ion on an anion-exchange resin (QMA cartridge). In vitro autoradiography of [18F]FAMTO demonstrated exquisite specific binding in CYP11B-rich pig adrenal glands. In vivo [18F]FAMTO rapidly accumulates in adrenal glands. Liver uptake was about 34% of that in the adrenals and all other organs were <12% of the adrenal uptake at 60 min post-injection. Metabolite analysis showed 13% unchanged [18F]FAMTO in blood at 10 min post-administration and rapid urinary excretion. In vitro assays in human blood showed a free fraction of 37.5%. CONCLUSIONS: [18F]FAMTO, a new 18F-labelled analogue of metomidate, was successfully synthesised. In vitro and in vivo characterization demonstrated high selectivity towards aldosterone-producing enzymes (CYP11B1 and CYP11B2), supporting the potential of this radiotracer for human investigation.

High-yielding 18F radiosynthesis of a novel oxytocin receptor tracer, a probe for nose-to-brain oxytocin uptake in vivo.

A novel Al18F labelled peptide tracer for PET imaging of oxytocin receptor has been accessed through a high radiochemical yield approach. This tracer showed comparable affinity and higher selectivity and stability compared to oxytocin, and was used to demonstrate direct nose-to-brain uptake following intranasal administration, a common yet controversial delivery route for oxytocin-based therapeutics.

BACE1: Now We Can See You.

No in vivo imaging biomarker currently exists for BACE, a drug target for Alzheimer's disease (AD). A strategy aiming to find a novel brain-penetrant positron emission tomography (PET) radiotracer for BACE1 led to the discovery of a highly potent and selective aminothiazine inhibitor, PF-06684511. This scaffold has been now evaluated as BACE1 PET radiotracer ([18F]PF-06684511) after labeling with fluorine-18 (18F), allowing its evaluation in non-human primates (NHP) as the first a brain-penetrant PET radiotracer for imaging BACE1 in vivo.