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.

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 behavior in healthy and diseased states.

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

Hydrogen [C]cyanide ([C]HCN) is a versatile C-labelling agent for the production of C-labelled compounds used for positron emission tomography (PET). However, the traditional method for [C]HCN production requires a dedicated infrastructure, limiting accessibility to [C]HCN. Herein, we report a simple and efficient [C]HCN production method that can be easily implemented in C production facilities.

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.

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 (C) 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 C (20.

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

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

A copper-catalysed radiosynthesis of carbon-11 radiolabelled carboxylic acids was developed by reacting terminal alkynes and cyclotron-produced carbon-11 carbon dioxide ([ C]CO ) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

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.

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

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.

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

A novel carboxylation radiosynthesis methodology is described starting from cyclotron-produced [C]CO 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 [C]CO delivery with a trapping efficiency of 21-89%.

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

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 Aβ plaque formation. The development of a carbon-11 analog of FPS-ZM1 (N-benzyl-4-chloro-N-cyclohexylbenzamide, [C]FPS-ZM1), possessing nanomolar affinity for RAGE, may enable the imaging of RAGE for early AD detection. Herein we report an optimized [C]CO-to-[C]CO chemical conversion for the synthesis of [C]FPS-ZM1 and brain autoradiography.

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.

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.

Development of [F]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 ([C]MTO) is a positron emission tomography (PET) radiotracer able to selectively identify CYP11B1/2 expressing adrenocortical lesions of the adrenal gland.

High-yielding F 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 ([F]PF-06684511) after labeling with fluorine-18 (F), allowing its evaluation in non-human primates (NHP) as the first a brain-penetrant PET radiotracer for imaging BACE1 in vivo.

Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs.

Oxytocin (OT) is an exciting potential therapeutic agent, but it is highly sensitive to modification and suffers extensive degradation at elevated temperature and in vivo. Here we report studies towards OT analogs with favorable selectivity, affinity and potency towards the oxytocin receptor (OTR), in addition to improving stability of the peptide by bridging the disulfide region with substituted dibromo-xylene analogs. We found a sensitive structure-activity relationship in which meta-cyclized analogs (dOT) gave highest affinity (50 nM K), selectivity (34-fold), and agonist potency (34 nM EC, 87-fold selectivity) towards OTR.