Position paper to facilitate patient access to radiopharmaceuticals: considerations for a suitable pharmaceutical regulatory framework.

Background: Nuclear medicine has made enormous progress in the past decades. However, there are still significant inequalities in patient access among different countries, which could be mitigated by improving access to and availability of radiopharmaceuticals.

Main Body: This paper summarises major considerations for a suitable pharmaceutical regulatory framework to facilitate patient access to radiopharmaceuticals.

Automated Synthesis of F-BCPP-EF {2--Butyl-4-Chloro-5-{6-[2-(2[F]fluoroethoxy)-Ethoxy]-Pyridin-3-ylmethoxy}-2-Pyridazin-3-One for Imaging of Mitochondrial Complex 1 in Parkinson's Disease.

Mitochondrial complex I (MC-I) is an essential component of brain bioenergetics and can be quantified and studied using positron emission tomography (PET). A specific high affinity F radiotracer for MC-I enables monitoring of neurodegenerative disease progression and pathology PET imaging. To facilitate clinical research studies tracking MC-I activity in Parkinson's disease and other neurodegenerative diseases, a fully automated synthesis of the recently described 2-butyl-4-chloro-5-{6-[2-(2[F]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2-pyridazin-3-one ([F] BCPP-EF, ) was developed.

Synthesis of Ga-radiopharmaceuticals using both generator-derived and cyclotron-produced Ga as exemplified by [Ga]Ga-PSMA-11 for prostate cancer PET imaging.

[Ga]Ga-PSMA-11, a urea-based peptidomimetic, is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that targets the prostate-specific membrane antigen (PSMA). The recent Food and Drug Administration approval of [Ga]Ga-PSMA-11 for PET imaging of patients with prostate cancer, expected follow-up approval of companion radiotherapeutics (e.g.

An updated synthesis of N '-([ C]methyl)naltrindole for positron emission tomography imaging of the delta opioid receptor.

A new method for the synthesis of the highly selective delta opioid receptor (DOR) antagonist radiotracer N '-([ C]methyl)naltrindole ([ C]MeNTI) is described. The original synthesis required hydrogenation of a benzyl protecting group after C-labeling, which is challenging in modern radiochemistry laboratories that tend to be heavily automated and operate according to current good manufacturing practice. To address this challenge, we describe development of a novel MeNTI precursor bearing a methoxymethyl acetal (MOM) protecting group, which is easily removed with HCl, and employ it in an updated synthesis of [ C]MeNTI.

Cyclotron-based production of Ga, [Ga]GaCl, and [Ga]Ga-PSMA-11 from a liquid target.

Purpose: To optimize the direct production of Ga on a cyclotron, via the Zn(p,n)Ga reaction using a liquid cyclotron target. We Investigated the yield of cyclotron-produced Ga, extraction of [Ga]GaCl and subsequent [Ga]Ga-PSMA-11 labeling using an automated synthesis module.

Methods: Irradiations of a 1.

Use of 55 PET radiotracers under approval of a Radioactive Drug Research Committee (RDRC).

Background: In the US, EU and elsewhere, basic clinical research studies with positron emission tomography (PET) radiotracers that are generally recognized as safe and effective (GRASE) can often be conducted under institutional approval. For example, in the United States, such research is conducted under the oversight of a Radioactive Drug Research Committee (RDRC) as long as certain requirements are met. Firstly, the research must be for basic science and cannot be intended for immediate therapeutic or diagnostic purposes, or to determine the safety and effectiveness of the PET radiotracer.

Development and implementation of ISAR, a new synthesis platform for radiopharmaceutical production.

Background: PET radiopharmaceutical development and the implementation of a production method on a synthesis module is a complex and time-intensive task since new synthesis methods must be adapted to the confines of the synthesis platform in use. Commonly utilized single fluid bus architectures put multiple constraints on synthesis planning and execution, while conventional microfluidic solutions are limited by compatibility at the macro-to-micro interface. In this work we introduce the ISAR synthesis platform and custom-tailored fluid paths leveraging up to 70 individually addressable valves on a chip-based consumable.

Futureproofing [F]Fludeoxyglucose manufacture at an Academic Medical Center.

Background: We recently upgraded our [F]fludeoxyglucose (FDG) production capabilities with the goal of futureproofing our FDG clinical supply, expanding the number of batches of FDG we can manufacture each day, and improving patient throughput in our nuclear medicine clinic. In this paper we report upgrade of the synthesis modules to the GE FASTLab 2 platform (Phase 1) and cyclotron updates (Phase 2) from both practical and regulatory perspectives. We summarize our experience manufacturing FDG on the FASTLab 2 module with a high-yielding self-shielded niobium (Nb) fluorine-18 target.

An updated synthesis of [ C]carfentanil for positron emission tomography (PET) imaging of the μ-opioid receptor.

[ C]Carfentanil ([ C]CFN) is a selective radiotracer for in vivo positron emission tomography imaging studies of the μ-opioid system that, in our laboratories, is synthesized by methylation of the corresponding carboxylate precursor with [ C]MeOTf, and purified using a C2 solid-phase extraction cartridge. Changes in the commercial availability of common C2 cartridges have necessitated future proofing the synthesis of [ C]CFN to maintain reliable delivery of the radiotracer for clinical imaging studies. An updated synthesis of [ C]CFN is reported that replaces a now obsolete purification cartridge with a new commercially available version and also substitutes the organic solvents used in traditional production methods with ethanol.

Preclinical Evaluation of C-Sarcosine as a Substrate of Proton-Coupled Amino Acid Transporters and First Human Application in Prostate Cancer.

Sarcosine is a known substrate of proton-coupled amino acid transporters (PATs), which are overexpressed in selected tissues and solid tumors. Sarcosine, an -methyl derivative of the amino acid glycine and a metabolic product of choline, plays an important role for prostate cancer aggressiveness and progression. C-radiolabeled sarcosine was tested as a new PET imaging probe in comparison with C-choline in 2 prostate cancer tumor xenograft models (DU-145 and PC-3).

An updated radiosynthesis of [F]AV1451 for tau PET imaging.

Background: [F]AV1451 is a commonly used radiotracer for imaging tau deposits in Alzheimer's disease (AD) and related non-AD tauopathies. Existing radiosyntheses of [F]AV1451 require complex purifications to provide doses suitable for use in clinical imaging studies. To address this issue, we have modified the synthesis of [F]AV1451 to use only 0.

Investigation of Proposed Activity of Clarithromycin at GABAA Receptors Using [(11)C]Flumazenil PET.

Clarithromycin is a potential treatment for hypersomnia acting through proposed negative allosteric modulation of GABAA receptors. We were interested whether this therapeutic benefit might extend to Parkinson's disease (PD) patients because GABAergic neurotransmission is implicated in postural control. Prior to initiating clinical studies in PD patients, we wished to better understand clarithromycin's mechanism of action.

Green approaches to late-stage fluorination: radiosyntheses of (18)F-labelled radiopharmaceuticals in ethanol and water.

Green strategies for late-stage fluorination with (18)F, in which ethanol and water are the only solvents used throughout the entire radiolabeling process (azeotropic drying, nucleophilic fluorination, purification and formulation), have been developed and applied to the radiosyntheses of a range of radiopharmaceuticals commonly employed in clinical PET imaging.

High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer's disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection.

Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities.

(-)-[(18) F]Flubatine: evaluation in rhesus monkeys and a report of the first fully automated radiosynthesis validated for clinical use.

(-)-[(18) F]Flubatine was selected for clinical imaging of α4 β2 nicotinic acetylcholine receptors because of its high affinity and appropriate kinetic profile. A fully automated synthesis of (-)-[(18) F]flubatine as a sterile isotonic solution suitable for clinical use is reported, as well as the first evaluation in nonhuman primates (rhesus macaques). (-)-[(18) F]Flubatine was prepared by fluorination of the Boc-protected trimethylammonium iodide precursor with [(18) F]fluoride in an automated synthesis module.

Novel fluorine-18 PET radiotracers based on flumazenil for GABAA imaging in the brain.

Introduction: Two 7-fluoroimidazobenzodiazepines (AH114726 and GEH120348), analogs of flumazenil, were labeled with fluorine-18 and evaluated as alternative radioligands for in vivo imaging of the GABAA/benzodiazepine receptor by comparing them to [(11)C]flumazenil in rhesus monkey.

Methods: Radiotracers were prepared from the corresponding nitro-precursors in an automated synthesis module, and primate imaging studies were conducted on a Concorde MicroPET P4 scanner. The brain was imaged for 60 (12 × 5 min frames) or 90 min (18 × 5 min frames), and data was reconstructed using the 3D MAP algorithm.

A fully-automated one-pot synthesis of [18F]fluoromethylcholine with reduced dimethylaminoethanol contamination via [18F]fluoromethyl tosylate.

Introduction: A novel one-pot method for preparing [(18)F]fluoromethylcholine ([(18)F]FCH) via in situ generation of [(18)F]fluoromethyl tosylate ([(18)F]FCH2OTs), and subsequent [(18)F]fluoromethylation of dimethylaminoethanol (DMAE), has been developed.

Methods: [(18)F]FCH was prepared using a GE TRACERlab FXFN, although the method should be readily adaptable to any other fluorine-(18) synthesis module. Initially ditosylmethane was fluorinated to generate [(18)F]FCH2OTs.

Highlighting the Versatility of the Tracerlab Synthesis Modules. Part 1: Fully Automated Production of [F]Labelled Radiopharmaceuticals using a Tracerlab FX(FN).

The field of radiochemistry is moving towards exclusive use of automated synthesis modules for production of clinical radiopharmaceutical doses. Such a move comes with many advantages, but also presents radiochemists with the challenge of re-configuring synthesis modules for production of radiopharmaceuticals that require non-conventional radiochemistry whilst maintaining full automation. This review showcases the versatility of the Tracerlab FX(FN) synthesis module by presenting simple, fully automated methods for producing [(18)F]FLT, [(18)F]FAZA, [(18)F]MPPF, [(18)F]FEOBV, [(18)F]sodium fluoride, [(18)F]fluorocholine and [(18)F]SFB.

Automated production of [11C]acetate and [11C]palmitate using a modified GE Tracerlab FX(C-Pro).

As researchers explore new applications for positron emission tomography radiopharmaceuticals, the demand for effective and readily available radiopharmaceuticals continues to increase. The syntheses of two such radiopharmaceuticals, [(11)C]acetate and [(11)C]palmitate, can be automated on the GE Tracerlab FX(C-Pro) by utilizing Grignard reactions. Radiochemical purities of the [(11)C]acetate and the [(11)C]palmitate products were high (>98% and >99.

Fully automated preparation of [11C]choline and [18F]fluoromethylcholine using TracerLab synthesis modules and facilitated quality control using analytical HPLC.

Modifications of a GE TracerLab FX(C-Pro), which can be implemented for solid-phase [(11)C]methylation are described. The simplified procedure for synthesis of [(11)C]choline uses a single Sep-Pak CM-Light cation-exchange cartridge for both solid-supported reaction and purification. Compared with the commonly used two Sep-Pak method, the low back-pressure of this Sep-Pak enables efficient and reliable production of [(11)C]choline using a TracerLab FX(C-Pro) without requirement for any gas pressure adjustment.

An automated method for preparation of [(18)F]sodium fluoride for injection, USP to address the technetium-99m isotope shortage.

The worldwide shortage of technetium-99m has created an immediate and urgent need for access to [(18)F]sodium fluoride for PET imaging of bone metastasis. In order to facilitate global availability of [(18)F]sodium fluoride for diagnostic nuclear medicine imaging procedures, a straightforward method for rapid production of [(18)F]sodium fluoride for injection, USP, using a modified GE Tracerlab FX-FN is presented.

Positron emission tomography imaging of (2R,3R)-5-[(18)F]fluoroethoxybenzovesamicol in rat and monkey brain: a radioligand for the vesicular acetylcholine transporter.

Introduction: The regional brain distribution of (2R,3R)-5-[(18)F]fluoroethoxy-benzovesamicol ((-)-[(18)F]FEOBV), a radioligand for the vesicular acetylcholine transporter (VAChT), was examined in vivo in mice, rats and rhesus monkeys.

Methods: Regional brain distributions of (-)-[(18)F]FEOBV in mice were determined using ex vivo dissection. MicroPET imaging was used to determine the regional brain pharmacokinetics of the radioligand in rat and rhesus monkey brains.

Studies into radiolytic decomposition of fluorine-18 labeled radiopharmaceuticals for positron emission tomography.

Radiolytic decomposition of high specific concentration radiopharmaceuticals is an undesired side-effect that can hamper development of novel PET tracers. This was particularly evident in a series of carbon-11 and fluorine-18 labeled mono- and dimethyl-substituted aryl amines, where rapid decomposition was observed in isolation and formulation steps. We tested a number of additives that inhibit radiolysis and can be safely added to the synthesis procedures (purification and isolation) and reformulation steps to provide suitable clinical formulations.

Pharmacokinetics of [(18)F]fluoroalkyl derivatives of dihydrotetrabenazine in rat and monkey brain.

The specific binding and regional brain pharmacokinetics of new fluorine-18 ([(18)F])-labeled radioligands for the vesicular monoamine transporter (VMAT2) were examined in the rat and primate brain. In the rat, 9-[(18)F]fluoropropyl-(+/-)-9-O-desmethyldihydrotetrabenazine ([(18)F]FP-(+/-)-DTBZ) showed better specific binding in the striatum than either (+)-[(11)C]dihydrotetrabenazine ((+)-[(11)C]DTBZ) or 9-[(18)F]fluoroethyl-(+/-)-9-O-desmethyldihydrotetrabenazine ([(18)F]FE-(+/-)-DTBZ). Using microPET, the regional brain pharmacokinetics of [(18)F]FE-(+/-)-DTBZ, [(18)F]FP-(+/-)-DTBZ and (+)-[(11)C]DTBZ were examined in the same monkey brain.