[F]Tosyl fluoride as a versatile [F]fluoride source for the preparation of F-labeled radiopharmaceuticals.

Positron emission tomography (PET) is an in vivo imaging technology that utilizes positron-emitting radioisotope-labeled compounds as PET radiotracers that are commonly used in clinic and in various research areas, including oncology, cardiology, and neurology. Fluorine-18 is the most widely used PET-radionuclide and commonly produced by proton bombardment of O-enriched water in a cyclotron. The [F]fluoride thus obtained generally requires processing by azeotropic drying in order to completely remove HO before it can be used for nucleophilic radiofluorination.

First-in-Humans Evaluation of Safety and Dosimetry of Cu-LLP2A for PET Imaging.

There remains an unmet need for molecularly targeted imaging agents for multiple myeloma (MM). The integrin very late antigen 4 (VLA4), is differentially expressed in malignant MM cells and in pathogenic inflammatory microenvironmental cells. [Cu]Cu-CB-TE1A1P-LLP2A (Cu-LLP2A) is a VLA4-targeted, high-affinity radiopharmaceutical with promising utility for managing patients diagnosed with MM.

Investigating Tau and Amyloid Tracer Skull Binding in Studies of Alzheimer Disease.

Off-target binding of [F]flortaucipir (FTP) can complicate quantitative PET analyses. An underdiscussed off-target region is the skull. Here, we characterize how often FTP skull binding occurs, its influence on estimates of Alzheimer disease pathology, its potential drivers, and whether skull uptake is a stable feature across time and tracers.

The Development of F Fluorthanatrace: A PET Radiotracer for Imaging Poly (ADP-Ribose) Polymerase-1.

Fluorine 18 (F) fluorthanatrace (F-FTT) is a PET radiotracer for imaging poly (adenosine diphosphate-ribose) polymerase-1 (PARP-1), an important target for a class of drugs known as PARP inhibitors, or PARPi. This article describes the stepwise development of this radiotracer from its design and preclinical evaluation to the first-in-human imaging studies and the initial validation of F-FTT as an imaging-based biomarker for measuring PARP-1 expression levels in patients with breast and ovarian cancer. A detailed discussion on the preparation and submission of an exploratory investigational new drug application to the Food and Drug Administration is also provided.

Proceedings: PET Drugs-A Workshop on Inspections Management and Regulatory Considerations.

Recent advances in the development of new molecular imaging agents for PET have led to the approval of several new molecular entities for PET imaging by the U.S. Food and Drug Administration (FDA) within the last 10 y.

Determination of molar activity of [F]fluoride by HPLC via sulfonyl derivatization.

The molar activity of [F]fluoride was determined by HPLC of sulfonyl fluorides, which have high UV absorbance and are formed exclusively from sulfonyl chlorides and [F]fluoride in aqueous solution. The measurable limit of sulfonyl fluorides is as low as 0.1 ppm, allowing measurements up to the theoretical molar activity of [F]fluoride.

Global Issues of Radiopharmaceutical Access and Availability: A Nuclear Medicine Global Initiative Project.

The Nuclear Medicine Global Initiative was formed in 2012 by 13 international organizations to promote human health by advancing the field of nuclear medicine and molecular imaging by supporting the practice and application of nuclear medicine. The first project focused on standardization of administered activities in pediatric nuclear medicine and resulted in 2 articles. For its second project the Nuclear Medicine Global Initiative chose to explore issues impacting on access and availability of radiopharmaceuticals around the world.

US and EU radiopharmaceutical diagnostic and therapeutic nonclinical study requirements for clinical trials authorizations and marketing authorizations.

New regulatory guidance documents from the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recently been finalized or are in draft format outlining new pathways for preclinical safety testing. The US and the European Union appear to be moving in a similar direction focussing and refining preclinical safety data requirements for both radiodiagnostics and radiotherapeutics. We here summarize these recent documents from both the US and European perspective.

Harmonization of United States, European Union and Canadian First-in-Human Regulatory Requirements for Radiopharmaceuticals-Is This Possible?

In recent years, several new radiotracers and radionuclide therapies have been developed. There is a renaissance in nuclear medicine and molecular imaging today, for example, in terms of the ability to image and treat neuroendocrine and prostate malignancies. In order to be able to bring a new drug product from bench to bedside and assist patients, while also ensuring patient safety, stringent regulations must be met.

Future cancer research priorities in the USA: a Lancet Oncology Commission.

We are in the midst of a technological revolution that is providing new insights into human biology and cancer. In this era of big data, we are amassing large amounts of information that is transforming how we approach cancer treatment and prevention. Enactment of the Cancer Moonshot within the 21st Century Cures Act in the USA arrived at a propitious moment in the advancement of knowledge, providing nearly US$2 billion of funding for cancer research and precision medicine.

The role of exploratory investigational new drugs for translating radiopharmaceuticals into first-in-human studies.

The Food and Drug Administration has provided a mechanism to reduce time and resources expended on new pharmaceuticals, including radiopharmaceuticals, in order to identify the most promising agents for further development. The exploratory investigational new drug guidance describes early phase 1 exploratory approaches involving microdoses of potential drug candidates that are consistent with regulatory requirements while maintaining the safety needed for human subjects, allowing sponsors to move ahead more quickly with the development of new agents.

Regulatory Requirements for PET Drug Production.

The Food and Drug Administration (FDA) issued the final rule for title 21 of Code of Federal Regulations part 212 regarding the regulations on current good manufacturing practice for PET drugs. The regulations are intended to ensure that PET drugs meet the safety and quality assurance requirements of the Federal Food, Drug, and Cosmetic Act. The new regulation became effective December 12, 2011, but the FDA used regulatory discretion to allow new drug applications and abbreviated new drug applications to be filed until June 12, 2012, without interruption of the existing PET drug production for human use.

Optimization of the preparation of fluorine-18-labeled steroid receptor ligands 16alpha-[18F]fluoroestradiol (FES), [18F]fluoro furanyl norprogesterone (FFNP), and 16beta-[18F]fluoro-5alpha-dihydrotestosterone (FDHT) as radiopharmaceuticals.

Fluorine-18-labeled steroid receptor tracers, 16α-[(18)F]fluoroestradiol (FES), [(18)F]fluoro furanyl norprogesterone (FFNP), and 16β-[(18)F]fluoro-5α-dihydrotestosterone (FDHT), are important imaging tools for studies of breast and prostate cancers using positron emission tomography (PET). The automated production of these ligands with high specific activity (SA) as radiopharmaceuticals requires modification and optimization of the currently reported methods. [(18)F]FES with high SA was synthesized in over 60% radiochemical yield (RCY) at the end of synthesis (EOS) using a small amount of precursor (1) (as low as 0.

Diversification in the Supply Chain of (99)Mo Ensures a Future for (99m)Tc.

The uncertain availability of (99m)Tc has become a concern for nuclear medicine departments across the globe. An issue for the United States is that currently it is dependent on a supply of (99m)Tc (from (99)Mo) that is derived solely by production outside the United States. Since the United States uses half the world's (99)Mo production, the U.

Radiopharmacy: regulations and legislations in relation to human applications.

Radiopharmaceuticals (RPs) have attracted tremendous interest as molecular imaging tracers in diagnostic applications and as biomarkers in drug development, in particular using Positron Emission Tomography (PET). This article summarizes important legal documents and guidelines in relation to human application of PET-RPs that pose a major challenge in implementing the full potential of this technology, thereby differentiating the US from the European situation. Regulations are reviewed with respect to licensing, conducting clinical trials and RP production - including Good Manufacturing Practice (GMP) for radioactive compounds.