Automated radiosynthesis of [F]DPA-714 on a commercially available IBA Synthera®.

The goal of this work was to develop a reliable method to produce the well-validated microglial activation PET tracer, [F]DPA-714, routinely for clinical and preclinical research using an IBA Synthera®. Optimization of literature methods included reduced precursor mass and use of TBA HCO as the phase transfer agent in place of Kryptofix® 222 in a 65-min synthesis with an average activity yield of 24.6 ± 3.

Positron Emission Tomography Detects Expression of Disialoganglioside GD2 in Mouse Models of Primary and Metastatic Osteosarcoma.

The cell membrane glycolipid GD2 is expressed by multiple solid tumors, including 88% of osteosarcomas and 98% of neuroblastomas. However, osteosarcomas are highly heterogeneous, with many tumors exhibiting GD2 expression on <50% of the individual cells, while some tumors are essentially GD2-negative. Anti-GD2 immunotherapy is the current standard of care for high-risk neuroblastoma, but its application to recurrent osteosarcomas, for which no effective therapies exist, has been extremely limited.

Improved, one-pot synthesis of 6-[ F]fluorodopamine and quality control testing for use in patients with neuroblastoma.

6-[ F]Fluorodopamine ([ F]F-DA) is taken into cells via the norepinephrine transporter (NET). Recent [ F]F-DA positron emission tomography-computed tomography (PET-CT) imaging of adult neuroendocrine tumors shows a dramatic improvement in sensitivity over the standard-of-care, meta-iodobenzylguanidine (MIBG) single-photon emission computed tomography (SPECT)-CT. A new precursor (ALPdopamine™) allows no-carrier-added synthesis resulting in high-molar activity [ F]F-DA.

Clinical Applications of Small-molecule PET Radiotracers: Current Progress and Future Outlook.

Radiotracers, or radiopharmaceuticals, are bioactive molecules tagged with a radionuclide used for diagnostic imaging or radiotherapy and, when a positron-emitting radionuclide is chosen, the radiotracers are used for PET imaging. The development of novel PET radiotracers in many ways parallels the development of new pharmaceuticals, and small molecules dominate research and development pipelines in both disciplines. The 4 decades since the introduction of [F]FDG have seen the development of many small molecule PET radiotracers.

Thermolysis and radiofluorination of diaryliodonium salts derived from anilines.

Aniline-derived diaryliodonium salts were synthesized and functionalized in good to excellent yields by judicious utilization of electron-withdrawing protecting groups. This simple approach opens another route to radiolabeling amino arenes in relatively complex molecules, such as flutemetamol.

Efficient automated syntheses of high specific activity 6-[18F]fluorodopamine using a diaryliodonium salt precursor.

6-[(18)F]Fluorodopamine (6-[(18) F]F-DA) is a positron emission tomography radiopharmaceutical used to image sympathetic cardiac innervation and neuroendocrine tumors. Imaging with 6-[(18)F]F-DA is constrained, in part, by the bioactivity and neurotoxicity of 6-[(19)F]fluorodopamine. Furthermore, routine access to this radiotracer is limited by the inherent difficulty of incorporation of [(18)F]fluoride into electron-rich aromatic substrates.

A practical, automated synthesis of meta-[(18)F]fluorobenzylguanidine for clinical use.

Many neuroendocrine tumors, such as neuroblastoma (NB), arise from neural crest cells of the sympathetic nervous system. This nerve-like phenotype has been exploited for functional imaging using radioactive probes originally designed for neuronal and adrenal medullary applications. NB imaging with meta-[(123)I]iodobenzylguanidine ([(123)I]MIBG) is limited by the emissions of (123)I, which lead to poor image resolution and challenges in quantification of its accumulation in tumors.

Evaluation of the biodistribution of 11C-methionine in children and young adults.

Unlabelled: The purpose of this study was to evaluate the biodistribution of (11)C-labeled methionine in non-tumor-involved organs in pediatric patients studied for malignant diseases.

Methods: Ninety-three children and young adults with known or suspected malignancies underwent (11)C-methionine PET and CT scans. Imaging began 5-15 min after injection of 740 MBq (20 mCi) per 1.

64Cu-p-NH2-Bn-DOTA-hu14.18K322A, a PET radiotracer targeting neuroblastoma and melanoma.

Unlabelled: The hu14.18K322A variant of the GD2-targeting antibody hu14.18 has been shown to elicit a level of antibody-dependent cell-mediated cytotoxicity toward human neuroblastoma cells similar to that of the parent antibody.

Molecular imaging of cancer with radiolabeled peptides and PET.

Radiolabeled peptides hold promise for diagnosis and therapy of cancer as well as for early monitoring of therapy outcomes, patient stratification, etc. This manuscript focuses on the development of peptides labeled with 18F, 64Cu, 68Ga and other positron-emitting radionuclides for PET imaging. The major techniques for radionuclide incorporation are briefly discussed.

A novel technology for the imaging of acidic prostate tumors by positron emission tomography.

Solid tumors often develop an acidic environment due to the Warburg effect. The effectiveness of diagnosis and therapy may therefore be enhanced by the design and use of pH-sensitive agents that target acidic tumors. Recently, a novel technology was introduced to target acidic tumors using pH low insertion peptide (pHLIP), a peptide that inserts across cell membranes as an alpha-helix when the extracellular pH (pH(e)) is acidic.

In vitro and in vivo evaluation of bifunctional bisthiosemicarbazone 64Cu-complexes for the positron emission tomography imaging of hypoxia.

The copper(II) bisthiosemicarbazonato complex, copper-diacetyl-bis(N4-methylthiosemicarbazonate) (Cu-ATSM), has been used clinically as a positron emission tomography (PET) tracer for the delineation of hypoxia. Six novel, asymmetric bis(thiosemicarbazones) derived from diacetyl-2-(4-N-methyl-3-thiosemicarbazone)-3-(4-N-amino-3-thiosemicarbazone) (H2ATSM/A), one of which contained a nitroimidazole functionality, were radiolabeled with 64Cu (t1/2=12.7 h, beta+=19.

Examining the relationship between Cu-ATSM hypoxia selectivity and fatty acid synthase expression in human prostate cancer cell lines.

Introduction: Positron emission tomography (PET) imaging with copper (II)-diacetyl-bis(N4-Methylthiosemicarbazone)(Cu-ATSM) for delineating hypoxia has provided valuable clinical information, but investigations in animal models of prostate cancer have shown some inconsistencies. As a defense mechanism in prostate cancer cells, the fatty acid synthesis pathway harnesses its oxidizing power for improving the redox balance despite conditions of extreme hypoxia, potentially altering Cu-ATSM hypoxia selectivity.

Methods: Human prostate tumor-cultured cell lines (PC-3, 22Rv1, LNCaP and LAPC-4), were treated with a fatty acid synthase (FAS) inhibitor (C75, 100 microM) under anoxia.

1-11C-acetate as a PET radiopharmaceutical for imaging fatty acid synthase expression in prostate cancer.

Unlabelled: Although it is accepted that the metabolic fate of 1-(11)C-acetate is different in tumors than in myocardial tissue because of different clearance patterns, the exact pathway has not been fully elucidated. For decades, fatty acid synthesis has been quantified in vitro by the incubation of cells with (14)C-acetate. Fatty acid synthase (FAS) has been found to be overexpressed in prostate carcinomas, as well as other cancers, and it is possible that imaging with 1-(11)C-acetate could be a marker for its expression.

Gallium-68-labeled DOTA-rhenium-cyclized alpha-melanocyte-stimulating hormone analog for imaging of malignant melanoma.

Introduction: Diagnosis of malignant melanoma is critical, since a patient's prognosis is poor. Previous studies have shown that 64Cu- and 86Y-DOTA-ReCCMSH(Arg11) have the potential for early detection of malignant melanoma by exploiting the sensitivity and high resolution of positron emission tomography (PET). This encouraged us to investigate DOTA-ReCCMSH(Arg11) labeled with another beta+-emitting radionuclide, 68Ga.

Cu-ATSM: a radiopharmaceutical for the PET imaging of hypoxia.

Copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone), Cu-ATSM, labeled with a positron emitting isotope of copper ((60)Cu, (61)Cu, (62)Cu or (64)Cu) has been shown, in vitro and in vivo, to be selective for hypoxic tissue. In silico studies have explored the mechanism of its hypoxia selectivity, and clinical studies with this agent have shown non-invasive imaging data that is predictive of a cancer patients' response to conventional therapy. This Perspective discusses the evolution of Cu-ATSM, how its selectivity can be improved upon, and where this metal-ligand platform could be taken in the future.

Preparation, biodistribution, and small animal PET of 45Ti-transferrin.

Unlabelled: Investigation of 45Ti-transferrin was pursued to provide insight into the mechanism of action of titanocene dichloride, a chemotherapeutic agent currently in clinical trials.

Methods: Plasma protein-binding studies of processed 45Ti were performed by solubilizing the 45Ti residue in 0.05N HCl, of which 1.

Production, processing and small animal PET imaging of titanium-45.

Introduction: Titanium-45 was prepared as a tool for elucidation of the mechanism of action of titanium anticancer drugs in vivo using microPET imaging.

Methods: Titanium-45 was produced by the 45Sc(p,n)45Ti nuclear reaction using 14.5 MeV protons.