Development Of Positron Emission Tomography Tracers Research Articles

Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[11C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2.

Metabotropic glutamate 2 receptors (mGlu2) are involved in the pathogenesis of several CNS disorders and neurodegenerative diseases. Pharmacological modulation of this target represents a potential disease-modifying approach for the treatment of substance abuse, depression, schizophrenia, and dementias. While quantification of mGlu2 receptors in the living brain by positron emission tomography (PET) would help us better understand signaling pathways relevant to these conditions, few successful examples have been demonstrated to image mGlu2 in vivo, and a suitable PET tracer is yet to be identified. Herein we report the design and synthesis of a radiolabeled negative allosteric modulator (NAM) for mGlu2 PET tracer development based on a quinoline 2-carboxamide scaffold. The most promising candidate, 7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[11C]methoxyphenyl) quinoline-2-carboxamide ([11C]QCA) was prepared in 13% radiochemical yield (non-decay-corrected at the end of synthesis) with >99% radiochemical purity and >74 GBq/μmol (2 Ci/μmol) specific activity. While the tracer showed limited brain uptake (0.3 SUV), probably attributable to effects on PgP/Bcrp efflux pump, in vitro autoradiography studies demonstrated heterogeneous brain distribution and specific binding. Thus, [11C]QCA is a chemical probe that provides the basis for the development of a new generation mGlu2 PET tracers.

Label-free assay for the assessment of nonspecific binding of positron emission tomography tracer candidates

Positron emission tomography (PET) is a valuable non-invasive technique for the visualization of drug tissue distribution and receptor occupancy at the target site in living animals and men. Many potential PET tracers, however, fail due to an unfavorably high non-specific binding (NSB) to non-target proteins and phospholipid membranes which compromises the sensitivity of PET. Hence, there is a high demand to assess the extent of NSB as early as possible in the PET tracer development process, preferentially before ligands are radiolabeled and elaborate imaging studies are performed. The purpose of this study was to establish a novel Lipid Membrane Binding Assay (LIMBA) for assessing the tendency of potential tracers to bind non-specifically to brain tissue. The assay works with unlabeled compounds and allows the medium-throughput measurement of brain tissue/water distribution coefficients, logDbrain (pH7.4), at minimal expense of animal tissue. To validate LIMBA, logDbrain (pH7.4) values were measured and compared with NSB estimates derived from in vivo PET studies in human brain (n=10 tracers, literature data), and in vitro autoradiography studies in rat and mouse brain slices (n=30 tritiated radioligands). Good agreement between logDbrain (pH7.4) and the volume of distribution in brain of non-specifically bound tracer in PET was achieved, pertaining to compounds classified as non-substrates of P-glycoprotein (R2≥0.88). The ability of LIMBA for the prediction of NSB was further supported by the strong correlation between logDbrain (pH7.4) and NSB in brain autoradiography (R2≥0.76), whereas octanol/water distribution coefficients, logDoct (pH7.4) were less predictive. In conclusion, LIMBA provides a fast and reliable tool for identifying compounds with unfavorably high NSB in brain tissue. The data may be used in conjunction with other parameters like target affinity, density and membrane permeability for the selection of most promising compounds to be further investigated in vivo as potential novel PET tracers.

(11) C]Carbon monoxide in labeling chemistry and positron emission tomography tracer development: scope and limitations.

[(11) C]Carbon monoxide is an attractive precursor for labeling carbonyl position in a wide range of organic compounds. The use of [(11) C]carbon monoxide in transition metal-mediated coupling reactions has been explored by several groups during the last 15 years, and an impressive number of the synthesis of [carbonyl-(11) C]compounds have been published to date. The application of radical-mediated [(11) C]carbonylation has also been explored in some extent. However, the main limitations to apply this potential precursor in (11) C-labeling chemistry are low concentration, poor solubility in commonly used organic solvents, and low reactivity. A couple of technical solutions such as high-pressure reactor system, microfluidic system, and different approaches to confine [(11) C]CO to the reaction media at ambient pressure have been developed over the years. Although considerable advances in [(11) C]carbon monoxide chemistry have been reported in recent years, its application in positron emission tomography tracer development is still an area of work in progress. This review summarizes all contributions to the area of radiolabeling using [(11) C]carbon monoxide published between 1995 and 2014 and discusses the scope and limitations of this method in clinical positron emission tomography tracer development.

Development of carbon-11 labelled PET tracers-radiochemical and technological challenges in a historic perspective.

The development of positron emission tomography (PET) from being an exclusive and expensive research tool at major research institutes to a clinically useful modality found at most major hospitals around the world is largely dependent on radiochemistry and synthesis technology achievements by a few pioneer researchers starting their PET careers 40 to 50 years ago. Especially, the introduction of [(11) C]methyl iodide resulted in a quantum jump in the history of PET tracer development enabling the smooth labelling of a multitude of useful tracers. A more recent and still challenging methodological improvement is transition metal mediated (11) C-carbonylations, having a large synthetic potential that has, however, not yet been realized in the clinical setting. This mini-review focuses on the history of carbon-11 radiochemistry and related technology developments and the role this played in PET tracer developments, especially emphasizing radiolabelling of endogenous compounds. A few examples will be presented of how the use of radiolabelled endogenous substances have provided fundamental information of in vivo biochemistry using the concept of position-specific labelling in different positions in the same molecule.

Optimization of Pentadentate Bispidines as Bifunctional Chelators for64Cu Positron Emission Tomography (PET)

Pentadentate bispidine ligands (3,7-diazabicyclo[3.3.1]nonanes) are optimized for maximum complex stability and facile functionalization with respect to their coupling to biological vector molecules and/or fluorescence markers for PET (positron emission tomography) and multimodal imaging (i.e., PET and optical imaging). The pentadentate ligand with two tertiary amine donors, two p-methoxy substituted pyridines, and one unsubsituted pyridine group is shown to best fulfill important conditions for PET applications, i.e., fast complexation with Cu(II) and high in vivo stability, and this was predicted from the solution chemistry, in particular the Cu(II/I) redox potentials. Also, solvent partition experiments to model the lipophilicity of the Cu(II) complexes indicate that the bis p-methoxy substituted ligand leads to cationic complexes with an appreciable lipophilicity. This is supported by the biodistribution experiments that show that the complex with the p-methoxy substituted ligand is excreted very quickly and primarily via the renal route and therefore is ideally suited for the development of PET tracers with ligands of this type coupled to biomolecules.

RGD‐based PET tracers for imaging receptor integrin αvβ3 expression

Positron emission tomography (PET) imaging of receptor integrin αv β3 expression may play a key role in the early detection of cancer and cardiovascular diseases, monitoring disease progression, evaluating therapeutic response, and aiding anti-angiogenic drugs discovery and development. The last decade has seen the development of new PET tracers for in vivo imaging of integrin αv β3 expression along with advances in PET chemistry. In this review, we will focus on the radiochemistry development of PET tracers based on arginine-glycine-aspartic acid (RGD) peptide, present an overview of general strategies for preparing RGD-based PET tracers, and review the recent advances in preparations of (18) F-labeled, (64) Cu-labeled, and (68) Ga-labeled RGD tracers, RGD-based PET multivalent probes, and RGD-based PET multimodality probes for imaging receptor integrin αv β3 expression.

Radiolabelling with short‐lived PET (positron emission tomography) isotopes using microfluidic reactors

AbstractThis mini‐review covers the issues concerning the application of microfluidics towards radiolabelling with short‐lived isotopes used for PET (positron emission tomography), and surveys the literature in this area. The application of microfluidic reactors to radiolabelling reactions is currently receiving a great deal of interest because of the potential advantages they have over conventional labelling systems. The volume and variety of radiolabelling reactions for PET is expected to grow markedly over the coming years due to increased demands for PET scanning. High demands and expectations for radiolabelled compounds will have to be met by exploiting new types of chemistry and technologies, such as microfluidics, to improve the production and development of PET tracers. Copyright © 2008 Society of Chemical Industry

18F fluoroethylations: different strategies for the rapid translation of 11C-methylated radiotracers

The translation of 11C-labeled compounds into their respective 18F-labeled derivatives is an important tool in the rapid development of positron emission tomography (PET) tracers. Thus, our aim was the development of a general method for the preparation of 18F-fluoroethylated compounds that (a) is applicable to a variety of precursors, (b) can be performed in a fully automated commercially available synthesizer and (c) enables this rapid translation of 11C-methylated tracers into their 18F-fluoroethylated analogs sharing the same precursor molecules. Ten methods for the preparation and purification of different 18F-fluoroethylating agents were compared. Subsequently, five 18F-labeled PET tracers were synthesized under fully automated conditions. Radiochemical yields ranged from 34.4% to 60.8%, and time consumption ranged from 20 to 55 min for all methods. Use of 1-bromo-2-[18F]fluoroethane and distillation evinced as the method of choice. We were able to develop a general method for the preparation of a variety of 18F-fluoroethylated molecules. The provided tool is solely based on commercially available resources and has the potential to simplify and accelerate innovative PET tracer development in the future.

PET tracer development - a tale of mice and men

PET scanning is an emerging technology for the clinical evaluation of many disease processes in man. The vast majority of clinical positron emission tomography (PET) studies are performed using a single tracer, fluorodeoxyglucose. Despite the excellent diagnostic performance of this tracer, it has recognised limitations. New tracers offer the potential to both address these limitations, and to establish new applications for PET. Small animal PET is a logical technique for validating new tracers relevant to human diseases. However, interspecies differences in the handling of chemicals may significantly influence the handling of novel tracers. This requires caution in extrapolating findings in animals to expectations of performance in man. Already there are several examples where biodistribution studies in mice would not have predicted the clinical utility of existing PET tracers. Nevertheless, application of a systematic approach to tracer development is likely to speed transition of new tracers from animals into man.