The potential of carbon‐11 and fluorine‐18 chemistry: illustration through the development of positron emission tomography radioligands targeting the translocator protein 18 kDa

Abstract

The TSPO (translocator protein), also known as the peripheral benzodiazepine receptor, is upregulated in the brain of subjects suffering from neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. Moreover, this overexpression has been proved to be linked to microglia activation making thus the TSPO a marker of choice of neuroinflammatory processes and therefore a potential target for the development of radioligands for positron emission tomography imaging. The discovery of selective TSPO ligands and their labelling with the short-lived positron-emitter isotopes carbon-11 and fluorine-18 emerged in the mid-1980s with the preparation of the 3-isoquinolinecarboxamide [(11) C]PK11195. To date, an impressive number of promising compounds-[(11) C]PK11195-challengers-have been developed; some radioligands-for example, [(11) C]PBR28, [(11) C]DPA-713, [(18) F]FEDAA1106 and [(18) F]DPA-714-are currently used in clinical trials. As illustrated in this review, the methodologies applied for the preparation of these compounds remain mainly [(11) C]methylations using [(11) C]MeI or [(11) C]MeOTf and SN 2-type nucleophilic aliphatic [(18) F]fluorinations-two processes illustrating the state-of-the-art arsenal of reactions that involves these two short-lived radioisotopes-but alternative processes, such as [(11) C]carbonylations using [(11) C]CO and [(11) C]COCl2 as well as SN Ar-type nucleophilic [(18) F]fluorinations, have also been reported and as such, reviewed herein.

A Facile Radiolabeling of [18F]FDPA via Spirocyclic Iodonium Ylides: Preliminary PET Imaging Studies in Preclinical Models of Neuroinflammation

“…A TSPO-specific PET ligand is utilized as a translational imaging tool to evaluate the status of neuroinflammation (activated microglia) in living brain. 8, 9 [ 11 C]PK11195 was the first extensively evaluated PET ligand for TSPO; however, low signal-to-noise ratio and high non-specific binding hampered its further advance. 10 Intensive efforts therefore have been made to improve PET imaging quality and quantitative process with the development of a rich library of TSPO PET ligands.…”

Alternative approaches for PET radiotracer development in Alzheimer's disease: imaging beyond plaque

“…The recognized limitations of ( R )‐[ 11 C]‐PK11195 as a TSPO imaging tool are attributed to complex multi‐state binding models, high non‐specific binding, and high binding to plasma proteins; issues which fueled the development of many other radiotracers. Well‐established 11 C‐based and 18 F‐based radiotracers targeting TSPO (for reviews see), include [ 18 F]‐PBR111, 11 C‐radiolabeled and 18 F‐radiolabeled versions of PBR06 and PBR28, as well as [ 18 F]‐FEPPA, provide excellent tools for interrogating the spatial and temporal dynamics of microglial cell activation during AD development, progression, and treatment (Figure ).…”

[Carboxyl‐11C]Labelling of Four High‐Affinity cPLA2α Inhibitors and Their Evaluation as Radioligands in Mice by Positron Emission Tomography

“…[7] Thus, cPLA2a is potentially an attractive biomarker for quantifying disease and for designing drugs to treat neuroinflammation and oxidative stress associated disorders. The developmento fP ET radioligandst hat specifically target cPLA2a could helpt oe valuate and understand the role of this enzyme in the pathophysiology of human diseases and would be complementary to efforts to develop PET radioligands for other neuroinflammation targets, [8] such as translocator 18 kDa protein (TSPO), [8][9][10] COXs, [8,11,12] P2X purinoceptor 7( P2X 7 ), [8,13] and cannabinoid receptor subtype 2( CB 2 ). [8,14] So far,o nly [ 11 C]arachidonic acid has been used with PET for preclinical and clinical imaging [15,16] to explore brain cPLA2 activity.…”