PET Tracers for Mapping Adenosine Receptors as Probes for Diagnosis of CNS Disorders

Abstract

Adenosine is an endogenous modulator of several physiological functions in the central nervous system (CNS). The effect is mediated by a receptor family that consists of at least four subtypes: A 1 , A 2A , A 2B and A 3 receptors. The adenosine receptors play a role in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, epilepsy and schizophrenia. Knowledge on adenosine receptor densities and status are important for understanding the mechanisms underlying the pathogenesis of diseases and for developing new therapeutics. Positron emission tomography (PET) offers a non-invasive tool to investigate these features in vivo, provided that suitable radiopharmaceuticals are available. As a consequence of the development of xanthine-type adenosine receptor antagonists with high affinity and high selectivity, several PET ligands labeled with carbon-11 (half-life of 20.4 min) and fluorine-18 (half-life of 109.8 min) have been proposed for mapping the adenosine A 1 and A 2A receptors (A 1 R and A 2A R, respectively) and the adenosine uptake site in the CNS since 1995. Later non-xanthine-type antagonists for A 2A R were radiolabeled. So far two tracers for A 1 R, [ 18 F]CPFPX and [ 11 C]MPDX, and a tracer for A 2A R, [ 11 C]TMSX (also called [ 11 C]KF18446), have been applied to humans. For the other subtypes and the adenosine uptake site no suitable radioligands have been developed yet. This paper gives an overview of the current status on PET tracers for mapping adenosine receptors and the development of new compounds that may lead to new PET tracers.

The Adenosinergic System

“…Xanthine derivatives, such as [ 11 C]KF15372, [ 11 C]MPDX, [ 11 C]EPDX and [ 18 F]CPFPX, were synthesized as candidates for in vivo imaging of A 1 in brain (Bauer et al 2003a,b;Fukumitsu et al 2003;Ishiwata et al1995Ishiwata et al , 2007. Xanthine derivatives, such as [ 11 C]KF15372, [ 11 C]MPDX, [ 11 C]EPDX and [ 18 F]CPFPX, were synthesized as candidates for in vivo imaging of A 1 in brain (Bauer et al 2003a,b;Fukumitsu et al 2003;Ishiwata et al1995Ishiwata et al , 2007.…”

“…[ 11 C]FR194921, a highly selective non-xanthine derived antagonist, has also been proposed as a suitable radiotracer for in vivo imaging of A 1 in brain Matsuya et al 2005). Within these PET radiotracers, only [ 18 F]CPFPX and [ 11 C]MPDX have been used in human clinical studies (Elmenhorst et al 2012;Fukumitsu et al 2003;Ishiwata et al 2007;Meyer et al 2006a, b). Within these PET radiotracers, only [ 18 F]CPFPX and [ 11 C]MPDX have been used in human clinical studies (Elmenhorst et al 2012;Fukumitsu et al 2003;Ishiwata et al 2007;Meyer et al 2006a, b).…”

Adenosine A1 Receptors in the Central Nervous System: Their Functions in Health and Disease, and Possible Elucidation by PET Imaging

“…PET may therefore be applied to measure regional AR densities in the living human brain and the dose-dependent occupancy of cerebral AR by therapeutic drugs. A comprehensive overview of PET tracers for the different AR subtypes has been presented in some recent reviews [43,44].…”

Efficient Radiosynthesis of 2-[18F]Fluoroadenosine: A New Route to 2-[18F]Fluoropurine Nucleosides

“…22 A recent review highlighted the interest of PET imaging agents for mapping of adenosine receptors in CNS. 23 The adenosine receptors also mediate a wide range of responses in the heart, 24 and the use of labeled adenosine with β þ -emitting atoms for PET studies was envisaged as an attractive candidate for local blood flow measurement. 15 A preliminary study was to evaluate [ 18 F]-6 in male Sprague-Dawley rats.…”