Evaluation of [4‐O‐methyl‐¹¹C]KW‐6002 as a potential PET ligand for mapping central adenosine A_2A receptors in rats

Abstract

KW-6002, a xanthine-based adenosine A(2A) antagonist, was labelled with the positron emitter carbon-11 by O-methylation of its precursor, KF23325, using [(11)C]iodomethane and was evaluated in rats as a putative in vivo radioligand for positron emission tomography (PET). Following intravenous injection of [(11)C]KW-6002, radioactivity was measured in blood, plasma, peripheral tissues, and in discrete brain tissues over a 2-h time period commensurate with PET scanning. In brain, [(11)C]KW-6002 showed highest retention in striata, with evidence of saturable binding, and lowest retention in frontal cortex (a tissue low in adenosine A(2A) receptors). PET scanning with [(11)C]KW-6002 demonstrated a specific signal in the striata which could be described using compartmental modelling. Specific binding was, however, also detected in extrastriatal regions, including brain areas reported to have low adenosine A(2A) receptor density. Blocking studies with the A(1) selective antagonist KF15372 and the non xanthine-type A(2A) antagonist ZM 241385 failed to elucidate the nature of this binding. Thus, although [(11)C]KW-6002 shows some potential for development as a PET ligand for quantifying striatal adenosine A(2A) receptor function, its in vivo selectivity requires further investigation.

Kinetic Modeling, Test–Retest, and Dosimetry of 123I-MNI-420 in Humans

“…Arterial blood samples (1 mL) were obtained from the ulnar or radial arteries at selected time points after radiotracer injection ( 3,6,10,30,80,120,150, and 200 min after injection were also collected for metabolite analysis. All samples were collected into ethylenediaminetetraacetic acid-coated tubes and radioactivity in whole blood and plasma assessed using a well-type g-counter with a 22-to 190-keV window (2480; Perkin Elmer Wallac).…”

“…The pharmacology and brain distribution of A 1 and A 2A have been extensively investigated. A 1 is widely distributed in the human brain, including the hippocampus, cortex, thalamus, globus pallidus, and cerebellum (3,5); conversely, A 2A is more selectively distributed in the striatum, nucleus accumbens, and olfactory tubercule. Lower levels of A 2A are present in the hippocampus and cortex (1)(2)(3)(4)(5).…”

“…Thephysi ologic action of extracellular adenosine, a neuromodulator synthesized via conversion of extracellular adenine nucleotides, occurs by interaction with 4 different G-protein-coupled receptors: A 1 , A 2A , A 2B , and A 3 (1)(2)(3)(4). The pharmacology and brain distribution of A 1 and A 2A have been extensively investigated.…”

“…A variety of PET radiotracers have been developed over the years for imaging A 2A in the brain (1)(2)(3)(4)(10)(11), and recently our group has reported the development of a new SPECT radiotracer, 123 I-MNI-420, to image brain A 2A . Preliminary evaluation of 123 I-MNI-420 in nonhuman primates showed binding in brain regions with an expected high density of A 2A , and tracer uptake was blocked by the selective A 2A antagonist preladenant in a dose-dependent manner (12), stimulating the development of this radiotracer for human use.…”

Characterization in Humans of 18F-MNI-444, a PET Radiotracer for Brain Adenosine 2A Receptors

“…The development of selective A 2A radiotracers would provide the opportunity to study and understand multiple neuropsychiatric and neurodegenerative disorders and could also accelerate and aid drug-discovery programs targeting A 2A . In this context, several compounds have been proposed for in vivo imaging of A 2A in the brain (6,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”