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Selective adenosine antagonists for mapping central nervous system adenosine receptors with positron emission tomography: Carbon‐11 labeled KF15372 (A 1 ) and KF17837 (A 2A )
Author(s) -
Suzuki Fumio,
Ishiwata Kiichi
Publication year - 1998
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199811/12)45:3/4<312::aid-ddr30>3.0.co;2-9
Subject(s) - adenosine , adenosine a2a receptor , adenosine receptor , receptor , chemistry , medicine , ex vivo , adenosine a1 receptor , in vivo , pharmacology , endocrinology , striatum , biology , biochemistry , dopamine , agonist , in vitro , microbiology and biotechnology
During the past decade, many neuroreceptors in humans and other animals have been visualized in vivo by positron emission tomography (PET) with corresponding radioligands. Because adenosine is a neuromodulator, PET assessment of the adenosine receptor system offers us an opportunity to understand the neurotransmission system in general. The 11 C‐labeled selective adenosine A 1 antagonists KF15372 ([3‐propyl‐ 11 C]8‐dicyclopropylmethyl‐1, 3‐dipropylxanthine) and a 11 C‐methyl derivative [ 11 C]KF26345 and selective adenosine A 2A antagonist KF17837 ([7‐methyl‐ 11 C]‐( E )‐8‐(3,4‐dimethoxystyryl)‐1,3‐dipropyl‐7‐methylxanthine) and KF18446 ([7‐methyl‐ 11 C]‐( E )‐8‐3,4,5‐trimethoxystyryl)‐1,3,7‐trimethylxanthine were evaluated in vivo as potential PET ligands for mapping CNS adenosine A 1 and A 2A receptors. [ 11 C]KF15372 and [ 11 C]KF263345: Tissue sampling and ex vivo autoradiography (ARG) suggest that the regional brain distribution of [ 11 C]KF15372 and [ 11 C]KF26345 is consistent with that of the adenosine A 1 receptors found in mice and rats. The brain uptake was competitively reduced by the coadministration of A 1 , but not by A 2A antagonists. The ex vivo ARG on the rat model with unilateral orbital enucleation, visualized the A 1 receptor deficiency in the presynaptic terminals. PET with these ligands visualized the A 1 receptors in the monkey and cat brain. [ 11 C]KF17837 and [ 11 C]KF18446: In mice, a high uptake of two ligands was found in the striatum in which A 2A receptors are highly enriched. The uptake was decreased by coinjection of carrier KF17837 or other xanthine‐type A 2A antagonists, but not by four nonxanthine‐type A 2A antagonists or A 1 antagonists. In the rat brain, ex vivo ARG showed the A 2A receptor‐specific uptake of two ligands in the striatum. In PET studies of the monkey and cat brain, the A 2A receptors in the striatum was clearly visualized. These pieces of evidence demonstrated the potential of 11 C‐labeled selective xanthine‐type adenosine antagonists as PET ligands for mapping CNS adenosine A 1 and A 2A receptors. Drug Dev. Res. 45:312–323, 1998. © 1998 Wiley‐Liss, Inc.