Abstract
PurposeSince the adenosine A3 receptor (A3R) is considered to be of high clinical importance in the diagnosis and treatment of ischaemic conditions (heart and brain), glaucoma, asthma, arthritis, cancer and inflammation, a suitable and selective A3R PET tracer such as [18F]FE@SUPPY would be of high clinical value for clinicians as well as patients. A3R was discovered in the late 1990s, but there is still little known regarding its distribution in the CNS and periphery. Hence, in autoradiographic experiments the distribution of A3R in human brain and rat tissues was investigated and the specific binding of the A3R antagonist FE@SUPPY and MRS1523 compared. Immunohistochemical staining (IHC) experiments were also performed to validate the autoradiographic findings.MethodsFor autoradiographic competition experiments human post-mortem brain and rat tissues were incubated with [125I]AB-MECA and highly selective compounds to block the other adenosine receptor subtypes. Additionally, IHC was performed with an A3 antibody.ResultsSpecific A3R binding of MRS1523 and FE@SUPPY was found in all rat peripheral tissues examined with the highest amounts in the spleen (44.0 % and 46.4 %), lung (44.5 % and 45.0 %), heart (39.9 % and 42.9 %) and testes (27.4 % and 29.5 %, respectively). Low amounts of A3R were found in rat brain tissues (5.9 % and 5.6 %, respectively) and human brain tissues (thalamus 8.0 % and 9.1 %, putamen 7.8 % and 8.2 %, cerebellum 6.0 % and 7.8 %, hippocampus 5.7 % and 5.6 %, caudate nucleus 4.9 % and 6.4 %, cortex 4.9 % and 6.3 %, respectively). The outcome of the A3 antibody staining experiments complemented the results of the autoradiographic experiments.ConclusionThe presence of A3R protein was verified in central and peripheral tissues by autoradiography and IHC. The specificity and selectivity of FE@SUPPY was confirmed by direct comparison with MRS1523, providing further evidence that [18F]FE@SUPPY may be a suitable A3 PET tracer for use in humans.
Highlights
Adenosine exerts its various effects via four different Gprotein-coupled receptors: adenosine A1, adenosine A2A, adenosine A2B and adenosine A3 receptor (A1R, A2AR, A2BR and A3R, respectively)
Specific A3R binding of MRS1523 and FE@SUPPY was found in all rat peripheral tissues examined with the highest amounts in the spleen (44.0 % and 46.4 %), lung (44.5 % and 45.0 %), heart (39.9 % and 42.9 %) and testes (27.4 % and 29.5 %, respectively)
Low amounts of A3R were found in rat brain tissues (5.9 % and 5.6 %, respectively) and human brain tissues
Summary
Adenosine exerts its various effects via four different Gprotein-coupled receptors: adenosine A1, adenosine A2A, adenosine A2B and adenosine A3 receptor (A1R, A2AR, A2BR and A3R, respectively). The most recently discovered receptor in the adenosine receptor family is the A3 subtype. Benarroch has stated that the A3R is present in the hippocampus and cerebellum in medium or low abundance [2]. Others have found A3R in the thalamus and hypothalamus [3], an in the rat in the hippocampus [4, 5] and cortex [6]. Medium density has been reported in the liver and bladder, and low densities have been found in the heart, aorta, stomach, jejunum, proximal colon, kidney and eyes [7]. The presence of A3R has been confirmed in smooth muscle tissue of blood vessels and the aorta of rats [8]
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