Background

[PubMed]

Adenosine is an endogenous nucleoside that modulates a number of physiologic functions in the central nervous system (CNS) and in peripheral organs such as the heart, kidney, and muscle (1, 2). The effect is mediated by two major subtypes of receptors (A₁ and A_2A receptors) and two minor subtypes (A_2B and A₃). In the CNS, A₁ receptors are present both pre- and postsynaptically in the hippocampus, cerebral cortex, thalamus, striatum, and cerebellum. A_2A receptors are highly concentrated and co-localized with dopamine D₁ and D₂ receptors in the striatum, nucleus accumbens, and olfactory tubercle. A_2A receptors are also present in low amounts in the hippocampus and cortex. A_2B receptors are widely distributed, but the density is higher in the gastrointestinal tract. A₃ receptors are also widely distributed but with higher density in the testis. A₁ and A₃ receptors mediate inhibition of adenylyl cyclase, whereas A_2A and A_2B receptors mediate stimulation. Changes in the adenosine receptor functions are implicated in epilepsy, ischemic cerebral stroke, movement disorders, sleep disorders, and psychiatric disorders (3-5).

A_2A receptors have been studied in vivo by positron emission tomography (PET) using [7-methyl-¹¹C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([¹¹C]TMSX), a methylxanthine analog of KF17387 with selective A_2A antagonistic activity (6). TMSX showed better selectivity for A_2A over A₁ receptors than KF17387 and had little affinity in various neuroreceptor-binding assays (7). [¹¹C]TMSX is being developed as a PET agent for the non-invasive study of A_2A receptors in the human brain and heart.

Synthesis

[PubMed]

In the report by Ishiwata et al. (8), [¹¹C]TMSX was synthesized by alkylation of the 7-desmethyl precursor ((E)-8-(3,4,5-trimethoxystyryl)-1,3-dimethylxanthine) with [¹¹C]methyl iodide. Purification by high-performance liquid chromatography (HPLC) provided a decay-corrected radiochemical yield of 25-46%, radiochemical purity >99%, and specific activity of 10-72 GBq/μmol (0.27-1.95 Ci/μmol) in 20-25 min.

Kawamura et al. (9) described the synthesis of [¹¹C]TMSX from the desmethyl precursor with [¹¹C]methyl triflate in the presence of Cs₂CO₃. This procedure provided improved radiochemical yield (decay-corrected) of 55.3 ± 5.2% based on [¹¹C]methyl triflate. No time of synthesis or specific activity was reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

In the study by Ishiwata et al. (8), the K_i values of TMSX and KF17837 were 5.9 and 1.0 nM, respectively, for the A_2A receptors and 1,600 and 62 nM for the A₁ receptors. Hence, TMSX showed better selectivity for A_2A over A₁ receptors than KF17387. In vitro autoradiography (ARG) studies of brain sections with [¹¹C]TMSX showed high binding in the caudate putamen, nucleus accumbens, and olfactory tubercle with a striatum/cortex ratio of 8.4 ± 2.2. TMSX (20 μM) blocked 91% of [¹¹C]TMSX binding in the striatum but only 54% in the cortex. Saturation binding experiments of [¹¹C]TMSX in the rat striatum and cortex gave estimated K_d values of 9.8 and 16.4 nM, with B_max values of 170 and 33 fmol/mm³ tissue, respectively (7).

Animal Studies

Human Studies

[PubMed]

Ishiwata et al. (13) reported on PET myocardial imaging in 1 healthy volunteer after injection of 590 MBq (16 mCi) of [¹¹C]TMSX. The levels in the left ventricular wall, left ventricular anterior wall, and interventricular septum increased during the first 3 min after injection and then decreased gradually. In contrast, the radioactivity in the lung decreased rapidly. The fraction of unchanged [¹¹C]TMSX in blood samples, as determined by HPLC, was 97, 94, and 95% at 10, 30, and 60 min, respectively. In other studies of 2 subjects, infusion of theophylline (3.3 mg/kg) reduced the distribution volumes (DVs; baseline values, 3.62-3.73) of the three heart regions by 18-22% as determined by Logan analysis (14). The DV (1.57) of the brachii muscle was reduced by 10%. The A_2A receptors have also been preliminarily visualized in human brain with relatively high DVs in the caudate (1.72) and putamen (1.72), followed by the thalamus (1.64), cerebellum (1.52), brainstem (1.42), and cerebral cortex (1.26) (15). Mishina et al. (16) was used a two-tissue, three-compartment model to estimate the distribution of A_2A receptors in the brain (n = 5) using metabolite-correction arterial input function. The binding potential (BP) was the largest in the anterior (1.25) and posterior putamen (1.20), followed by la the head of caudate nucleus (1.05), thalamus (1.03), and frontal cortex lobe (0.46). On the other hand, Naganawa et al. (17) showed that Logan plot estimated BPs matching those derived from compartment analysis (n = 5) with or without arterial blood sampling. Without the metabolite correction, the estimate of BP underestimated the true value by only 5%. Internal dosimetry data for [¹¹C]TMSX in humans are not available in the literature.

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