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Technetium- and Rhenium-Labelled Fatty Acids as Model Compounds for Myocardial Metabolism Imaging
(2002)
In an attempt to develop new technetium-based radiopharmaceuticals for the non-invasive diagnosis of oxidative myocardial metabolism, rhenium model compounds according to the 3+1' mixed ligand approach as well as the organometallic tricarbonyl-design were synthesized. The geometrical impact of different chelates on the integrity of the fatty acid head structure was determined by single crystal X-ray analyses. To evaluate the diagnostic potential of the analogous Technetium-99m compounds, fatty acid complexes of the 3+1' mixed ligand type were prepared on n.c.a.-level and studied in the isolated constant-flow-perfused guinea pig heart model; compared to established [123I]Iodine-labelled fatty acid radiotracers, the tested Technetium-99m derivatives showed a specific, however significantly lower myocardial extraction rate.
Tc(III) and Re(III) complexes [M(NS3)(CNR)] (M = Re, 99mTc, NS3 = 2,2?,2?-nitrilotris(ethanethiol), CNR = functionalized isocyanide bearing a derivative of WAY 100635) have been synthesized and characterized. Re was used as Tc surrogate for chemical characterization and in vitro receptor-binding studies. For two representatives subnanomolar affinities for the 5-HT1A as well as for the alpha1-adrenergic receptor were reached. Biodistribution studies in rats of the 99mTc complexes showed brain uptakes between 0.3 and 0.5% ID/organ (5 min p.i.). In vitro autoradiography of one 99mTc representative in sections of post mortem human brain indicate its accumulation in 5-HT1A receptor-rich brain regions. However, addition of the specific 5-HT1A receptor agonist 8-OH-DPAT as well as the alpha1-adrenoceptor antagonist prazosin could not substantially block this tracer accumulation. A preliminary SPET study in a monkey showed negligible brain uptake.
This paper reports the synthesis, biological evaluation, in vitro and ex vivo autoradiography of the first Tc-99m ligand with subnanomolar affinity for the 5-HT1A receptor and a remarkably high affinity for the alpha1-adrenergic receptor. The neutral 3+1 mixed-ligand complex combines 4-(6-mercaptohexyl)-1-(2-methoxyphenyl)piperazine as monodentate and 3-(N-methyl)azapentane-1,5-dithiol as tridentate unit with oxotechnetium(V). The analogous rhenium complex was synthesized for complete structural characterization and used in receptor binding assays. In competition experiments both complexes display subnanomolar affinity for the 5-HT1A receptor (IC500.24 nM for Re, 0.13 nM for Tc) but also very high affinities for the alpha1-adrenergic receptor (IC50 0.05 nM for Re, 0.03 nM for Tc). Biodistribution studies show a brain uptake in rat of 0.22% ID five minutes post injection. In vitro autoradiographic studies in rat brain and postmortem human brain indicate accumulation of the Tc-99m complex in brain areas which are rich in 5-HT1A receptors or in alpha1-adrenergic receptors. This in vitro enrichment can be blocked respectively by the 5-HT1A receptor agonist 8-OH-DPAT or by prazosin hydrochloride, an alpha1-adrenergic receptor antagonist. Ex vivo autoradiographic studies in rats show a slight accumulation of the Tc-99m complex in 5-HT1A receptor-rich areas of the brain, which could not be blocked, as well as in regions rich in alpha1-adrenergic receptors, which could be blocked by prazosin hydrochloride.