title: Technetium-99m labeled 1-(4-fluorobenzyl)-4-(2-mercapto-2-methyl-4-azapentyl)-4-(2-mercapto-2-methylpropylamino)-piperidine and iodine-123 metaiodobenzylguanidine for studying cardiac adrenergic function: a comparison of the uptake characteristics in vascular smooth muscle cells and neonatal cardiac myocytes, and an investigation in rats.
abstract: In developing technetium-99m-based radioligands for in vivo studies of cardiac adrenergic neurons, we compared the uptake characteristics of the (99m)Tc-labeled 1-(4-fluorobenzyl)-4-(2-mercapto-2-methyl-4-azapentyl)-4-(2-mercapto-2-methylpropylamino)-piperidine ((99m)Tc-FBPBAT) with those of the clinically established meta-[(123)I]iodobenzylguanidine ((123)I-MIBG) in rat vascular smooth muscle cells and neonatal cardiac myocytes. Furthermore, the cardiac and extracardiac uptake of both radiopharmaceuticals was assessed in intact rats and in rats pretreated with various alpha- and beta-adrenoceptor drugs, and adrenergic reuptake blocking agents. The uptake of (99m)Tc-FBPBAT and (123)I-MIBG into vascular smooth muscle cells and neonatal cardiac myocytes was rapid; more than 85% of the radioactivity accumulation into the cells occurring within the first 3 minutes. Radioactivity uptake after a 60-minute incubation at 37 degrees C (pH 7.4) varied from 15% to 65% of the total loaded activity per million cells. In all cases, (99m)Tc-FBPBAT showed the higher uptake, relative to (123)I-MIBG, at any given cell concentration. The cellular uptake of (99m)Tc-FBPBAT was lower at 4 degrees C and 20 degrees C than at 37 degrees C. In contrast, the (123)I-MIBG uptake was only slightly temperature dependent. Inhibition experiments confirmed that the cellular uptake of (123)I-MIBG is mediated by the uptake-I carrier, whereas alpha(1)- and beta(1)-adrenoceptors were predominantly involved in the uptake of (99m)Tc-FBPBAT into the cardiovascular tissues. Biodistribution studies in rats showed that (99m)Tc-FBPBAT accumulated in myocardium after intravenous injection. Radioactivity in rat heart amounted to 2.32% and 1.91% of the injected dose per gram at 15 and 60 minutes postinjection, compared with 3.10% and 2.21% injected dose per gram of tissue (%ID/g) in the experiment with (123)I-MIBG, respectively. Prazosin, urapidil, and metoprolol were as effective as treatment with other adrenergic drugs in lowering cardiac uptake of (99m)Tc-FBPBAT. Uptake reduction was more pronounced in myocardium than in other adrenergic-rich organs, including the lung, spleen, kidney, and adrenals, suggesting that the (99m)Tc-FBPBAT uptake in myocardium specifically reflects a high degree of alpha(1)/beta(1)-receptor binding to cardiac adrenergic neurons. In comparison, reduction of cardiac and pulmonary uptake of (123)I-MIBG was effective after pretreatment of rats with desipramine and reserpine, confirming distinct neuronal binding sites for (99m)Tc-FBPBAT and (123)I-MIBG. (99m)Tc-FBPBAT was excreted via urine and to a lower degree via feces. Urine analysis 6 hours p.i. revealed that more than 40% of the total excreted radioactivity was unmetabolized (99m)Tc-FBPBAT. In conclusion, the uptake of (99m)Tc-FBPBAT in rat myocardium specifically reflects binding to cardiac adrenergic neurons. The (99m)Tc-FBPBAT uptake appears to be predominantly mediated via the alpha(1)/beta(1)-adrenoceptor pathway. These data indicate that (99m)Tc-FBPBAT, like (123)I-MIBG, may be suitable for mapping cardiac adrenergic innervation by SPET, especially for alpha(1)/beta(1)-adrenoceptors as target in numerous heart diseases.
authors.affiliation: Department of Nuclear Medicine, Saarland University Medical Centre, D-66421 Homburg, Germany. rassam@uniklinik-saarland.de
authors.forename: Samuel
authors.initials: S
authors.lastname: Samnick
authors.forename: Claudia
authors.initials: C
authors.lastname: Scheuer
authors.forename: Sven
authors.initials: S
authors.lastname: Münks
authors.forename: Amr M
authors.initials: AM
authors.lastname: El-Gibaly
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.forename: Carl-Martin
authors.initials: CM
authors.lastname: Kirsch
mesh_terms: D019797:3-Iodobenzylguanidine / Q000493:pharmacokinetics*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D006321:Heart / Q000000981:diagnostic imaging; D008297:Male; D008657:Metabolic Clearance Rate; D032342:Muscle Cells / Q000000981:diagnostic imaging / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000000981:diagnostic imaging / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009928:Organ Specificity; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D011941:Receptors, Adrenergic; C489866:technetium 99m 1-(4-fluorobenzyl)-4-(2-mercapto-2-methyl-4-azapentyl)-4-(2-mercapto-2-methylpropylamino)piperidine; D019797:3-Iodobenzylguanidine