RESUMEN
As an effort to improve 18 F-radiolabeling of biomolecules in method robustness and versatility, we report the synthesis and radiolabeling of a new azido precursor potentially useful for the so-called "click reaction," in particular the ligand-free version of the copper(I)-catalyzed alkyne-azide cycloaddition. The new azido precursor may help to overcome problems sometimes exhibited by most of the currently used analogues, as it is safe to handle and it displays long-term chemical stability, thus facilitating the development of new radiolabeling procedures. Moreover, the formed 18 F-labeled 1,2,3-triazole is potentially metabolically stable and could enhance the in vivo circulation time. The above azido precursor was successfully radiolabeled with 18 F, with 51% radiochemical yield (nondecay-corrected). As a proof of concept, the 18 F-labeled azide was then tested with a suitable alkyne functionalized aminoacid (l-propargylglycine), showing 94% of conversion, and a final radiochemical yield of 27% (>99% radiochemical purity), nondecay-corrected, with a total preparation time of 104 minutes.
Asunto(s)
Radioisótopos de Flúor/química , Radiofármacos/química , Alquinos/química , Azidas/química , Alcohol Bencilo/química , Catálisis , Química Clic , Cobre/química , Marcaje IsotópicoRESUMEN
The effects of growth hormone (GH) deficiency on cardiac function were studied in young male rats administered an anti-GH-releasing hormone (GHRH) serum from postnatal day 20 to 40. Dependence of heart abnormalities on GH deficiency was ascertained by giving a group of anti-GHRH serum-treated rats GH replacement therapy. Heart preparations from anti-GHRH serum-treated rats, undergoing low-flow ischemia, showed a progressive increase in left ventricular end-diastolic pressure with poor recovery of mechanical activity and increased coronary perfusion pressure upon reperfusion. Hearts from anti-GHRH serum + GH-treated rats, undergoing global reduction to the flow, showed only a minimal increase of left ventricular end-diastolic pressure and, upon reperfusion, cardiac mechanical activity recovered almost completely. Similar findings were also observed in heart preparations from control (normal rabbit serum-treated) rats. Infusion of acetylcholine (10(-6) M) into heart preparations in the preischemic period increased coronary perfusion pressure values more markedly in hearts from normal rabbit serum- and anti-GHRH serum + GH-treated rats than in those from anti-GHRH serum-treated rats. These results indicate that selective GH deficiency in young male rats renders the heart more sensitive to ischemic damage and leads to an impairment of cardiac muscarinic receptor function.
Asunto(s)
Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Hormona del Crecimiento/deficiencia , Isquemia Miocárdica/fisiopatología , Acetilcolina/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Hormona del Crecimiento/genética , Hormona del Crecimiento/uso terapéutico , Sueros Inmunes , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Hipófisis/metabolismo , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-DawleyRESUMEN
The effects of the alpha-2 adrenoceptor agonist clonidine (CLO) on the growth hormone (GH) regulatory neuronal systems, growth hormone-releasing hormone (GHRH) and somatostatin (SS), were studied in adult male rats given a single or a short-term administration (1, 3 and 6 days) of the drug. Acute administration of CLO significantly decreased hypothalamic GHRH content [leaving unaltered GHRH messenger RNA (mRNA) levels] and increased plasma GH levels; hypothalamic SS content/mRNA levels and pituitary GH content/mRNA levels remained unchanged. In 1- and 3-day CLO-treated rats, by contrast, decreased hypothalamic GHRH content was coupled with a significant reduction in GHRH mRNA levels. In these rats, pituitary GH content and mRNA levels were also significantly increased, whereas hypothalamic SS content and mRNA levels remained unaltered. In 6-day CLO-treated rats, hypothalamic GHRH content and mRNA levels were still significantly reduced, plasma GH levels were increased, but to a lesser extent than in 1- and 3-day CLO-treated rats, and pituitary GH content and mRNA reverted to control levels. Hypothalamic SS content and mRNA levels remained unaltered. These results indicate that 1) functional activation of alpha-2 adrenergic receptors by CLO increases GHRH release from the hypothalamus, 2) CLO, via GHRH, increases GH secretion and biosynthesis, which in turn feeds back in the hypothalamus to reduce GHRH biosynthesis, and 3) reduction of hypothalamic GH-stimulatory activity tones down the initial pituitary somatotropic hyperfunction. Unaltered hypothalamic SS content and mRNA levels in all CLO-treated rats suggests that the somatostatinergic system is less sensitive than the GHRH system to changes in circulating GH levels.