Synthesis and preliminary biological characterization of a new potential (125)I-radioligand for dopamine and serotonin receptors.
The synthesis and a preliminary biological characterization of a new class of N-benzyl-aminoalcohols which have serotonin (5-HT(2)) and dopamine (D(2)) receptor affinity is described. In vitro competition binding studies were conducted with the new molecules and (3)H-spiperone on crude membrane preparation from rat striatum and frontal cortex. One of these compounds, 3-benzylamino-1-(4-fluoro-2-iodophenyl)-propan-1-ol (6f), whose IC(50) values are in the micromolar range for both the D(2) and 5-HT(2) receptors, was prepared in iodine-125 labelled form (6i) by nucleophilic substitution of the bromine atom of 3-benzylamino-1-(2-bromo-4-fluorophenyl)-propan-1-ol (6d). In the in vivo studies, conducted on rats, the radiolabelled molecule 6i shows a good capacity to cross the blood-brain barrier (BBB) with a mean value of first pass cerebral extraction (E) of ca. 50% when the regional cerebral blood flow, measured with microsphere technique, is in the experimental animal's physiologic range (0.8-1 mL/min/g). A preliminary in vitro autoradiographic distribution on coronal rat brain slices of the radioiodinated molecule showed that it was preferentially localized in the striatum and in the cerebral regions rich in dopamine- and serotonin receptors, even if a high non-specific binding was observed.
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Dipartimento di Chimica Organica U. Schiff, e Centro di Studio sulla Chimica e la Struttura dei Composti Eterociclici e loro Applicazioni, CNR, Università di Firenze, Via G. Capponi 9, Firenze I-50121, Italy. guarna@chimorg.unifi.it
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D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D007457:Iodine Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D020005:Propanols / Q000138:chemical synthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
C449099:3-benzylamino-1-(4-fluoro-2-iodophenyl)-propan-1-ol; D007457:Iodine Radioisotopes; D020005:Propanols; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin