Synthesis and biological characterization of novel 2-quinolinecarboxamide ligands of the peripheral benzodiazepine receptors bearing technetium-99m or rhenium.
Potential receptor imaging agents based on Tc-99m for the in vivo visualization of the peripheral benzodiazepine receptor (PBR) have been designed on the basis of the information provided by the previously published structure-affinity relationship studies, which suggested the existence of tolerance to voluminous substituents in the receptor area interacting with 3-position of the quinoline nucleus of 2-quinolinecarboxamides 5. In the first step of the investigation, the stereoelectronic features of the above-indicated receptor area were also probed by means of 4-phenyl-3-[(1-piperazinyl)methyl]-2-quinolinecarboxamide derivatives bearing different substituents on the terminal piperazine nitrogen atom (compounds 6a-f). The structure-affinity relationship data confirmed the existence of a tolerance to bulky lipophilic substituents and stimulated the design of bifunctional ligands based on the 4-phenyl-3-[(1-piperazinyl)methyl]-2-quinolinecarboxamide moiety (compounds 6h,j,k,m). The submicromolar PBR affinity of rhenium complexes 6j,m suggests that the presence of their metal-ligand moieties with encaged rhenium is fairly compatible with the interaction with the PBR binding site. Thus, in order to obtain information on the in vivo behavior of these bifunctional ligands, (99m)Tc-labeled compounds 6h,k were synthesized and evaluated in preliminary biodistribution and single photon emission tomography (SPET) studies. The results suggest that both tracers do not present a clear preferential distribution in tissues rich in PBR, probably because of their molecular dimensions, which may hamper both the intracellular diffusion toward PBR and the interaction with the binding site.
Cappelli
Andrea
A
Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy. cappelli@unisi.it
Mancini
Alessandra
A
Sudati
Francesco
F
Valenti
Salvatore
S
Anzini
Maurizio
M
Belloli
Sara
S
Moresco
Rosa Maria
RM
Matarrese
Mario
M
Vaghi
Mauro
M
Fabro
Andrea
A
Fazio
Ferruccio
F
Vomero
Salvatore
S
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D015195:Drug Design; D007700:Kinetics; D008024:Ligands; D008297:Male; D011804:Quinolines / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D012211:Rhenium / Q000737:chemistry*; D013667:Technetium / Q000737:chemistry*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
C530252:2-quinolinecarboxamide; D002352:Carrier Proteins; D003432:Cross-Linking Reagents; D008024:Ligands; D011804:Quinolines; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; D012211:Rhenium; D013667:Technetium