RESUMEN
Single amino acid chelates (SAACs) and SAAC-like bifunctional ligands can be exploited in the design of a variety of bioconjugates for facile metallation with the M(CO)3 (+) unit with M = (99m) Tc or Re. When the donor groups of the ligand are quinolone, thiazole or other similarly conjugated heterocycles, the rhenium complexes are fluorescent, affording complementary and isostructural fluorescent probes to the radioactive (99m) Tc analogues. The versatility of the approach has been demonstrated by the preparation of bioconjugates incorporating peptides, biotin, folic acid, thymidine and vitamin B12 . In addition, the unusual photophysical properties observed for rhenium of the [bisthiazole-diamino butane-Re(CO)3 (+) ] derivative [BTBA-Re(CO)3 ](+) are discussed.
Asunto(s)
Aminoácidos/química , Quelantes/química , Imagen Óptica/métodos , Cintigrafía/métodos , Renio/química , Tecnecio/química , Animales , HumanosRESUMEN
Through the development and application of a unique approach for producing Re-metallopeptides, a new class of peptide-derived probes that are designed to target beta-amyloid plaques was developed. Derivatives of a class of beta-breaker peptides having the core sequence lvffa or affvl (lower case letters represent D-amino acids) and the single amino acid chelate quinoline (SAACQ) ligand which can bind Re and (99m)Tc were prepared on an automated peptide synthesizer. Both monomeric and dimeric peptides were synthesized in modest to good yields where in select examples a biotin-containing amino acid derivative was included to act as a linker point for further conjugation to carrier proteins. The Re complexes for all reported peptides were prepared similarly and screened for their ability to inhibit fibrillogenesis. Two of the reported compounds showed excellent inhibitory properties (8a: 40 +/- 5% amyloid formation versus control; 16: 40 +/- 4%) and warrant further investigation. For one of these leads, the (99m)Tc analogue was synthesized and the product showed high stability toward histidine and cysteine challenges, making it a viable candidate for in vivo biodistribution studies.
Asunto(s)
Péptidos beta-Amiloides/efectos de los fármacos , Metaloproteínas/síntesis química , Sondas Moleculares/síntesis química , Oligopéptidos/química , Fragmentos de Péptidos/efectos de los fármacos , Renio/química , Tecnecio/química , Péptidos beta-Amiloides/química , Evaluación Preclínica de Medicamentos , Marcaje Isotópico , Ligandos , Metaloproteínas/química , Metaloproteínas/farmacocinética , Conformación Molecular , Sondas Moleculares/química , Sondas Moleculares/farmacocinética , Fragmentos de Péptidos/química , Biblioteca de Péptidos , Estereoisomerismo , Relación Estructura-ActividadAsunto(s)
Interpretación Estadística de Datos , Sistemas de Liberación de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/ética , Evaluación Preclínica de Medicamentos/métodos , Ética en Investigación , Radiofármacos/farmacocinética , Tamaño de la Muestra , Animales , Internacionalidad , Proyectos de InvestigaciónRESUMEN
The reaction of biotinamine with two equivalents of 2-quinoline aldehyde in the presence of Na(OAc)3BH in dichloroethane provides N,N-bis(methylquinoline)biotinamine (L1), a molecule displaying a tridentate donor terminus which has proven effective in coordinating to the {M(CO)3}+ core (M = Tc, Re). Reaction of L1 with (NEt4)2[Re(CO)3Br3] yields [Re(CO)3(L1)]Br, a compound with an absorbance at 350 nm and luminescence emission maxima at 425 and 580 nm. The luminescence lifetime of 11.4 mus, which is associated with the 580 nm emission, is sufficiently prolonged to enable time-gating techniques to be used during in vitro imaging studies and to overcome interference from endogenous fluorescence. Exposure of avidin beads to {Re(CO)3(L1)]Br resulted in binding, which was qualitatively imaged using fluorescence microscopy. The 99mTc analogue [99mTc(CO)3(L1)]+1 was prepared by reacting L1 with [99mTc(CO)3(H2O)3]+1 and purified by HPLC. The 99mTc complex is chemically robust and resistant to cysteine and histidine challenges. This study demonstrates that complementary fluorescent and radioactive biotin-derived probes may be readily prepared to allow direct correlation of in vitro and in vivo molecular imaging studies.