RESUMO
Cocaine addiction is a major problem for which there is no approved pharmacotherapy. We have developed a vaccine to cocaine (dAd5GNE), based on the cocaine analog GNE linked to the capsid proteins of a serotype 5 adenovirus, designed to evoke anti-cocaine antibodies that sequester cocaine in the blood, preventing access to the CNS. To assess the efficacy of dAd5GNE in a large animal model, positron emission tomography (PET) and the radiotracer [(11)C]PE2I were used to measure cocaine occupancy of the dopamine transporter (DAT) in nonhuman primates. Repeat administration of dAd5GNE induced high anti-cocaine titers. Before vaccination, cocaine displaced PE2I from DAT in the caudate and putamen, resulting in 62±4% cocaine occupancy. In contrast, dAd5GNE-vaccinated animals showed reduced cocaine occupancy such that when anti-cocaine titers were >4 × 10(5), the cocaine occupancy was reduced to levels of <20%, significantly below the 47% threshold required to evoke the subjective 'high' reported in humans.
Assuntos
Anticorpos/imunologia , Cocaína/antagonistas & inibidores , Cocaína/imunologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Vacinas/farmacologia , Adenoviridae/química , Animais , Anticorpos/sangue , Capsídeo/metabolismo , Radioisótopos de Carbono , Núcleo Caudado/diagnóstico por imagem , Núcleo Caudado/efeitos dos fármacos , Núcleo Caudado/metabolismo , Cocaína/análogos & derivados , Cocaína/química , Cocaína/farmacologia , Feminino , Macaca mulatta , Neuroimagem , Nortropanos/síntese química , Putamen/diagnóstico por imagem , Putamen/efeitos dos fármacos , Putamen/metabolismo , Ensaio Radioligante , Cintilografia , Vacinas/químicaRESUMO
We have determined the systemic biodistribution of the hormone leptin by PET imaging. PET imaging using (18)F- and (68)Ga-labeled leptin revealed that, in mouse, the hormone was rapidly taken up by megalin (gp330/LRP2), a multiligand endocytic receptor localized in renal tubules. In addition, in rhesus monkeys, 15% of labeled leptin localized to red bone marrow, which was consistent with hormone uptake in rodent tissues. These data confirm a megalin-dependent mechanism for renal uptake in vivo. The significant binding to immune cells and blood cell precursors in bone marrow is also consistent with prior evidence showing that leptin modulates immune function. These experiments set the stage for similar studies in humans to assess the extent to which alterations of leptin's biodistribution might contribute to obesity; they also provide a general chemical strategy for (18)F labeling of proteins for PET imaging of other polypeptide hormones.