Iodine-123 labeled reboxetine analogues for imaging of noradrenaline transporter in brain using single photon emission computed tomography

摘要

Preliminary investigation of the radioiodinated(S,S)-reboxetine analogue, 123I-INER, in baboons showed this tracer to have promise for imaging the noradrenaline transporter(NAT) using single photon emission computed tomography(SPECT). More recently, the radioiodinated(R,S)-stereoisomer of 123I-INER, 123I-NKJ64, has been synthesized and preliminary evaluation in rats has been reported. This article reports the brain distribution and pharmacokinetic properties of 123I-NKJ64 in baboons and compares results with 123I-INER data in the same species. SPECT studies were conducted in two ovariectomized adult female baboons using two different protocols:(1) bolus of 123I-INER or 123I-NKJ64; and(2) bolus plus constant infusion of 123I-NKJ64 with reboxetine(2.0 mg/kg) administration at equilibrium. Following bolus injection, both radiotracers rapidly and avidly entered the baboon brain. The regional brain accumulation of 123I-NKJ64 did not match the known distribution of NAT in baboon brain, contrasting with previous results obtained in rats. Conversely, the regional distribution of 123I-INER was consistent with known distribution of NAT in baboon brain. No displacement of 123I-NKJ64 was observed following administration of reboxetine. This contrasts with previous data obtained for 123I-INER, where 60% of specific binding was displaced by a lower dose of reboxetine. These data suggest that 123I-NKJ64 may lack affinity and selectivity for NAT in baboon brain and 123I-INER is the most promising iodinated reboxetine analogue developed to date for in vivo imaging of NAT in brain using SPECT. This study highlights the importance of species differences during radiotracer development and the stereochemical configuration of analogues of reboxetine in vivo.