Development of SPECT imaging agents for the norepinephrine transporters: [123I]INER

Abstract

A series of reboxetine analogs was synthesized and evaluated for in vitro binding as racemic mixtures. The best candidate (INER) was synthesized as the optically pure (S,S) enantiomer, labeled with iodine-123 and its in vivo binding determined by SPECT imaging in baboons. The in vivo specificity, selectivity and kinetics of [ 123 I]INER make it a promising agent for imaging NET in vivo by noninvasive SPECT imaging.The norepinephrine transporter (NET) is a protein with twelve transmembrane-spanning domains, located at the pre-synaptic terminal of noradrenergic neurons. The principal physiological function of NET is to removes excess norepinephrine (NE) from the synaptic cleft to terminate the action of NE (avoiding over-stimulation) and to recycle NE into the presynaptic neuron (active reuptake) for later re-release. Brain structures known to be rich in NET include the locus coerulus, (brainstem area); thalamus, hippocampus and throughout the cerebral cortex, whereas low densities are found in cerebellum and striatum. 4 NET has been implicated in the pathophysiology of numerous neuropsychiatric and neurodegenerative disorders, including depression (reduced level of NE in the synapse appears to down-regulate the level of NET), 5,6 arousal, 7 anxiety, 8,9 attention-deficit/hyperactivity disorder (atomoxetine 1 is the first non-stimulant selective NET inhibitor for the treatment of ADHD 10 ), 11 and Alzheimer's disease. 12 Therefore, the development of a specific radioligand to quantify the variation of NET density in vivo will be of great utility as a diagnostic tool to better understand the etiology and pathogenesis of these neuropsychiatric disorders, as well as a tool to evaluated potential new drugs targeting the NET.

(R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

“…The regional cerebral distribution was consistent with the density of NET and a higher midbrain to striatum ratio was found at 180 minutes post injection [21]. A similar brain distribution pattern was observed in dynamic SPECT imaging of baboon using 5 [22]. Although the longer physical half-life of 123 I (13.3 h) is compatible with the slower kinetics of this ligand, it is still far from ideal as a specific brain imaging agent for NET.…”

“…Recently, a novel reboxetine derivative iodinated at position 2 of the phenoxy ring, (S,S)-IPBM 5 (also named as [ 123 I]INER) ( Fig.1) has been reported [21,22]. (S,S)-IPBM 5 displayed high affinity and selectivity for NET in binding assay experiments.…”

(R)‐N‐Methyl‐3‐(3′‐[18F]fluoropropyl)phenoxy)‐3‐phenylpropanamine (18F‐MFP3) as a potential PET imaging agent for norepinephrine transporter

“…Ex vivo experiments of 125 I-IPBM showed high levels of radioactivity in the LC and the anteroventricular thalamic nucleus and regional distribution correlated well with reported 3 H-nisoxetine binding 25. The same chemical structure 7 , radiolabeled with iodine-123 referred as 123 I-INER ( K i = 0.84 nM) was found to have comparable properties reported for MIPP 26. This group has recently reported additional carbon-11 and fluorine-18 derivatives of reboxetine, with promising properties for carbon-11 labeled analogs 27…”

Synthesis, Radiosynthesis, and Biological Evaluation of Carbon-11 and Fluorine-18 Labeled Reboxetine Analogues: Potential Positron Emission Tomography Radioligands for in Vivo Imaging of the Norepinephrine Transporter

“…Tin precursor 15 was prepared by palladium-catalyzed stannylation of iodo compound 17 24, easily synthesized by reacting 6 with 2-iodophenol under Mitsunobu conditions with inversion of configuration. The obvious synthetic strategy for obtaining tin precursor 16 focused on the stannylation of iodo compound 18 .…”