6533b835fe1ef96bd12a010f

RESEARCH PRODUCT

18F-labeling and evaluation of novel MDL 100907 derivatives as potential 5-HT2A antagonists for molecular imaging.

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Abstract Introduction The serotonergic system, especially the 5-HT2A receptor, is involved in various diseases and conditions. It is a very interesting target for medicinal applications. Methods Two novel 5-HT2A tracers, namely, [ 18 F]DD-1 and the enantiomeric pure ( R )-[ 18 F]MH.MZ, were radiolabeled by 18 F-fluoroalkylation of the corresponding desmethyl analogue. In vitro binding autoradiography on rat brain slices was performed to test the affinity and selectivity of these tracers. Moreover, first μPET experiments of ( R )-[ 18 F]MH.MZ were carried out in Sprague-Dawley rats. Results [ 18 F]DD-1 ( K i =3.23 nM) and ( R )-[ 18 F]MH.MZ ( K i =0.72 nM) were 18 F-fluoroalkylated by the secondary synthon [ 18 F]FETos in a radiochemical yield (RCY) of >70%. The final formulation for both tracers took no longer than 100 min with an overall RCY of ∼40%. It provided [ 18 F]tracers with a purity >96% and a typical specific activity of 25–35 GBq/μmol. Autoradiographic images of ( R )-[ 18 F]MH.MZ ( 5 ) and [ 18 F]DD-1 ( 4 ) showed excellent visualization and selectivity of the 5-HT2A receptor for ( R )-[ 18 F]MH.MZ and less specific binding for [ 18 F]DD-1. The binding potential (BP) of ( R )-[ 18 F]MH.MZ was determined to be 2.6 in the frontal cortex and 2.2 in the cortex ( n =4), whereas the cortex-to-cerebellum ratio was determined to be 3.2 at steady state ( n =4). Cortex-to-cerebellum ratios of ( R )-[ 18 F]MH.MZ were almost twice as much as compared with the racemic [ 18 F]MH.MZ. Thereby, equal levels of specific activities were used. High uptake could be demonstrated in cortex regions. Conclusion Labeling of both novel tracers was carried out in high RCY. Autoradiography revealed ( R )-[ 18 F]MH.MZ as a very selective and affine 5-HT2A tracer ( K i =0.72 nM), whereas [ 18 F]DD-1 showed no reasonable distribution pattern on autoradiographic sections. Moreover, results from μPET scans of ( R )-[ 18 F]MH.MZ hint on improved molecular imaging characteristics compared with those of [ 18 F]MH.MZ. Therefore, ( R )-[ 18 F]MH.MZ appears to be a highly potent and selective serotonergic PET ligand in small animals.