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

TY - JOUR

T1 - 18F-labeling and evaluation of novel MDL 100907 derivatives as potential 5-HT2A antagonists for molecular imaging

AU - Debus, Fabian

AU - Herth, Matthias Manfred

AU - Piel, Markus

AU - Buchholz, Hans-Georg

AU - Bausbacher, Nicole

AU - Kramer, Vasko

AU - Lüddens, Hartmut

AU - Rösch, Frank

N1 - (c) 2010 Elsevier Inc. All rights reserved.

PY - 2010/5

Y1 - 2010/5

N2 - 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, [18F]DD-1 and the enantiomeric pure (R)-[18F]MH.MZ, were radiolabeled by 18F-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)-[18F]MH.MZ were carried out in Sprague-Dawley rats. Results: [18F]DD-1 (Ki=3.23 nM) and (R)-[18F]MH.MZ (Ki=0.72 nM) were 18F-fluoroalkylated by the secondary synthon [18F]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 [18F]tracers with a purity >96% and a typical specific activity of 25-35 GBq/Μmol. Autoradiographic images of (R)-[18F]MH.MZ (5) and [18F]DD-1 (4) showed excellent visualization and selectivity of the 5-HT2A receptor for (R)-[18F]MH.MZ and less specific binding for [18F]DD-1. The binding potential (BP) of (R)-[18F]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)-[18F]MH.MZ were almost twice as much as compared with the racemic [18F]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)-[18F]MH.MZ as a very selective and affine 5-HT2A tracer (Ki=0.72 nM), whereas [18F]DD-1 showed no reasonable distribution pattern on autoradiographic sections. Moreover, results from ΜPET scans of (R)-[18F]MH.MZ hint on improved molecular imaging characteristics compared with those of [18F]MH.MZ. Therefore, (R)-[18F]MH.MZ appears to be a highly potent and selective serotonergic PET ligand in small animals.

AB - 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, [18F]DD-1 and the enantiomeric pure (R)-[18F]MH.MZ, were radiolabeled by 18F-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)-[18F]MH.MZ were carried out in Sprague-Dawley rats. Results: [18F]DD-1 (Ki=3.23 nM) and (R)-[18F]MH.MZ (Ki=0.72 nM) were 18F-fluoroalkylated by the secondary synthon [18F]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 [18F]tracers with a purity >96% and a typical specific activity of 25-35 GBq/Μmol. Autoradiographic images of (R)-[18F]MH.MZ (5) and [18F]DD-1 (4) showed excellent visualization and selectivity of the 5-HT2A receptor for (R)-[18F]MH.MZ and less specific binding for [18F]DD-1. The binding potential (BP) of (R)-[18F]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)-[18F]MH.MZ were almost twice as much as compared with the racemic [18F]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)-[18F]MH.MZ as a very selective and affine 5-HT2A tracer (Ki=0.72 nM), whereas [18F]DD-1 showed no reasonable distribution pattern on autoradiographic sections. Moreover, results from ΜPET scans of (R)-[18F]MH.MZ hint on improved molecular imaging characteristics compared with those of [18F]MH.MZ. Therefore, (R)-[18F]MH.MZ appears to be a highly potent and selective serotonergic PET ligand in small animals.

KW - Animals

KW - Autoradiography

KW - Fluorine Radioisotopes

KW - Fluorobenzenes

KW - Male

KW - Molecular Imaging

KW - Piperidines

KW - Positron-Emission Tomography

KW - Radioactive Tracers

KW - Radiochemistry

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptor, Serotonin, 5-HT2A

KW - Serotonin 5-HT2 Receptor Antagonists

U2 - 10.1016/j.nucmedbio.2010.02.002

DO - 10.1016/j.nucmedbio.2010.02.002

M3 - Journal article

C2 - 20447561

SN - 0969-8051

VL - 37

SP - 487

EP - 495

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

IS - 4

ER -