18F-labeling and evaluation of novel MDL 100907 derivatives as potential 5-HT2A antagonists for molecular imaging
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18F-labeling and evaluation of novel MDL 100907 derivatives as potential 5-HT2A antagonists for molecular imaging. / Debus, Fabian; Herth, Matthias Manfred; Piel, Markus; Buchholz, Hans-Georg; Bausbacher, Nicole; Kramer, Vasko; Lüddens, Hartmut; Rösch, Frank.
In: Nuclear Medicine and Biology, Vol. 37, No. 4, 05.2010, p. 487-95.Research output: Contribution to journal › Journal article › Research › peer-review
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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, [(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 microPET 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 approximately 40%. It provided [(18)F]tracers with a purity >96% and a typical specific activity of 25-35 GBq/mumol. 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 microPET 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.
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, [(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 microPET 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 approximately 40%. It provided [(18)F]tracers with a purity >96% and a typical specific activity of 25-35 GBq/mumol. 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 microPET 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.
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
VL - 37
SP - 487
EP - 495
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
SN - 0969-8051
IS - 4
ER -
ID: 130890718