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

Fabian Debus; Matthias Manfred Herth; Markus Piel; Hans-Georg Buchholz; Nicole Bausbacher; Vasko Kramer; Hartmut Lüddens; Frank Rösch

doi:10.1016/j.nucmedbio.2010.02.002

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

Fabian Debus, Matthias Manfred Herth, Markus Piel, Hans-Georg Buchholz, Nicole Bausbacher, Vasko Kramer, Hartmut Lüddens, Frank Rösch

19 Citations (Scopus)

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, [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 (K_i=3.23 nM) and (R)-[¹⁸F]MH.MZ (K_i=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 (K_i=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.

Original language	English
Journal	Nuclear Medicine and Biology
Volume	37
Issue number	4
Pages (from-to)	487-95
Number of pages	9
ISSN	0969-8051
DOIs	https://doi.org/10.1016/j.nucmedbio.2010.02.002
Publication status	Published - May 2010

Keywords

Animals
Autoradiography
Fluorine Radioisotopes
Fluorobenzenes
Male
Molecular Imaging
Piperidines
Positron-Emission Tomography
Radioactive Tracers
Radiochemistry
Rats
Rats, Sprague-Dawley
Receptor, Serotonin, 5-HT2A
Serotonin 5-HT2 Receptor Antagonists

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10.1016/j.nucmedbio.2010.02.002

Cite this

@article{5a037df5d3e64ab791630927a3958779,

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

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, [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.",

keywords = "Animals, Autoradiography, Fluorine Radioisotopes, Fluorobenzenes, Male, Molecular Imaging, Piperidines, Positron-Emission Tomography, Radioactive Tracers, Radiochemistry, Rats, Rats, Sprague-Dawley, Receptor, Serotonin, 5-HT2A, Serotonin 5-HT2 Receptor Antagonists",

author = "Fabian Debus and Herth, {Matthias Manfred} and Markus Piel and Hans-Georg Buchholz and Nicole Bausbacher and Vasko Kramer and Hartmut L{\"u}ddens and Frank R{\"o}sch",

year = "2010",

month = may,

doi = "10.1016/j.nucmedbio.2010.02.002",

language = "English",

volume = "37",

pages = "487--95",

journal = "Nuclear Medicine and Biology",

issn = "0969-8051",

publisher = "Elsevier",

number = "4",

}

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

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 -

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

Abstract

Keywords

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