TY - JOUR
T1 - Synthesis and in vitro affinities of various MDL 100907 derivatives as potential 18F-radioligands for 5-HT2A receptor imaging with PET
AU - Herth, Matthias M
AU - Kramer, Vasko
AU - Piel, Markus
AU - Palner, Mikael
AU - Riss, Patrick J
AU - Knudsen, Gitte M
AU - Rösch, Frank
PY - 2009/4/15
Y1 - 2009/4/15
N2 - Radiolabelled piperidine derivatives such as [(11)C]MDL 100907 and [(18)F]altanserin have played an important role in diagnosing malfunction in the serotonergic neurotransmission. A variety of novel piperidine MDL 100907 derivatives, possible to label with (18)F-fluorine, were synthesized to improve molecular imaging properties of [(11)C]MDL 100907. Their in vitro affinities to a broad spectrum of neuroreceptors and their lipophilicities were determined and compared to the clinically used reference compounds MDL 100907 and altanserin. The novel compounds MA-1 (53) and (R)-MH.MZ (56) show K(i)-values in the nanomolar range towards the 5-HT(2A) receptor and insignificant binding to other 5-HT receptor subtypes or receptors. Interestingly, compounds MA-1 (53), MH.MZ (55) and (R)-MH.MZ (56) provide a receptor selectivity profile similar to MDL 100907. These compounds could possibly be preferable antagonistic (18)F-tracers for visualization of the 5-HT(2A) receptor status. Medium affine compounds (VK-1 (32), (51), (52), (54)) were synthesized and have K(i) values between 30 and 120 nM. All promising compounds show logP values between 2 and 3, that is, within the range of those for the established radiotracers altanserin and MDL 100907. The novel compounds MA-1 (53) and (R)-MH.MZ (56) thus appear to be promising high affine and selective tracers of (18)F-labelled analogues for 5-HT(2A) imaging with PET.
AB - Radiolabelled piperidine derivatives such as [(11)C]MDL 100907 and [(18)F]altanserin have played an important role in diagnosing malfunction in the serotonergic neurotransmission. A variety of novel piperidine MDL 100907 derivatives, possible to label with (18)F-fluorine, were synthesized to improve molecular imaging properties of [(11)C]MDL 100907. Their in vitro affinities to a broad spectrum of neuroreceptors and their lipophilicities were determined and compared to the clinically used reference compounds MDL 100907 and altanserin. The novel compounds MA-1 (53) and (R)-MH.MZ (56) show K(i)-values in the nanomolar range towards the 5-HT(2A) receptor and insignificant binding to other 5-HT receptor subtypes or receptors. Interestingly, compounds MA-1 (53), MH.MZ (55) and (R)-MH.MZ (56) provide a receptor selectivity profile similar to MDL 100907. These compounds could possibly be preferable antagonistic (18)F-tracers for visualization of the 5-HT(2A) receptor status. Medium affine compounds (VK-1 (32), (51), (52), (54)) were synthesized and have K(i) values between 30 and 120 nM. All promising compounds show logP values between 2 and 3, that is, within the range of those for the established radiotracers altanserin and MDL 100907. The novel compounds MA-1 (53) and (R)-MH.MZ (56) thus appear to be promising high affine and selective tracers of (18)F-labelled analogues for 5-HT(2A) imaging with PET.
KW - Animals
KW - Binding, Competitive
KW - Fluorine Radioisotopes/chemistry
KW - Fluorobenzenes/chemical synthesis
KW - Humans
KW - Kinetics
KW - Ligands
KW - Mice
KW - NIH 3T3 Cells
KW - Piperidines/chemical synthesis
KW - Positron-Emission Tomography
KW - Radioligand Assay
KW - Radiopharmaceuticals/chemical synthesis
KW - Rats
KW - Receptor, Serotonin, 5-HT2A/analysis
KW - Structure-Activity Relationship
U2 - 10.1016/j.bmc.2009.03.021
DO - 10.1016/j.bmc.2009.03.021
M3 - Journal article
C2 - 19329329
SN - 0968-0896
VL - 17
SP - 2989
EP - 3002
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
IS - 8
ER -