Synthesis and in vitro affinities of various MDL 100907 derivatives as potential 18F-radioligands for 5-HT2A receptor imaging with PET

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

N1 - Keywords: Animals; Binding, Competitive; Fluorine Radioisotopes; Fluorobenzenes; Humans; Kinetics; Ligands; Mice; NIH 3T3 Cells; Piperidines; Positron-Emission Tomography; Radioligand Assay; Radiopharmaceuticals; Rats; Receptor, Serotonin, 5-HT2A; Structure-Activity Relationship

PY - 2009

Y1 - 2009

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.

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 -