Radiosynthesis and Evaluation of an ¹⁸F-Labeled Positron Emission Tomography (PET) Radioligand for Brain Histamine Subtype-3 Receptors Based on a Nonimidazole 2-Aminoethylbenzofuran Chemotype

Abstract

A known chemotype of H3 receptor ligand was explored for development of a radioligand for imaging brain histamine subtype 3 (H3) receptors in vivo with positron emission tomography (PET), namely non-imidazole 2-aminoethylbenzofurans, represented by the compound (R)-(2-(2-(2-methylpyrrolidin-1-yl)ethyl)benzofuran-5-yl)(4-fluorophenyl)methanone (9). Compound 9 was labeled with fluorine-18 (t1/2= 109.7 min) in high specific activity by treating the prepared nitro analog (12) with cyclotron-produced [18F]fluoride ion. [18F]9 was studied with PET in mouse and in monkey after intravenous injection. [18F]9 showed favorable properties as a candidate PET radioligand, including moderately high brain uptake with a high proportion of H3 receptor-specific signal in the absence of radiodefluorination. The nitro compound 12 was found to have even higher H3 receptor affinity, indicating the potential of this chemotype for the development of further promising PET radioligands.

Considerations in the Development of Reversibly Binding PET Radioligands for Brain Imaging

“…Br, NO 2, Me 3 N + ) in ortho or para orientation to a strong electron-withdrawing group ( e.g., CO, NO 2 , CN). The earlier mentioned radioligand [ 18 F]XB-1 (Table 4) is an example produced by such a process [159]. For some radioligands, such as [ 18 F]FPEB (Table 4), this type of procedure can also be adequately effective with a nitrile group in meta orientation [366].…”

Design and Synthesis of Norendoxifen Analogues with Dual Aromatase Inhibitory and Estrogen Receptor Modulatory Activities

“…Evaporation of the solvent provided the product 22 as a yellow solid (1.28 g, 94%): mp 194-197 °C (lit. 41 198-200 °C). 1 H NMR (300 MHz, methanol- d 4 and CDCl 3 ) δ 8.32-8.29 (m, 2 H), 7.85-7.82 (m, 2 H), 7.71-7.67 (m, 2 H), 6.89-6.85 (m, 2 H).…”

11C‐labeled and 18F‐labeled PET ligands for subtype‐specific imaging of histamine receptors in the brain

“…Another non‐imidazole‐based radioligand was the radiofluorinated 2‐aminoethylbenzofuran [ 18 F]XB‐1 (Scheme ). This antagonist/inverse agonist inhibited human H 3 R with a p K i of 9.57 and a K i of 1.9 nM, and showed a >100‐fold lower affinity for other histamine receptor subtypes as well as various other receptors and transporters. The radioligand was synthesized from the nitro precursor by substitution with [ 18 F]fluoride using microwave heating .…”

“…This antagonist/inverse agonist inhibited human H 3 R with a p K i of 9.57 and a K i of 1.9 nM, and showed a >100‐fold lower affinity for other histamine receptor subtypes as well as various other receptors and transporters. The radioligand was synthesized from the nitro precursor by substitution with [ 18 F]fluoride using microwave heating . In a total synthesis time of about 110 min, [ 18 F]XB‐1 was obtained with an RCY of ~9%, a specific activity of ~49 GBq/µmol, and an RCP >99%.…”

“…In a series of H 3 R inverse agonists, two spiro‐isobenzofuranones occurred as highly potent inhibitors: a 5‐methoxy (IC 50 of 0.54 nM) and a 5‐fluoromethoxy derivative (IC 50 of 0.90 nM) . Based on these compounds, 5‐[ 11 C]methoxy and 5‐[ 18 F]fluorodideuteromethoxy derivatives have been synthesized and evaluated in vivo (here and in noted as [ 11 C]Merck 1b and [ 18 F]Merck 2b, respectively, Scheme ). With a log D 7.4 of 2.2 for [ 11 C]Merck 1b and of 2.1 for [ 18 F]Merck 2b, together with low P‐glycoprotein affinity, it was expected that the radioligands were able to enter the brain sufficiently.…”