Synthesis and Evaluation of (S)-4-(3-(2‘-[¹¹C]Isopropylamino)-2-hydroxypropoxy)-2H-benzimidazol-2-one ((S)-[¹¹C]CGP 12388) and (S)-4-(3-((1‘-[¹⁸F]Fluoroisopropyl)amino)-2-hydroxypropoxy)-2H-benzimidazol-2-one ((S)-[¹⁸F]Fluoro-CGP 12388) for Visualization of β-Adrenoceptors with Positron Emission Tomography

Abstract

The beta-adrenoceptor antagonist (S)-[11C]CGP 12177 (4-(3-(tert-butylamino)-2-hydroxypropoxy)-2H-benzimidazol -2[11C]- one) is a generally accepted radioligand for cardiac and pulmonary PET studies. The synthesis of [11C]CGP 12177 is a laborious and often troublesome procedure. Therefore, (S)-CGP 12388 (4-(3-(isopropylamino)-2-hydroxypropoxy) -2H-benzimidazol-2-one), 5, the isopropyl analogue of CGP 12177, has been labeled with carbon-11 in the isopropyl group via a reductive alkylation by [11C]acetone (3) of the corresponding (S)-desisopropyl compound 2. The fluoro-substituted analogue of (S)-CGP 12388 was prepared by reacting 2 with [18F]fluoroacetone (4). (S)-[11C]CGP 12388 (5) was easily prepared via a one-pot procedure. The radiochemical yield of (S)-[11C]CGP 12388 (600-800 Ci/mmol, EOS) was 18% (EOB) with a total synthesis time of 35 min, whereas (S)-[18F]fluoro-CGP 12388 (6) (> 2000 Ci/mmol, EOS) was synthesized in 105 min with a radiochemical yield of 12% (EOB). Biodistribution studies in rats demonstrated specific binding to beta-adrenoceptors of (S)-[18F]fluoro-CGP 12388 and (S)-[11C]CGP 12388 in lung and heart. The lungs were clearly visualized with PET studies of rats. Total/nonspecific binding at 60 min postinjection was 5.6 for (S)-[11C]CGP 12388 and 2.0 for the (S)-18F compound. Due to its facile synthetic procedure and in vivo data, (S)-[11C]CGP 12388 is a promising beta-adrenoceptor ligand for clinical PET.

Reductive N‐alkylation of secondary amines with [2‐11C]acetone

“…7,8,10,15 In this procedure, a solution of primary amine in methanol and acetic acid is added to the (unquenched) MeLi solution. Unfortunately, we were not able to prepare [ 11 C]1-isopropyl-4-phenylpiperazine ([ 11 C]iPPP) via this route.…”

“…[1][2][3] Reductive alkylation reactions with 11 C-labeled carbonyl compounds such as formaldehyde, 4 acetaldehyde 5,6 and acetone 7 have been applied for the synthesis of potential positron emission tomography (PET) tracers and ligands. [8][9][10][11][12][13][14][15] In contrast to the [ 11 C]aldehydes, reductive alkylation reactions using [2-11 C]acetone are limited to primary aliphatic amines (Figure 1), [7][8][9][10][11][12][13][14][15] which generally react faster than primary aromatic and secondary aliphatic amines. 1 Nevertheless, it would be useful to develop a labeling method for secondary amines with [2-11 C]acetone since the R 2 N-isopropyl moiety is present in many biologically active compounds ( Figure 2).…”

Synthesis of an18F-labelled high affinityβ1-adrenoceptor PET radioligand based on ICI 89,406

“…18 The radiosynthesis of an 18 F-labelled analogue of CGP 12388 has also been described. 19,20 In contrast, the clinical application of candidate b 1 -AR selective radioligands, such as (þ=À) 24 is limited due to high non-specific binding, rapid metabolism or a tissue uptake that does not reflect binding to b-ARs. [21][22][23][24] In summary, no b 1 -selective radioligand suitable for the non-invasive assessment of cardiac b 1 -AR is clinically established for single photon emission computed tomography (SPECT) or PET.…”

Synthesis and evaluation of novel phenoxypropanolamine derivatives containing acetanilides as potent and selective β3-adrenergic receptor agonists

“…Compound 4 was synthesized from 2-pyridylacetic acid (2) and 4-aminobenzylcyanide, 0968 followed by hydrogenation of the cyano group with Raney-nickel. Compound 4 was coupled with appropriate (S)-2-aryloxymethyloxirane [15][16][17][18] to afford the desired products (5a-f). Acetanilides 8a-c were prepared from the corresponding ethyl arylacetates 6a-c, as illustrated in Scheme 2.…”

“…On the other hand, compound 12 was treated with propionaldehyde and borane to yield an N-propylaniline analogue 15. The coupling of 15 with 1-benzylimidazol-2-ylacetic acid, followed by deprotection of the Boc group afforded N-propyl-1-benzylimidazol-2-ylacetanilide derivative (17).…”