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Synthesis and in silico evaluation of novel compounds for PET-based investigations of the norepinephrine transporter.

ABSTRACT: Since the norepinephrine transporter (NET) is involved in a variety of diseases, the investigation of underlying dysregulation-mechanisms of the norepinephrine (NE) system is of major interest. Based on the previously described highly potent and selective NET ligand 1-(3-(methylamino)-1-phenylpropyl)-3-phenyl-1,3-dihydro-2H-benzimidaz- ol-2-one (Me@APPI), this paper aims at the development of several fluorinated methylamine-based analogs of this compound. The newly synthesized compounds were computationally evaluated for their interactions with the monoamine transporters and represent reference compounds for PET-based investigation of the NET.

SUBMITTER: Neudorfer C

PROVIDER: S-EPMC6272146 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Synthesis and in silico evaluation of novel compounds for PET-based investigations of the norepinephrine transporter.

Neudorfer Catharina C Seddik Amir A Shanab Karem K Jurik Andreas A Rami-Mark Christina C Holzer Wolfgang W Ecker Gerhard G Mitterhauser Markus M Wadsak Wolfgang W Spreitzer Helmut H

Molecules (Basel, Switzerland) 20150120 1

Since the norepinephrine transporter (NET) is involved in a variety of diseases, the investigation of underlying dysregulation-mechanisms of the norepinephrine (NE) system is of major interest. Based on the previously described highly potent and selective NET ligand 1-(3-(methylamino)-1-phenylpropyl)-3-phenyl-1,3-dihydro-2H-benzimidaz- ol-2-one (Me@APPI), this paper aims at the development of several fluorinated methylamine-based analogs of this compound. The newly synthesized compounds were com ...[more]

PMID: 25608857

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Project description:Both (131)I- and (123)I-labeled meta-iodobenzylguanidine (MIBG) have been widely used in the clinic for targeted imaging of the norepinephrine transporter (NET). The human NET (hNET) gene has been imaged successfully with (124)I-MIBG positron emission tomography (PET) at time points of >24 h post-injection (p.i.). (18)F-labeled MIBG analogs may be ideal to image hNET expression at time points of <8 h p.i. We developed improved methods for the synthesis of known MIBG analogs, [(18)F]MFBG and [(18)F]PFBG and evaluated them in hNET reporter gene-transduced C6 rat glioma cells and xenografts.[(18)F]MFBG and [(18)F]PFBG were synthesized manually using a three-step synthetic scheme. Wild-type and hNET reporter gene-transduced C6 rat glioma cells and xenografts were used to comparatively evaluate the (18)F-labeled analogs with [(123)I]/[(124)I]MIBG.The fluorination efficacy on benzonitrile was predominantly determined by the position of the trimethylammonium group. The para-isomer afforded higher yields (75?±?7%) than meta-isomer (21?±?5%). The reaction of [(18)F]fluorobenzylamine with 1H-pyrazole-1-carboximidamide was more efficient than with 2-methyl-2-thiopseudourea. The overall radiochemical yields (decay-corrected) were 11?±?2% (n?=?12) for [(18)F]MFBG and 41?±?12% (n?=?5) for [(18)F]PFBG, respectively. The specific uptakes of [(18)F]MFBG and [(18)F]PFBG were similar in C6-hNET cells, but 4-fold less than that of [(123)I]/[(124)I]MIBG. However, in vivo [(18)F]MFBG accumulation in C6-hNET tumors was 1.6-fold higher than that of [(18)F]PFBG at 1 h p.i., whereas their uptakes were similar at 4 h. Despite [(18)F]MFBG having a 2.8-fold lower affinity to hNET and approximately 4-fold lower cell uptake in vitro compared to [(123)I]/[(124)I]MIBG, PET imaging demonstrated that [(18)F]MFBG was able to visualize C6-hNET xenografts better than [(124)I]MIBG. Biodistribution studies showed [(18)F]MFBG and (123)I-MIBG had a similar tumor accumulation, which was lower than that of no-carrier-added [(124)I]MIBG, but [(18)F]MFBG showed a significantly more rapid body clearance and lower uptake in most non-targeting organs.[(18)F]MFBG and [(18)F]PFBG were synthesized in reasonable radiochemical yields under milder conditions. [(18)F]MFBG is a better PET ligand to image hNET expression in vivo at 1-4 h p.i. than both [(18)F]PFBG and [(123)I]/[(124)I]MIBG.

Dataset Information

Synthesis and in silico evaluation of novel compounds for PET-based investigations of the norepinephrine transporter.

Publications

Synthesis and in silico evaluation of novel compounds for PET-based investigations of the norepinephrine transporter.

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