Synthesis of N1′-([18F]fluoroethyl)naltrindole ([18F]FEtNTI): a radioligand for positron emission tomographic studies of delta opioid receptors

Abstract

N1′‐([18F]fluoroethyl)naltrindole ([18F]FEtNTI), a novel analog of the delta opioid receptor antagonist naltrindole (NTI), has been prepared for evaluation as a radioligand for use in positron emission tomography. The precursor for radiolabeling was obtained in four steps from naltrexone hydrochloride with an overall yield of 47%. Nucleophilic displacement of a tosylate leaving group by [18F]fluoride, followed by hydrogenolysis (H2, 10% Pd/C) of a benzyl protecting group on the phenolic moiety, gave [18F]FEtNTI. The average (n=5) time for radiosynthesis, HPLC purification, and formulation was 77 min from end of bombardment. [18F]FEtNTI of high radiochemical purity was obtained with an average specific activity of 846 mCi/μmol at end of synthesis, and an average radiochemical yield of 10% (not corrected for decay). Copyright © 1999 John Wiley & Sons, Ltd.

Indium-Labeled Macrocyclic Conjugates of Naltrindole: High-Affinity Radioligands for In Vivo Studies of Peripheral δ Opioid Receptors

“…Thus, the data represents binding of the novel ligands in vitro in one of the few tissues where δ opioid receptors have been characterized from the species to be used for in vivo studies (vide infra). The overall opioid receptor binding profile obtained for NTI agreed well with determinations by others using similar radioligands and tissues. 6b,, The major finding for the novel compounds is the use of linkers having six to nine atoms preserves the high δ opioid receptor affinity of NTI and maintains or improves δ selectivity. These chelators ( 10 , 15 , 16 ) and their indium(III) complexes ( 18 , 19 , 20 ) give picomolar apparent affinities ( K i s) for δ opioid receptors accompanied by >100-fold selectivities against secondary interactions at μ and κ sites.…”

“…In the first, conjugates were prepared by reductive amination of N 1‘-aldehyde derivatives with DO3A to afford three- and six-carbon alkyl linkers (Scheme ). NTI, with the phenol protected by a tosyl moiety ( 2 ),6a was selectively alkylated at the indole nitrogen with 3-bromopropionaldehyde dimethylacetal to give 3 (77%), or with 6-bromohexanenitrile to give 7 (96%). Excess alkylating agent was required for good conversion due to competing β-elimination.…”

“…Opioid receptor binding assays (Table ) were performed using membranes from fresh CD1 mouse (δ, [ 3 H]NTI) or frozen guinea pig (μ, [ 3 H]DAMGO; κ, [ 3 H]U69,593) brains . Although guinea pig brain has a significant population of δ sites, 6b, we chose to use mouse brain for these primary site assays because δ receptors, and their interactions with [ 3 H]NTI, are well defined in this tissue 26a…”

Indium-Labeled Macrocyclic Conjugates of Naltrindole: High-Affinity Radioligands for In Vivo Studies of Peripheral δ Opioid Receptors

“…Thus, the data represents binding of the novel ligands in vitro in one of the few tissues where δ opioid receptors have been characterized from the species to be used for in vivo studies (vide infra). The overall opioid receptor binding profile obtained for NTI agreed well with determinations by others using similar radioligands and tissues. 6b,, The major finding for the novel compounds is the use of linkers having six to nine atoms preserves the high δ opioid receptor affinity of NTI and maintains or improves δ selectivity. These chelators ( 10 , 15 , 16 ) and their indium(III) complexes ( 18 , 19 , 20 ) give picomolar apparent affinities ( K i s) for δ opioid receptors accompanied by >100-fold selectivities against secondary interactions at μ and κ sites.…”

“…In the first, conjugates were prepared by reductive amination of N 1‘-aldehyde derivatives with DO3A to afford three- and six-carbon alkyl linkers (Scheme ). NTI, with the phenol protected by a tosyl moiety ( 2 ),6a was selectively alkylated at the indole nitrogen with 3-bromopropionaldehyde dimethylacetal to give 3 (77%), or with 6-bromohexanenitrile to give 7 (96%). Excess alkylating agent was required for good conversion due to competing β-elimination.…”

“…Opioid receptor binding assays (Table ) were performed using membranes from fresh CD1 mouse (δ, [ 3 H]NTI) or frozen guinea pig (μ, [ 3 H]DAMGO; κ, [ 3 H]U69,593) brains . Although guinea pig brain has a significant population of δ sites, 6b, we chose to use mouse brain for these primary site assays because δ receptors, and their interactions with [ 3 H]NTI, are well defined in this tissue 26a…”

Microwave‐Assisted Rapid One‐Pot Synthesis of Fused and Non‐Fused Indoles and 5‐[18F]Fluoroindoles from Phenylazocarboxylates

“…Within our study, and under conditions identical to those described above (Scheme ), dihydrotestosterone could be converted to the indoloterpene 13 in 52 % yield under simultaneous acetylation of the hydroxy group. Moreover, the microwave‐assisted indole synthesis enabled the preparation of the 5′‐fluoronaltrindole derivative 14 in 52 % yield from naltrexone, whereat the so far unknown [ 18 F]fluoro‐substituted analogue of 14 would be a valuable compound for application in PET imaging studies of δ‐opioid receptor expression in vivo . Naltrindole itself is known as a highly selective δ‐opioid receptor antagonist and has recently been employed for crystallization and X‐ray structure analysis of the corresponding ligand receptor complex …”

Morphinan Alkaloids and Their Transformations: A Historical Perspective of a Century of Opioid Research in Hungary

“…Following the synthesis of the δ-OR-selective antagonist N 1′-([ 11 C]methyl)naltrindole ([ 11 C]MeNTI, (K i (μ) = 14 nM, K i (δ) = 0.02 nM, K i (κ) = 65 nM) [ 326 ], and N 1′-(2-[ 18 F]fluoroethyl)naltrindole ([ 18 F]FE-NTI, BU97001, affinities) was prepared [ 327 ].…”

Indium-Labeled Macrocyclic Conjugates of Naltrindole: High-Affinity Radioligands for In Vivo Studies of Peripheral δ Opioid Receptors

“…Thus, the data represents binding of the novel ligands in vitro in one of the few tissues where δ opioid receptors have been characterized from the species to be used for in vivo studies (vide infra). The overall opioid receptor binding profile obtained for NTI agreed well with determinations by others using similar radioligands and tissues. 6b,, The major finding for the novel compounds is the use of linkers having six to nine atoms preserves the high δ opioid receptor affinity of NTI and maintains or improves δ selectivity. These chelators ( 10 , 15 , 16 ) and their indium(III) complexes ( 18 , 19 , 20 ) give picomolar apparent affinities ( K i s) for δ opioid receptors accompanied by >100-fold selectivities against secondary interactions at μ and κ sites.…”

“…In the first, conjugates were prepared by reductive amination of N 1‘-aldehyde derivatives with DO3A to afford three- and six-carbon alkyl linkers (Scheme ). NTI, with the phenol protected by a tosyl moiety ( 2 ),6a was selectively alkylated at the indole nitrogen with 3-bromopropionaldehyde dimethylacetal to give 3 (77%), or with 6-bromohexanenitrile to give 7 (96%). Excess alkylating agent was required for good conversion due to competing β-elimination.…”

“…Opioid receptor binding assays (Table ) were performed using membranes from fresh CD1 mouse (δ, [ 3 H]NTI) or frozen guinea pig (μ, [ 3 H]DAMGO; κ, [ 3 H]U69,593) brains . Although guinea pig brain has a significant population of δ sites, 6b, we chose to use mouse brain for these primary site assays because δ receptors, and their interactions with [ 3 H]NTI, are well defined in this tissue 26a…”

Microwave‐Assisted Rapid One‐Pot Synthesis of Fused and Non‐Fused Indoles and 5‐[18F]Fluoroindoles from Phenylazocarboxylates

“…Within our study, and under conditions identical to those described above (Scheme ), dihydrotestosterone could be converted to the indoloterpene 13 in 52 % yield under simultaneous acetylation of the hydroxy group. Moreover, the microwave‐assisted indole synthesis enabled the preparation of the 5′‐fluoronaltrindole derivative 14 in 52 % yield from naltrexone, whereat the so far unknown [ 18 F]fluoro‐substituted analogue of 14 would be a valuable compound for application in PET imaging studies of δ‐opioid receptor expression in vivo . Naltrindole itself is known as a highly selective δ‐opioid receptor antagonist and has recently been employed for crystallization and X‐ray structure analysis of the corresponding ligand receptor complex …”

Morphinan Alkaloids and Their Transformations: A Historical Perspective of a Century of Opioid Research in Hungary

“…Following the synthesis of the δ-OR-selective antagonist N 1′-([ 11 C]methyl)naltrindole ([ 11 C]MeNTI, (K i (μ) = 14 nM, K i (δ) = 0.02 nM, K i (κ) = 65 nM) [ 326 ], and N 1′-(2-[ 18 F]fluoroethyl)naltrindole ([ 18 F]FE-NTI, BU97001, affinities) was prepared [ 327 ].…”

Indium-Labeled Macrocyclic Conjugates of Naltrindole: High-Affinity Radioligands for In Vivo Studies of Peripheral δ Opioid Receptors

“…Thus, the data represents binding of the novel ligands in vitro in one of the few tissues where δ opioid receptors have been characterized from the species to be used for in vivo studies (vide infra). The overall opioid receptor binding profile obtained for NTI agreed well with determinations by others using similar radioligands and tissues. 6b,, The major finding for the novel compounds is the use of linkers having six to nine atoms preserves the high δ opioid receptor affinity of NTI and maintains or improves δ selectivity. These chelators ( 10 , 15 , 16 ) and their indium(III) complexes ( 18 , 19 , 20 ) give picomolar apparent affinities ( K i s) for δ opioid receptors accompanied by >100-fold selectivities against secondary interactions at μ and κ sites.…”

“…In the first, conjugates were prepared by reductive amination of N 1‘-aldehyde derivatives with DO3A to afford three- and six-carbon alkyl linkers (Scheme ). NTI, with the phenol protected by a tosyl moiety ( 2 ),6a was selectively alkylated at the indole nitrogen with 3-bromopropionaldehyde dimethylacetal to give 3 (77%), or with 6-bromohexanenitrile to give 7 (96%). Excess alkylating agent was required for good conversion due to competing β-elimination.…”

“…Opioid receptor binding assays (Table ) were performed using membranes from fresh CD1 mouse (δ, [ 3 H]NTI) or frozen guinea pig (μ, [ 3 H]DAMGO; κ, [ 3 H]U69,593) brains . Although guinea pig brain has a significant population of δ sites, 6b, we chose to use mouse brain for these primary site assays because δ receptors, and their interactions with [ 3 H]NTI, are well defined in this tissue 26a…”

Microwave‐Assisted Rapid One‐Pot Synthesis of Fused and Non‐Fused Indoles and 5‐[18F]Fluoroindoles from Phenylazocarboxylates

“…Within our study, and under conditions identical to those described above (Scheme ), dihydrotestosterone could be converted to the indoloterpene 13 in 52 % yield under simultaneous acetylation of the hydroxy group. Moreover, the microwave‐assisted indole synthesis enabled the preparation of the 5′‐fluoronaltrindole derivative 14 in 52 % yield from naltrexone, whereat the so far unknown [ 18 F]fluoro‐substituted analogue of 14 would be a valuable compound for application in PET imaging studies of δ‐opioid receptor expression in vivo . Naltrindole itself is known as a highly selective δ‐opioid receptor antagonist and has recently been employed for crystallization and X‐ray structure analysis of the corresponding ligand receptor complex …”

Morphinan Alkaloids and Their Transformations: A Historical Perspective of a Century of Opioid Research in Hungary

“…Following the synthesis of the δ-OR-selective antagonist N 1′-([ 11 C]methyl)naltrindole ([ 11 C]MeNTI, (K i (μ) = 14 nM, K i (δ) = 0.02 nM, K i (κ) = 65 nM) [ 326 ], and N 1′-(2-[ 18 F]fluoroethyl)naltrindole ([ 18 F]FE-NTI, BU97001, affinities) was prepared [ 327 ].…”