Synthesis of 6‐chloro‐3‐((2‐(S)‐azetidinyl)methoxy)‐5‐(2‐[18F]fluoropyridin‐4‐yl)pyridine ([18F]NIDA 522131), a novel potential radioligand for studying extrathalamic nicotinic acetylcholine receptors by PET

Zhang, Yi; Horti, Andrew G.

doi:10.1002/jlcr.883

Cited by 12 publications

(5 citation statements)

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“…These data suggest that [ 18 F](−)- 6b might be a radiotracer of choice for PET imaging of nAChR in the extrathalamic regions. This radioligand is superior to the previous extrathalamic nAChR radioligands and [ 18 F](−)- 3 , 4 , 5 , and merits further investigation.…”

Section: Resultsmentioning

confidence: 91%

Discovery of (−)-7-Methyl-2-exo-[3′-(6-[¹⁸F]fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a Radiolabeled Antagonist for Cerebral Nicotinic Acetylcholine Receptor (α4β2-nAChR) with Optimal Positron Emission Tomography Imaging Properties

et al. 2008

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Several isomers of 7-methyl-2-exo-([(18)F]fluoropyridinyl-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane have been developed as radioligands with optimized brain kinetics for PET imaging of nAChR. The binding assay demonstrated that all isomers are beta-nAChR selective ligands with Ki = 0.02-0.3 nM. The experimental lipophilicity values of all isomers were in the optimal range for the cerebral radioligands (log D7.4= 0.67-0.99). The isomers with higher binding affinity manifested slow baboon brain kinetics, whereas the isomer with the lowest binding affinity (Ki = 0.3 nM) ((-)-7-methyl-2- exo-[3'-(6-[(18)F]fluoropyridin-2-yl)-5'-pyridinyl]-7-azabicyclo[2.2.1]heptane, [(18)F](-)-6c) and greatest lipophilicity (log D 7.4 = 0.99) exhibited optimal brain kinetics. [(18)F](-)-6c manifests a unique combination of the optimally rapid brain kinetics, high BP and brain uptake, and favorable metabolic profile. Pharmacological studies showed that (-)-6c is an alpha4beta2-nAChR antagonist with low side effects in mice. This combination of imaging properties suggests that [(18)F]-(-)- 6c is a potentially superior replacement for 2-[(18)F]fluoro-A-85380 and 6-[(18)F]fluoro-A-85380, the only available nAChR PET radioligands for humans.

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Section: Resultsmentioning

confidence: 91%

Discovery of (−)-7-Methyl-2-exo-[3′-(6-[¹⁸F]fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a Radiolabeled Antagonist for Cerebral Nicotinic Acetylcholine Receptor (α4β2-nAChR) with Optimal Positron Emission Tomography Imaging Properties

et al. 2008

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“…A further class of nicotinic acetylcholine radioligands are those based on a 3-[2-azetidinylmethoxy]pyridine core, whereby 18 F is incorporated into a 2 position of a pyridine ring by S N Ar. − A [ 18 F]fluoropyridinyl derivative of cytosine has been investigated as a radioligand for nicotinic receptors …”

Section: F-fluorination Of (Hetero)arenes Using An [18f]f¯ Sourcementioning

confidence: 99%

¹⁸F-Labeling of Arenes and Heteroarenes for Applications in Positron Emission Tomography

2016

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Diverse radiochemistry is an essential component of nuclear medicine; this includes imaging techniques such as positron emission tomography (PET). As such, PET can track diseases at an early stage of development, help patient care planning through personalized medicine and support drug discovery programs. Fluorine-18 is the most frequently used radioisotope in PET radiopharmaceuticals for both clinical and preclinical research. Its physical and nuclear characteristics (97% β(+) decay, 109.8 min half-life, 635 keV positron energy) and high specific activity make it an attractive nuclide for labeling and molecular imaging. Arenes and heteroarenes are privileged candidates for (18)F-incorporation as they are metabolically robust and therefore widely used by medicinal chemists and radiochemists alike. For many years, the range of (hetero)arenes amenable to (18)F-fluorination was limited by the lack of chemically diverse precursors, and of radiochemical methods allowing (18)F-incorporation in high selectivity and efficiency (radiochemical yield and purity, specific activity, and radio-scalability). The appearance of late-stage fluorination reactions catalyzed by transition metal or small organic molecules (organocatalysis) has encouraged much research on the use of these activation manifolds for (18)F-fluorination. In this piece, we review all of the reactions known to date to install the (18)F substituent and other key (18)F-motifs (e.g., CF3, CHF2, OCF3, SCF3, OCHF2) of medicinal relevance onto (hetero)arenes. The field has changed significantly in the past five years, and the current trend suggests that the radiochemical space available for PET applications will expand rapidly in the near future.

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“…[ 18 F]NIDA522131 and 2FA were synthesized as described previously (Horti et al. 1998; Zhang and Horti 2004) and [ 18 F]Fluoride was produced using an RDS111 negative ion cyclotron. The radiochemical purity of both radioligands was greater than 99%.…”

Section: Methodsmentioning

confidence: 99%

“…2004). Several ligands from this series exhibited extremely high affinities for α 4 β 2 * nAChRs (K d 3–10 pmol/L) and were suitable for radiolabeling with 18 F. In the current paper we describe the evaluation of one of these compounds, 6‐chloro‐3‐((2‐(S)‐azetidinyl)methoxy)‐5‐(2‐fluoropyridin‐4‐yl)pyridine (NIDA522131) (Zhang and Horti 2004). In vitro binding characteristics of NIDA522131 were studied in direct binding assays with radiofluorinated NIDA522131 and in competition assays with two established nicotinic radioligands, 5‐[ 125 I]Iodo‐3‐(2( S )‐azetidinylmethoxy)pyridine (5‐[ 125 I]IA) and a radioiodinated analog of epibatidine [(+/−)‐exo‐2‐(2‐[ 125 I]iodo‐5‐pyridyl)‐7‐azabicyclo[2.2.1]heptane ([ 125 I]IPH)].…”

mentioning

confidence: 99%

NIDA522131, a new radioligand for imaging extrathalamic nicotinic acetylcholine receptors: in vitro and in vivo evaluation

Chefer

Pavlova

Zhang

et al. 2007

Journal of Neurochemistry

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A novel radioligand, 6‐chloro‐3‐((2‐(S)‐azetidinyl)methoxy)‐5‐(2‐fluoropyridin‐4‐yl)pyridine (NIDA522131), for imaging extrathalamic nicotinic acetylcholine receptors (nAChRs) was characterized in vitro and in vivo using positron emission tomography. The Kd and T1/2 of dissociation of NIDA522131 binding measured at 37°C in vitro were 4.9 ± 0.4 pmol/L and 81 ± 5 min, respectively. The patterns of radioactivity distribution in monkey brain in vivo was similar to that of 2‐[18F]fluoro‐3‐(2(S)‐azetidinylmethoxy)pyridine (2FA), a radioligand that has been successfully used in humans, and matched the α4β2* nAChRs distribution. Comparison between [18F]NIDA522131 and 2FA demonstrated better in vivo binding properties of the new radioligand and substantially greater radioactivity accumulation in brain. Consistent with [18F]NIDA522131 elevated affinity for nAChRs and its increased lipophilicity, both, the total and non‐displaceable distribution volumes were substantially higher than those of 2FA. Estimated binding potential values in different brain regions, characterizing the specificity of receptor binding, were 3–4 fold higher for [18F]NIDA522131 than those of 2FA. Pharmacological evaluation in mice demonstrated a toxicity that was comparable to 2FA and is in agreement with a 2300 fold higher affinity at α4β2* versus α3β4* nAChRs. These results suggest that [18F]NIDA522131 is a promising positron emission tomography radioligand for studying extrathalamic nAChR in humans.

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Synthesis of 6‐chloro‐3‐((2‐(S)‐azetidinyl)methoxy)‐5‐(2‐[¹⁸F]fluoropyridin‐4‐yl)pyridine ([¹⁸F]NIDA 522131), a novel potential radioligand for studying extrathalamic nicotinic acetylcholine receptors by PET

Cited by 12 publications

References 10 publications

Discovery of (−)-7-Methyl-2-exo-[3′-(6-[¹⁸F]fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a Radiolabeled Antagonist for Cerebral Nicotinic Acetylcholine Receptor (α4β2-nAChR) with Optimal Positron Emission Tomography Imaging Properties

Discovery of (−)-7-Methyl-2-exo-[3′-(6-[¹⁸F]fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a Radiolabeled Antagonist for Cerebral Nicotinic Acetylcholine Receptor (α4β2-nAChR) with Optimal Positron Emission Tomography Imaging Properties

¹⁸F-Labeling of Arenes and Heteroarenes for Applications in Positron Emission Tomography

NIDA522131, a new radioligand for imaging extrathalamic nicotinic acetylcholine receptors: in vitro and in vivo evaluation

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Synthesis of 6‐chloro‐3‐((2‐(S)‐azetidinyl)methoxy)‐5‐(2‐[18F]fluoropyridin‐4‐yl)pyridine ([18F]NIDA 522131), a novel potential radioligand for studying extrathalamic nicotinic acetylcholine receptors by PET

Cited by 12 publications

References 10 publications

Discovery of (−)-7-Methyl-2-exo-[3′-(6-[18F]fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a Radiolabeled Antagonist for Cerebral Nicotinic Acetylcholine Receptor (α4β2-nAChR) with Optimal Positron Emission Tomography Imaging Properties

Discovery of (−)-7-Methyl-2-exo-[3′-(6-[18F]fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a Radiolabeled Antagonist for Cerebral Nicotinic Acetylcholine Receptor (α4β2-nAChR) with Optimal Positron Emission Tomography Imaging Properties

18F-Labeling of Arenes and Heteroarenes for Applications in Positron Emission Tomography

NIDA522131, a new radioligand for imaging extrathalamic nicotinic acetylcholine receptors: in vitro and in vivo evaluation

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Synthesis of 6‐chloro‐3‐((2‐(S)‐azetidinyl)methoxy)‐5‐(2‐[¹⁸F]fluoropyridin‐4‐yl)pyridine ([¹⁸F]NIDA 522131), a novel potential radioligand for studying extrathalamic nicotinic acetylcholine receptors by PET

Discovery of (−)-7-Methyl-2-exo-[3′-(6-[¹⁸F]fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a Radiolabeled Antagonist for Cerebral Nicotinic Acetylcholine Receptor (α4β2-nAChR) with Optimal Positron Emission Tomography Imaging Properties

Discovery of (−)-7-Methyl-2-exo-[3′-(6-[¹⁸F]fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a Radiolabeled Antagonist for Cerebral Nicotinic Acetylcholine Receptor (α4β2-nAChR) with Optimal Positron Emission Tomography Imaging Properties

¹⁸F-Labeling of Arenes and Heteroarenes for Applications in Positron Emission Tomography