Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2β-carbo-1'-fluoro-2-propoxy-3β-(4-chlorophenyl)tropanes. Ligands for the imaging of dopamine transporters by positron emission tomography

Dongxia Xing, Ping Chen, Robert Keil, Clinton D. Kilts, Bing Shi, Vernon M. Camp, Gene Malveaux, Timothy Ely, Michael J. Owens, John Votaw, Margaret Davis, John M. Hoffman, Roy A.E. BaKay, Thyagarajan Subramanian, Ray L. Watts, Mark M. Goodman

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

2β-(R)-Carbo-1-fluoro-2-propoxy-3β-(4-chlorophenyl)tropane ((R)-FIPCT, R-6) and 2β-(S)-carbo-1-fluoro-2-propoxy-3β-(4-chlorophenyl)tropane ((S)- FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [18F](R)-FIPCT and [18F](S)-FIPCT were synthesized in 5% radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2β-carbo-R-1-mesyloxy-2-propoxy-3β-(4-chlorophenyl)tropane (R- 12) and 2β-carbo-S-1-mesyloxy-2-propoxy-3β-(4-chlorophenyl)tropane (S-12) followed by treatment with no carrier-added potassium[18F]-fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [3]WIN 35428 and [3H]-citalopram, respectively, demonstrated the following order of DAT affinity (K(i) in nM): GBR 12909 (0.36) > CIT (0.48) > (S)-FIPCT (0.67) >> (R)-FIPCT (3.2). The affinity of (S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demonstrated that the brain uptake of [18F](R)-FIPCT and [18F](S)-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [18F](R)-FIPCT and [18F](S)-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [18F](R)-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with [18F](S)-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of [18F](R)-FIPCT and [18F](S)-FIPCT for DAT indicate [18F](R)-FIPCT and [18F](S)-FIPCT are potential radioligands for mapping brain DAT in humans using PET.

Original languageEnglish (US)
Pages (from-to)639-648
Number of pages10
JournalJournal of Medicinal Chemistry
Volume43
Issue number4
DOIs
StatePublished - Mar 13 2000

Fingerprint

Tropanes
Dopamine Plasma Membrane Transport Proteins
Fluorine
Charcoal
Positron-Emission Tomography
Primates
Putamen
Ligands
Serotonin Plasma Membrane Transport Proteins
Cerebellum
Brain Mapping
S 6
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Citalopram
Macaca mulatta
Neuroimaging
Radioactivity
Haplorhini
Brain

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Xing, Dongxia ; Chen, Ping ; Keil, Robert ; Kilts, Clinton D. ; Shi, Bing ; Camp, Vernon M. ; Malveaux, Gene ; Ely, Timothy ; Owens, Michael J. ; Votaw, John ; Davis, Margaret ; Hoffman, John M. ; BaKay, Roy A.E. ; Subramanian, Thyagarajan ; Watts, Ray L. ; Goodman, Mark M. / Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2β-carbo-1'-fluoro-2-propoxy-3β-(4-chlorophenyl)tropanes. Ligands for the imaging of dopamine transporters by positron emission tomography. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 4. pp. 639-648.
@article{83c5c12121dc469893d38e60944705bd,
title = "Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2β-carbo-1'-fluoro-2-propoxy-3β-(4-chlorophenyl)tropanes. Ligands for the imaging of dopamine transporters by positron emission tomography",
abstract = "2β-(R)-Carbo-1-fluoro-2-propoxy-3β-(4-chlorophenyl)tropane ((R)-FIPCT, R-6) and 2β-(S)-carbo-1-fluoro-2-propoxy-3β-(4-chlorophenyl)tropane ((S)- FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [18F](R)-FIPCT and [18F](S)-FIPCT were synthesized in 5{\%} radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2β-carbo-R-1-mesyloxy-2-propoxy-3β-(4-chlorophenyl)tropane (R- 12) and 2β-carbo-S-1-mesyloxy-2-propoxy-3β-(4-chlorophenyl)tropane (S-12) followed by treatment with no carrier-added potassium[18F]-fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [3]WIN 35428 and [3H]-citalopram, respectively, demonstrated the following order of DAT affinity (K(i) in nM): GBR 12909 (0.36) > CIT (0.48) > (S)-FIPCT (0.67) >> (R)-FIPCT (3.2). The affinity of (S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demonstrated that the brain uptake of [18F](R)-FIPCT and [18F](S)-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [18F](R)-FIPCT and [18F](S)-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [18F](R)-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with [18F](S)-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of [18F](R)-FIPCT and [18F](S)-FIPCT for DAT indicate [18F](R)-FIPCT and [18F](S)-FIPCT are potential radioligands for mapping brain DAT in humans using PET.",
author = "Dongxia Xing and Ping Chen and Robert Keil and Kilts, {Clinton D.} and Bing Shi and Camp, {Vernon M.} and Gene Malveaux and Timothy Ely and Owens, {Michael J.} and John Votaw and Margaret Davis and Hoffman, {John M.} and BaKay, {Roy A.E.} and Thyagarajan Subramanian and Watts, {Ray L.} and Goodman, {Mark M.}",
year = "2000",
month = "3",
day = "13",
doi = "10.1021/jm9902234",
language = "English (US)",
volume = "43",
pages = "639--648",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "4",

}

Xing, D, Chen, P, Keil, R, Kilts, CD, Shi, B, Camp, VM, Malveaux, G, Ely, T, Owens, MJ, Votaw, J, Davis, M, Hoffman, JM, BaKay, RAE, Subramanian, T, Watts, RL & Goodman, MM 2000, 'Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2β-carbo-1'-fluoro-2-propoxy-3β-(4-chlorophenyl)tropanes. Ligands for the imaging of dopamine transporters by positron emission tomography', Journal of Medicinal Chemistry, vol. 43, no. 4, pp. 639-648. https://doi.org/10.1021/jm9902234

Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2β-carbo-1'-fluoro-2-propoxy-3β-(4-chlorophenyl)tropanes. Ligands for the imaging of dopamine transporters by positron emission tomography. / Xing, Dongxia; Chen, Ping; Keil, Robert; Kilts, Clinton D.; Shi, Bing; Camp, Vernon M.; Malveaux, Gene; Ely, Timothy; Owens, Michael J.; Votaw, John; Davis, Margaret; Hoffman, John M.; BaKay, Roy A.E.; Subramanian, Thyagarajan; Watts, Ray L.; Goodman, Mark M.

In: Journal of Medicinal Chemistry, Vol. 43, No. 4, 13.03.2000, p. 639-648.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2β-carbo-1'-fluoro-2-propoxy-3β-(4-chlorophenyl)tropanes. Ligands for the imaging of dopamine transporters by positron emission tomography

AU - Xing, Dongxia

AU - Chen, Ping

AU - Keil, Robert

AU - Kilts, Clinton D.

AU - Shi, Bing

AU - Camp, Vernon M.

AU - Malveaux, Gene

AU - Ely, Timothy

AU - Owens, Michael J.

AU - Votaw, John

AU - Davis, Margaret

AU - Hoffman, John M.

AU - BaKay, Roy A.E.

AU - Subramanian, Thyagarajan

AU - Watts, Ray L.

AU - Goodman, Mark M.

PY - 2000/3/13

Y1 - 2000/3/13

N2 - 2β-(R)-Carbo-1-fluoro-2-propoxy-3β-(4-chlorophenyl)tropane ((R)-FIPCT, R-6) and 2β-(S)-carbo-1-fluoro-2-propoxy-3β-(4-chlorophenyl)tropane ((S)- FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [18F](R)-FIPCT and [18F](S)-FIPCT were synthesized in 5% radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2β-carbo-R-1-mesyloxy-2-propoxy-3β-(4-chlorophenyl)tropane (R- 12) and 2β-carbo-S-1-mesyloxy-2-propoxy-3β-(4-chlorophenyl)tropane (S-12) followed by treatment with no carrier-added potassium[18F]-fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [3]WIN 35428 and [3H]-citalopram, respectively, demonstrated the following order of DAT affinity (K(i) in nM): GBR 12909 (0.36) > CIT (0.48) > (S)-FIPCT (0.67) >> (R)-FIPCT (3.2). The affinity of (S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demonstrated that the brain uptake of [18F](R)-FIPCT and [18F](S)-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [18F](R)-FIPCT and [18F](S)-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [18F](R)-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with [18F](S)-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of [18F](R)-FIPCT and [18F](S)-FIPCT for DAT indicate [18F](R)-FIPCT and [18F](S)-FIPCT are potential radioligands for mapping brain DAT in humans using PET.

AB - 2β-(R)-Carbo-1-fluoro-2-propoxy-3β-(4-chlorophenyl)tropane ((R)-FIPCT, R-6) and 2β-(S)-carbo-1-fluoro-2-propoxy-3β-(4-chlorophenyl)tropane ((S)- FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [18F](R)-FIPCT and [18F](S)-FIPCT were synthesized in 5% radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2β-carbo-R-1-mesyloxy-2-propoxy-3β-(4-chlorophenyl)tropane (R- 12) and 2β-carbo-S-1-mesyloxy-2-propoxy-3β-(4-chlorophenyl)tropane (S-12) followed by treatment with no carrier-added potassium[18F]-fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [3]WIN 35428 and [3H]-citalopram, respectively, demonstrated the following order of DAT affinity (K(i) in nM): GBR 12909 (0.36) > CIT (0.48) > (S)-FIPCT (0.67) >> (R)-FIPCT (3.2). The affinity of (S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demonstrated that the brain uptake of [18F](R)-FIPCT and [18F](S)-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [18F](R)-FIPCT and [18F](S)-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [18F](R)-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with [18F](S)-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of [18F](R)-FIPCT and [18F](S)-FIPCT for DAT indicate [18F](R)-FIPCT and [18F](S)-FIPCT are potential radioligands for mapping brain DAT in humans using PET.

UR - http://www.scopus.com/inward/record.url?scp=17744415283&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=17744415283&partnerID=8YFLogxK

U2 - 10.1021/jm9902234

DO - 10.1021/jm9902234

M3 - Article

VL - 43

SP - 639

EP - 648

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 4

ER -