Synthesis and in vitro and in vivo evaluation of 18F-labeled positron emission tomography (PET) ligands for imaging the vesicular acetylcholine transporter

Zhude Tu; Simon M.N. Efange; Jinbin Xu; Shihong Li; Lynne A. Jones; Stanley M. Parsons; Robert H. Mach

doi:10.1021/jm8012344

Synthesis and in vitro and in vivo evaluation of ¹⁸F-labeled positron emission tomography (PET) ligands for imaging the vesicular acetylcholine transporter

Zhude Tu, Simon M.N. Efange, Jinbin Xu, Shihong Li, Lynne A. Jones, Stanley M. Parsons, Robert H. Mach

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

Abstract

A new class of vesicular acetylcholine transporter inhibitor that incorporates a carbonyl group into the benzovesamicol structure was synthesized, and analogues were evaluated in vitro. (±)-trans-2-Hydroxy-3- (4-(4-[ ¹⁸F]fluorobenzoyl)piperidino)tetralin (9e) has K _i values of 2.70 nM for VAChT, 191 nM for σ ₁ and 251 nM for σ ₂. The racemic precursor (9d) was resolved via chiral HPLC, and (±)-[ ¹⁸F]9e,(-)-[ ¹⁸F]9e, and (+)-[ ¹⁸F]9e were respectively radiolabeled via microwave irradiation of the appropriate precursors with [ ¹⁸F]/F- and Kryptofix/K ₂CO ₃ in DMSO with radiochemical yields of ∼50-60% and specific activities of >2000 mCi/μmol. (-)-[ ¹⁸F]9e uptake in rat brain was consistent with in vivo selectivity for the VAChT with an initial uptake of 0.911 %ID/g in rat striatum and a striatum/cerebellum ratio of 1.88 at 30 min postinjection (p.i.). MicroPET imaging of macaques demonstrated a 2.1 ratio of (-)-[ ¹⁸F]9e in putamen versus cerebellum at 2 h p.i. (-)-[ ¹⁸F]9e has potential to be a PET tracer for clinical imaging of the VAChT.

Original language	English
Pages (from-to)	1358-1369
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	5
DOIs	https://doi.org/10.1021/jm8012344
State	Published - Mar 12 2009

Access to Document

10.1021/jm8012344

Cite this

@article{326ed12549984d59b430cfdceb83a47b,

title = "Synthesis and in vitro and in vivo evaluation of 18F-labeled positron emission tomography (PET) ligands for imaging the vesicular acetylcholine transporter",

abstract = "A new class of vesicular acetylcholine transporter inhibitor that incorporates a carbonyl group into the benzovesamicol structure was synthesized, and analogues were evaluated in vitro. (±)-trans-2-Hydroxy-3- (4-(4-[ 18F]fluorobenzoyl)piperidino)tetralin (9e) has K i values of 2.70 nM for VAChT, 191 nM for σ 1 and 251 nM for σ 2. The racemic precursor (9d) was resolved via chiral HPLC, and (±)-[ 18F]9e,(-)-[ 18F]9e, and (+)-[ 18F]9e were respectively radiolabeled via microwave irradiation of the appropriate precursors with [ 18F]/F- and Kryptofix/K 2CO 3 in DMSO with radiochemical yields of ∼50-60% and specific activities of >2000 mCi/μmol. (-)-[ 18F]9e uptake in rat brain was consistent with in vivo selectivity for the VAChT with an initial uptake of 0.911 %ID/g in rat striatum and a striatum/cerebellum ratio of 1.88 at 30 min postinjection (p.i.). MicroPET imaging of macaques demonstrated a 2.1 ratio of (-)-[ 18F]9e in putamen versus cerebellum at 2 h p.i. (-)-[ 18F]9e has potential to be a PET tracer for clinical imaging of the VAChT.",

author = "Zhude Tu and Efange, {Simon M.N.} and Jinbin Xu and Shihong Li and Jones, {Lynne A.} and Parsons, {Stanley M.} and Mach, {Robert H.}",

year = "2009",

month = mar,

day = "12",

doi = "10.1021/jm8012344",

language = "English",

volume = "52",

pages = "1358--1369",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

number = "5",

}

TY - JOUR

T1 - Synthesis and in vitro and in vivo evaluation of 18F-labeled positron emission tomography (PET) ligands for imaging the vesicular acetylcholine transporter

AU - Tu, Zhude

AU - Efange, Simon M.N.

AU - Xu, Jinbin

AU - Li, Shihong

AU - Jones, Lynne A.

AU - Parsons, Stanley M.

AU - Mach, Robert H.

PY - 2009/3/12

Y1 - 2009/3/12

N2 - A new class of vesicular acetylcholine transporter inhibitor that incorporates a carbonyl group into the benzovesamicol structure was synthesized, and analogues were evaluated in vitro. (±)-trans-2-Hydroxy-3- (4-(4-[ 18F]fluorobenzoyl)piperidino)tetralin (9e) has K i values of 2.70 nM for VAChT, 191 nM for σ 1 and 251 nM for σ 2. The racemic precursor (9d) was resolved via chiral HPLC, and (±)-[ 18F]9e,(-)-[ 18F]9e, and (+)-[ 18F]9e were respectively radiolabeled via microwave irradiation of the appropriate precursors with [ 18F]/F- and Kryptofix/K 2CO 3 in DMSO with radiochemical yields of ∼50-60% and specific activities of >2000 mCi/μmol. (-)-[ 18F]9e uptake in rat brain was consistent with in vivo selectivity for the VAChT with an initial uptake of 0.911 %ID/g in rat striatum and a striatum/cerebellum ratio of 1.88 at 30 min postinjection (p.i.). MicroPET imaging of macaques demonstrated a 2.1 ratio of (-)-[ 18F]9e in putamen versus cerebellum at 2 h p.i. (-)-[ 18F]9e has potential to be a PET tracer for clinical imaging of the VAChT.

AB - A new class of vesicular acetylcholine transporter inhibitor that incorporates a carbonyl group into the benzovesamicol structure was synthesized, and analogues were evaluated in vitro. (±)-trans-2-Hydroxy-3- (4-(4-[ 18F]fluorobenzoyl)piperidino)tetralin (9e) has K i values of 2.70 nM for VAChT, 191 nM for σ 1 and 251 nM for σ 2. The racemic precursor (9d) was resolved via chiral HPLC, and (±)-[ 18F]9e,(-)-[ 18F]9e, and (+)-[ 18F]9e were respectively radiolabeled via microwave irradiation of the appropriate precursors with [ 18F]/F- and Kryptofix/K 2CO 3 in DMSO with radiochemical yields of ∼50-60% and specific activities of >2000 mCi/μmol. (-)-[ 18F]9e uptake in rat brain was consistent with in vivo selectivity for the VAChT with an initial uptake of 0.911 %ID/g in rat striatum and a striatum/cerebellum ratio of 1.88 at 30 min postinjection (p.i.). MicroPET imaging of macaques demonstrated a 2.1 ratio of (-)-[ 18F]9e in putamen versus cerebellum at 2 h p.i. (-)-[ 18F]9e has potential to be a PET tracer for clinical imaging of the VAChT.

UR - http://www.scopus.com/inward/record.url?scp=64349102960&partnerID=8YFLogxK

U2 - 10.1021/jm8012344

DO - 10.1021/jm8012344

M3 - Article

C2 - 19203271

AN - SCOPUS:64349102960

SN - 0022-2623

VL - 52

SP - 1358

EP - 1369

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

ER -

Synthesis and in vitro and in vivo evaluation of ¹⁸F-labeled positron emission tomography (PET) ligands for imaging the vesicular acetylcholine transporter

Abstract

Access to Document

Other files and links

Fingerprint

Cite this