Qi-huang Zheng

Name:

Organization: Indiana University School of Medicine

Department: Department of Radiology and Imaging Sciences

Title:

Chemicals
References

Synthesis and preliminary biological evaluation of radiolabeled 5-BDBD analogs as new candidate PET radioligands for P2X4 receptor

Co-reporter:Min Wang, Mingzhang Gao, Jill A. Meyer, Jonathan S. Peters, Hamideh Zarrinmayeh, Paul R. Territo, Gary D. Hutchins, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry 2017 Volume 25, Issue 14(Issue 14) pp:

Publication Date(Web):15 July 2017

DOI:10.1016/j.bmc.2017.05.031

P2X4 receptor has become an interesting molecular target for treatment and PET imaging of neuroinflammation and associated brain diseases such as Alzheimer’s disease. This study reports the first design, synthesis, radiolabeling and biological evaluation of new candidate PET P2X4 receptor radioligands using 5-BDBD, a specific P2X4 receptor antagonist, as a scaffold. 5-(3-Hydroxyphenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD analog, [11C]9) and 5-(3-Bromophenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD, [11C]8c) were prepared from their corresponding desmethylated precursors with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with SPE in 30–50% decay corrected radiochemical yields with 370–1110 GBq/µmol specific activity at EOB. 5-(3-[18F]Fluorophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]F-5-BDBD, [18F]5a) and 5-(3-(2-[18F]fluoroethoxy)phenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]FE-5-BDBD, [18F]11) were prepared from their corresponding nitro- and tosylated precursors by nucleophilic substitution with K[18F]F/Kryptofix 2.2.2 and isolated by HPLC-SPE in 5–25% decay corrected radiochemical yields with 111–740 GBq/µmol specific activity at EOB. The preliminary biological evaluation of radiolabeled 5-BDBD analogs indicated these new radioligands have similar biological activity with their parent compound 5-BDBD.Download high-res image (54KB)Download full-size image

Synthesis and preliminary biological evaluation of [11C]methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate for the fractalkine receptor (CX3CR1)

Co-reporter:Mingzhang Gao, Min Wang, Jill A. Meyer, Jonathan S. Peters, Hamideh Zarrinmayeh, Paul R. Territo, Gary D. Hutchins, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2017 Volume 27, Issue 12(Issue 12) pp:

Publication Date(Web):15 June 2017

DOI:10.1016/j.bmcl.2017.04.052

The reference standard methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate (5) and its precursor 2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucine (6) were synthesized from 6-amino-2-mercaptopyrimidin-4-ol and BnBr with overall chemical yield 7% in five steps and 4% in six steps, respectively. The target tracer [11C]methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate ([11C]5) was prepared from the acid precursor with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 40–50% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370–1110 GBq/μmol with a total synthesis time of ∼40-min from EOB. The radioligand depletion experiment of [11C]5 did not display specific binding to CX3CR1, and the competitive binding assay of ligand 5 found much lower CX3CR1 binding affinity.Download high-res image (37KB)Download full-size image

Synthesis of [11C]MK-1064 as a new PET radioligand for imaging of orexin-2 receptor

Co-reporter:Mingzhang Gao, Min Wang, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2016 Volume 26(Issue 15) pp:3694-3699

Publication Date(Web):1 August 2016

DOI:10.1016/j.bmcl.2016.05.083

The reference standard MK-1064 {5″-chloro-N-((5,6-dimethoxypyridin-2-yl)methyl)-[2,2′:5′,3″-terpyridine]-3′-carboxamide} was synthesized from methyl 2-chloro-5-iodonicotinate and 5-(chloropyridin-3-yl)boronic acid in 4 steps with 33% overall chemical yield. The precursor desmethyl-MK-1064 {5″-chloro-N-((5-hydroxy-6-methoxypyridin-2-yl)methyl)-[2,2′:5′,3″-terpyridine]-3′-carboxamide} for radiolabeling was synthesized from 2-bromopyridin-3-ol and 5″-chloro-[2,2′:5′,3″-terpyridine]-3′-carboxylic acid in 6 steps with 17% overall chemical yield. The target tracer [11C]MK-1064 {5″-chloro-N-((5-[11C]methoxy-6-methoxypyridin-2-yl)methyl)-[2,2′:5′,3″-terpyridine]-3′-carboxamide} was prepared by O-[11C]methylation of its corresponding precursor desmethyl-MK-1064 with [11C]CH3OTf under basic condition and isolated by a simplified solid-phase extraction (SPE) method in 50–60% decay corrected radiochemical yields based on [11C]CO2 at end of bombardment (EOB). The overall synthesis time from EOB was 23 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 185–555 GBq/μmol.

Synthesis of carbon-11-labeled imidazopyridine- and purine-thioacetamide derivatives as new potential PET tracers for imaging of nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1)

Co-reporter:Mingzhang Gao, Min Wang, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2016 Volume 26(Issue 5) pp:1371-1375

Publication Date(Web):1 March 2016

DOI:10.1016/j.bmcl.2016.01.081

The target tracer carbon-11-labeled imidazopyridine- and purine-thioacetamide derivatives, N-(3-[11C]methoxy-4-methoxyphenyl)-2-((5-methoxy-3H-imidazo[4,5-b]pyridin-2-yl)thio)acetamide (3-[11C]4a) and N-(4-[11C]methoxy-3-methoxyphenyl)-2-((5-methoxy-3H-imidazo[4,5-b]pyridin-2-yl)thio)acetamide (4-[11C]4a); 2-((6-amino-9H-purin-8-yl)thio)-N-(3-[11C]methoxy-4-methoxyphenyl)acetamide (3-[11C]8a) and 2-((6-amino-9H-purin-8-yl)thio)-N-(4-[11C]methoxy-3-methoxyphenyl)acetamide (4-[11C]8a), were prepared by O-[11C]methylation of their corresponding precursors with [11C]CH3OTf under basic condition (2 N NaOH) and isolated by a simplified solid-phase extraction (SPE) method in 50–60% radiochemical yields based on [11C]CO2 and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 23 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 185–555 GBq/μmol.

Synthesis of a PET tau tracer [11C]PBB3 for imaging of Alzheimer’s disease

Co-reporter:Min Wang, Mingzhang Gao, Zhidong Xu, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2015 Volume 25(Issue 20) pp:4587-4592

Publication Date(Web):15 October 2015

DOI:10.1016/j.bmcl.2015.08.053

The authentic standard PBB3 and its precursor N-desmethyl-PBB3 as well as TBS-protected N-desmethyl-PBB3 precursor for radiolabeling were synthesized from 5-bromo-2-nitropyridine, acrolein diethyl acetal, 6-methoxy-2-methylbenzothiazole, and diethylchlorophosphate with overall chemical yield 1% in six steps, 2% in five steps, and 1% in six steps, respectively. [11C]PBB3 was prepared from either desmethyl-PBB3 or TBS-protected desmethyl-PBB3 with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with SPE in 20–25% and 15–20% radiochemical yield, respectively, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity at EOB was 370–1110 GBq/μmol with a total synthesis time of ∼40-min from EOB.

Synthesis of [11C]CX-6258 as a new PET tracer for imaging of Pim kinases in cancer

Co-reporter:Min Wang, Reynaldo Tzintzun, Mingzhang Gao, Zhidong Xu, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2015 Volume 25(Issue 18) pp:3831-3835

Publication Date(Web):15 September 2015

DOI:10.1016/j.bmcl.2015.07.061

The reference standard CX-6258 {(E)-5-chloro-3-((5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one, 4a} and its desmethylated precursor N-desmethyl-CX-6258 {(E)-3-((5-(3-(1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)-5-chloroindolin-2-one, 5} for radiolabeling were synthesized from 5-bromo-2-furaldehyde and 3-carboxybenzeneboronic acid in 3 and 4 steps with 29–49% and 24–32% overall chemical yield, respectively. The target tracer [11C]CX-6258 {(E)-5-chloro-3-((5-(3-(4-[11C]methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one, [11C]4a} was prepared from N-desmethyl-CX-6258 (5) with [11C]CH3OTf under basic condition (2 N NaOH) through N-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40–50% radiochemical yield based on [11C]CO2 and decay corrected to end of bombardment (EOB) with 370–1110 GBq/μmol specific activity at EOB.

Synthesis of [11C]GSK1482160 as a new PET agent for targeting P2X7 receptor

Co-reporter:Mingzhang Gao, Min Wang, Mark A. Green, Gary D. Hutchins, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2015 Volume 25(Issue 9) pp:1965-1970

Publication Date(Web):1 May 2015

DOI:10.1016/j.bmcl.2015.03.021

The authentic standards GSK1482160 and its isomer, as well as the radiolabeling precursors desmethyl-GSK1482160 and Boc-protected desmethyl-GSK1482160 were synthesized from l-pyroglutamic acid, methyl l-pyroglutamate and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 27–28% in 3 steps, 58% in 4 steps, 76% in 1 step and 33% in 2 steps, respectively. [11C]GSK1482160 was prepared from either desmethyl-GSK1482160 or Boc-protected desmethyl-GSK1482160 with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with SPE in 40–50% and 30–40% radiochemical yield, respectively, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity at EOB was 370–1110 GBq/μmol with a total synthesis time of ∼40-min from EOB.

Concise and high-yield synthesis of T808 and T808P for radiosynthesis of [18F]-T808, a PET tau tracer for Alzheimer’s disease

Co-reporter:Mingzhang Gao, Min Wang, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2014 Volume 24(Issue 1) pp:254-257

Publication Date(Web):1 January 2014

DOI:10.1016/j.bmcl.2013.11.025

The authentic standard T808 and its corresponding mesylate precursor T808P were synthesized in six steps using ethyl vinyl ether and trichlorocetyl chloride as starting materials. The overall chemical yields of T808 and T808P were 35% and 52%, respectively. [18F]-T808 was synthesized from T808P by the nucleophilic substitution with K[18F]F/Kryptofix 2.2.2 and isolated by HPLC combined with solid-phase extraction (SPE) purification in 35–45% radiochemical yield with 37–370 GBq/μmol specific activity at end of bombardment (EOB).

Synthesis of carbon-11-labeled aminoalkylindole derivatives as new candidates of cannabinoid receptor radioligands for PET imaging of alcohol abuse

Co-reporter:Mingzhang Gao, Andy Chufan Gao, Min Wang, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2014 Volume 24(Issue 24) pp:5581-5586

Publication Date(Web):15 December 2014

DOI:10.1016/j.bmcl.2014.10.097

Carbon-11-labeled aminoalkylindole derivatives (1-butyl-7-[11C]methoxy-1H-indol-3-yl)(naphthalene-1-yl)methanone ([11C]3), 1-butyl-7-[11C]methoxy-3-(naphthalene-1-ylmethyl)-1H-indole ([11C]5), and 1-butyl-7-[11C]methoxy-3-(naphthalene-2-yl)-1H-indole ([11C]8) were prepared by O-[11C]methylation of their corresponding precursors with [11C]CH3OTf under basic condition (2 N NaOH) and isolated by a simplified solid-phase extraction (SPE) method in 50–60% radiochemical yields based on [11C]CO2 and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 23 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 185–555 GBq/μmol.

Synthesis of carbon-11-labeled 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine derivatives as new potential PET tracers for imaging of p38α mitogen-activated protein kinase

Co-reporter:Min Wang, Mingzhang Gao, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2014 Volume 24(Issue 16) pp:3700-3705

Publication Date(Web):15 August 2014

DOI:10.1016/j.bmcl.2014.07.017

The reference standards methyl 4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (10a), methyl 4-(2-methyl-5-(ethoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (10b) and corresponding precursors 4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (11a), methyl 4-(2-methyl-5-(ethoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (11b) were synthesized from methyl crotonate and 3-amino-4-methylbenzoic acid in multiple steps with moderate to excellent yields. The target tracer [11C]methyl 4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate ([11C]10a) and [11C]methyl 4-(2-methyl-5-(ethoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate ([11C]10b) were prepared from their corresponding precursors with [11C]CH3OTf under basic condition through O-[11C]methylation and isolated by a simplified solid-phase extraction (SPE) method in 50–60% radiochemical yields at end of bombardment (EOB) with 185–555 GBq/μmol specific activity at end of synthesis (EOS).

Synthesis of a new fluorine-18-labeled bexarotene analogue for PET imaging of retinoid X receptor

Co-reporter:Min Wang, Toni Davis, Mingzhang Gao, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2014 Volume 24(Issue 7) pp:1742-1747

Publication Date(Web):1 April 2014

DOI:10.1016/j.bmcl.2014.02.037

The first radiosynthesis of [11C]AZD8931 as a new potential PET agent for imaging of EGFR, HER2 and HER3 signaling

Co-reporter:Min Wang, Mingzhang Gao, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2014 Volume 24(Issue 18) pp:4455-4459

Publication Date(Web):15 September 2014

DOI:10.1016/j.bmcl.2014.07.092

The reference standard AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-methylacetamide} (11a) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-chloro-N-methylacetamide in 11 steps with 2–5% overall chemical yield. The precursor N-desmethyl-AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)acetamide} (11b) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-bromoacetamide in 11 steps with 2–4% overall chemical yield. The target tracer [11C]AZD8931 {2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-[11C]methylacetamide} ([11C]11a) was prepared from N-desmethyl-AZD8931 (11b) with [11C]CH3OTf under basic condition (NaH) through N-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40–50% radiochemical yield based on [11C]CO2 and decay corrected to end of bombardment (EOB) with 370–1110 GBq/μmol specific activity at EOB.

[11C]Olanzapine, radiosynthesis and lipophilicity of a new potential PET 5-HT2 and D2 receptor radioligand

Co-reporter:Mingzhang Gao, Zenas Shi, Min Wang, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2013 Volume 23(Issue 7) pp:1953-1956

Publication Date(Web):1 April 2013

DOI:10.1016/j.bmcl.2013.02.045

Olanzapine and its precursor desmethyl-Olanzapine were synthesized from malononitrile, propionaldehyde, 1-fluoro-2-nitrobenzene, and substituted piperazine in 4, 4, 5, and 5 steps with 35%, 32%, 26%, and 32% overall chemical yield, respectively. [11C]Olanzapine was prepared from desmethyl-Olanzapine with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40–50% radiochemical yield based on [11C]CO2 and decay corrected to end of bombardment (EOB), with 370–740 GBq/μmol specific activity at EOB. The calculated Log P (C Log P) value of [11C]Olanzapine is 3.39.

Synthesis of 2,6-difluoro-N-(3-[11C]methoxy-1H-pyrazolo[3,4-b]pyridine-5-yl)-3-(propylsulfonamidio)benzamide as a new potential PET agent for imaging of B-RafV600E in cancers

Co-reporter:Min Wang, Mingzhang Gao, Kathy D. Miller, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2013 Volume 23(Issue 4) pp:1017-1021

Publication Date(Web):15 February 2013

DOI:10.1016/j.bmcl.2012.12.027

The authentic standard 2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridine-5-yl)-3-(propylsulfonamidio)benzamide was synthesized from 2,6-difluorobenzoic acid and 3-amino-5-hydroxypyrazole in 9 steps with 1% overall chemical yield. Direct desmethylation of the reference standard with TMSCl/NaI gave the precursor 2,6-difluoro-N-(3-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-yl)-3-(propylsulfonamidio)benzamide for radiolabeling in 70% yield. The target tracer 2,6-difluoro-N-(3-[11C]methoxy-1H-pyrazolo[3,4-b]pyridine-5-yl)-3-(propylsulfonamidio)benzamide was prepared from the precursor with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 40–50% decay corrected radiochemical yields with 370–740 GBq/μmol specific activity at end of bombardment (EOB).Synthesis of a new PET agent 2,6-difluoro-N-(3-[11C]methoxy-1H-pyrazolo[3,4-b]pyridine-5-yl)-3-(propylsulfonamidio)benzamide for imaging of cancer B-RafV600E is presented.

The first synthesis of [11C]J147, a new potential PET agent for imaging of Alzheimer’s disease

Co-reporter:Min Wang, Mingzhang Gao, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2013 Volume 23(Issue 2) pp:524-527

Publication Date(Web):15 January 2013

DOI:10.1016/j.bmcl.2012.11.031

J147 was synthesized from 2,4-dimethylphenylhydrazine hydrochloride and 3-methoxybenzaldehyde in 2 steps with 71% overall yield. The precursor desmethyl-J147 was synthesized from 3-hydroxybenzaldehyde and 2,4-dimethylphenylhydrazine hydrochloride in 4 steps with 63% overall yield. [11C]J147 was prepared from desmethyl-J147 with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 35–50% radiochemical yield based on [11C]CO2 and decay corrected to end of bombardment (EOB), with 370–740 GBq/μmol specific activity at EOB.Synthesis of a new potential PET agent [11C]J147 for imaging of Alzheimer;s disease is presented.

Synthesis of (Z)-2-((1H-indazol-3-yl)methylene)-6-[11C]methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one as a new potential PET probe for imaging of the enzyme PIM1

Co-reporter:Mingzhang Gao, Min Wang, Kathy D. Miller, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2013 Volume 23(Issue 15) pp:4342-4346

Publication Date(Web):1 August 2013

DOI:10.1016/j.bmcl.2013.05.091

(Z)-2-((1H-Indazol-3-yl)methylene)-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one is a potent and selective proviral integration site in moloney murine leukemia virus kinase 1 (PIM1) inhibitor with an IC50 value of 3 nM. (Z)-2-((1H-Indazol-3-yl)methylene)-6-[11C]methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one, a new potential PET probe for imaging of the enzyme PIM1, was first designed and synthesized in 20–30% decay corrected radiochemical yield and 370–740 GBq/μmol specific activity at end of bombardment (EOB). The synthetic strategy was to prepare a carbon-11-labeled Boc-protected intermediate followed by a quick acidic de-protection.

A high-yield route to synthesize the P-glycoprotein radioligand [11C]N-desmethyl-loperamide and its parent radioligand [11C]loperamide

Co-reporter:Min Wang, Mingzhang Gao, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2013 23(19) pp: 5259-5263

Publication Date(Web):

DOI:10.1016/j.bmcl.2013.08.024

A new high-yield synthetic route to PET CB1 radioligands [11C]OMAR and its analogs

Co-reporter:Mingzhang Gao, Min Wang, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2012 Volume 22(Issue 11) pp:3704-3709

Publication Date(Web):1 June 2012

DOI:10.1016/j.bmcl.2012.04.030

OMAR analogs reference standards and their corresponding desmethylated precursors were synthesized from substituted anilines either in 4 and 5 steps with 27–32% and 24–31% yield, or in 3 and 4 steps with 21–30% and 19–28% yield, respectively. [11C]OMAR and its analog radioligands were prepared from their desmethylated precursors with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 50–65% radiochemical yields based on [11C]CO2 and decay corrected to end of bombardment (EOB), with 370–740 GBq/μmol specific activity at EOB.A new high-yield synthetic route to PET CB1 radioligands [11C]OMAR and its analogs is presented.

A new facile synthetic route to [11C]GSK189254, a selective PET radioligand for imaging of CNS histamine H3 receptor

Co-reporter:Min Wang, Mingzhang Gao, Brandon L. Steele, Barbara E. Glick-Wilson, Clive Brown-Proctor, Anantha Shekhar, Gary D. Hutchins, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2012 Volume 22(Issue 14) pp:4713-4718

Publication Date(Web):15 July 2012

DOI:10.1016/j.bmcl.2012.05.076

GSK189254 and its corresponding precursor GSK185071B were synthesized from 3-methoxyphenylacetic acid with 6-chloropyridine-3-carbolic acid or 6-chloronicotinamide in 8 and 7 steps with either 6% or 7% and either 14% or 16% yield, respectively. [11C]GSK189254 was prepared from GSK185071B with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 50–60% radiochemical yield based on [11C]CO2 and decay corrected to end of bombardment (EOB), with 370–740 GBq/μmol specific activity at EOB.

[11C]GSK2126458 and [18F]GSK2126458, the first radiosynthesis of new potential PET agents for imaging of PI3K and mTOR in cancers

Co-reporter:Min Wang, Mingzhang Gao, Kathy D. Miller, George W. Sledge, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2012 Volume 22(Issue 4) pp:1569-1574

Publication Date(Web):15 February 2012

DOI:10.1016/j.bmcl.2011.12.136

GSK2126458 is a highly potent inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) with low picomolar to subnanomolar activity. [11C]GSK2126458 and [18F]GSK2126458, new potential PET agents for imaging of PI3K and mTOR in cancer, were first designed and synthesized in 40–50% and 20–30% decay corrected radiochemical yield, and 370–740 and 37–222 GBq/μmol specific activity at end of bombardment (EOB), respectively.Radiosynthesis of [11C]GSK2126458 and [18F]GSK2126458, new potential PET agents for imaging of PI3K and mTOR in cancer, is first reported.

Radiosynthesis of [11C]Vandetanib and [11C]chloro-Vandetanib as new potential PET agents for imaging of VEGFR in cancer

Co-reporter:Mingzhang Gao, Christian M. Lola, Min Wang, Kathy D. Miller, George W. Sledge, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 11) pp:3222-3226

Publication Date(Web):1 June 2011

DOI:10.1016/j.bmcl.2011.04.049

Vandetanib (ZD6474) and its chlorine analogue chloro-Vandetanib are potent and selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors with low nanomolar IC50 values. [11C]Vandetanib and [11C]chloro-Vandetanib, new potential PET agents for imaging of VEGFR in cancer, were first designed, synthesized and labeled at nitrogen and oxygen positions from their corresponding N- and O-des-methylated precursors, in 40–50% decay corrected radiochemical yield and 370–555 GBq/μmol specific activity at end of bombardment (EOB).Radiosynthesis of [11C]Vandetanib and [11C]chloro-Vandetanib, new potential PET agents for imaging of VEGFR in cancer, is first reported.

[11C]Enzastaurin, the first design and radiosynthesis of a new potential PET agent for imaging of protein kinase C

Co-reporter:Min Wang, Lu Xu, Mingzhang Gao, Kathy D. Miller, George W. Sledge, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 6) pp:1649-1653

Publication Date(Web):15 March 2011

DOI:10.1016/j.bmcl.2011.01.100

Enzastaurin (LY317615) is a potent and selective protein kinase C (PKC) inhibitor with an IC50 value of ∼6 nM. [11C]Enzastaurin (3-(1-[11C]methyl-1H-indol-3-yl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-1H-indol-3-yl]-1H-pyrrole-2,5-dione), a new potential PET agent for imaging of PKC, was first designed and synthesized in 20–25% decay corrected radiochemical yield and 370–555 GBq/μmol specific activity at end of bombardment (EOB). The synthetic strategy was to prepare a carbon-11-labeled maleic anhydride intermediate followed by the conversion to maleimide.Radiosynthesis of [11C]Enzastaurin, a new potential PET agent for imaging of protein kinase C (PKC), is first reported.

The first synthesis of [11C]SB-216763, a new potential PET agent for imaging of glycogen synthase kinase-3 (GSK-3)

Co-reporter:Min Wang, Mingzhang Gao, Kathy D. Miller, George W. Sledge, Gary D. Hutchins, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 1) pp:245-249

Publication Date(Web):1 January 2011

DOI:10.1016/j.bmcl.2010.11.026

SB-216763 is a novel, potent and selective glycogen synthase kinase-3 (GSK-3) inhibitor with an IC50 value of 34 nM. [11C]SB-216763 (3-(2,4-dichlorophenyl)-4-(1-[11C]methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione), a new potential PET agent for imaging of GSK-3, was first designed and synthesized in 20–30% decay corrected radiochemical yield and 370–555 GBq/μmol specific activity at end of bombardment (EOB). The synthetic strategy was to prepare a carbon-11-labeled maleic anhydride intermediate followed by the conversion to maleimide.Radiosynthesis of [11C]SB-216763, a new potential PET agent for imaging of glycogen synthase kinase (GSK-3), is first reported.

Synthesis and in vitro biological evaluation of carbon-11-labeled quinoline derivatives as new candidate PET radioligands for cannabinoid CB2 receptor imaging

Co-reporter:Mingzhang Gao, Min Wang, Kathy D. Miller, Gary D. Hutchins, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry 2010 Volume 18(Issue 6) pp:2099-2106

Publication Date(Web):15 March 2010

DOI:10.1016/j.bmc.2010.02.011

Cannabinoids have been recently proposed as a new family of potential antitumor agents, and cannabinoid receptor 2 (CB2) is believed to be over-expressed in tumor cells. This study was designed to develop new radioligands for imaging of CB2 receptor in cancer using biomedical imaging technique positron emission tomography (PET). Carbon-11-labeled 2-oxoquinoline and 2-chloroquinoline derivatives, [11C]6a–d and [11C]9a–d, were prepared by O-[11C]methylation of their corresponding precursors using [11C]CH3OTf under basic conditions and isolated by a simplified solid-phase extraction (SPE) method in 40–50% radiochemical yields based on [11C]CO2 and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 15–20 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 111–185 GBq/μmol. Radioligand binding assays indicated compounds 6f, 6b, and 9f display potent in vitro binding affinities with nanomolar Ki values and at least 100–2000-fold selectivity for CB2.This paper reports the synthesis and in vitro biological evaluation of carbon-11-labeled quinoline derivatives as new candidate radioligands for PET imaging of cannabinoid CB2 receptor in cancer.

[11C]Dimebon, radiosynthesis and lipophilicity of a new potential PET agent for imaging of Alzheimer’s disease and Huntington’s disease

Co-reporter:Mingzhang Gao, Min Wang, Gary D. Hutchins, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2010 Volume 20(Issue 8) pp:2529-2532

Publication Date(Web):15 April 2010

DOI:10.1016/j.bmcl.2010.02.094

[11C]Dimebon (2-[11C]methyl-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole), a new potential PET agent for imaging of Alzheimer’s disease and Huntington’s disease, was prepared by N-[11C]methylation of desmethyl-Domebon precursor with [11C]CH3OTf and purified with a semi-preparative HPLC method in 30–40% decay corrected radiochemical yield and 222–296 GBq/μmol specific activity at EOB. The measured lipophilicity coefficient (Log P) value of [11C]Dimebon was 2.53.Radiosynthesis and lipophilicity of [11C]Dimebon, a new potential PET agent for imaging of Alzheimer’s disease and Huntington’s disease, are first reported.

Synthesis of [11C]FEDAA1106 as a new PET imaging probe of peripheral benzodiazepine receptor expression

Co-reporter:Min Wang, Mingzhang Gao, Gary D. Hutchins, Qi-Huang Zheng

European Journal of Medicinal Chemistry 2009 Volume 44(Issue 6) pp:2748-2753

Publication Date(Web):June 2009

DOI:10.1016/j.ejmech.2008.08.001

Peripheral benzodiazepine receptor (PBR) is associated with neuroinflammation and tumor progression. [11C]DAA1106 and [18F]FEDAA1106 are two promising radioligands for positron emission tomography (PET) imaging of PBR. This study was designed to develop a new radiolabeled analog of [11C]DAA1106 and [18F]FEDAA1106, [11C]FEDAA1106, for PET imaging of PBR expression in brain and cancer. Precursor N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-hydroxybenzyl)acetamide (9) was synthesized in multiple steps with moderate to high chemical yields. Precursor 9 was labeled by [11C]CH3OTf and isolated by high pressure liquid chromatography (HPLC) purification to provide target radioligand N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-[11C]methoxybenzyl)acetamide ([11C]FEDAA1106, [11C]10) in 60–70% radiochemical yields, decay corrected to end of bombardment (EOB), based on [11C]CO2. The specific activity of the target radiotracer [11C]10 was in a range of 111–185 GBq/μmol at the end of synthesis (EOS). This paper reports the synthesis of a new radioligand, [11C]FEDAA1106, for PET imaging of peripheral benzodiazepine receptor expression in brain and tumor.

Simple synthesis of carbon-11 labeled styryl dyes as new potential PET RNA-specific, living cell imaging probes

Co-reporter:Min Wang, Mingzhang Gao, Kathy D. Miller, George W. Sledge, Gary D. Hutchins, Qi-Huang Zheng

European Journal of Medicinal Chemistry 2009 Volume 44(Issue 5) pp:2300-2306

Publication Date(Web):May 2009

DOI:10.1016/j.ejmech.2008.02.033

A new type of styryl dyes have been developed as RNA-specific, live cell imaging probes for fluorescent microscopy technology to study nuclear structure and function. This study was designed to develop carbon-11 labeled styryl dyes as new probes for biomedical imaging technique positron emission tomography (PET) imaging of RNA in living cells. Precursors (E)-2-(2-(1-(triisopropylsilyl)-1H-indol-3-yl)vinyl)quinoline (2), (E)-2-(2,4,6-trimethoxystyryl)quinoline (3) and (E)-4-(2-(6-methoxyquinolin-2-yl)vinyl)-N,N-diemthylaniline (4), and standards styryl dyes E36 (6), E144 (7) and F22 (9) were synthesized in multiple steps with moderate to high chemical yields. Precursor 2 was labeled by [11C]CH3OTf, trapped on a cation-exchange CM Sep-Pak cartridge following a quick deprotecting reaction by addition of (n-Bu)4NF in THF, and isolated by solid-phase extraction (SPE) purification to provide target tracer [11C]E36 ([11C]6) in 40–50% radiochemical yields, decay corrected to end of bombardment (EOB), based on [11C]CO2. The target tracers [11C]E144 ([11C]7) and [11C]F22 ([11C]9) were prepared by N-[11C]methylation of the precursors 3 and 4, respectively, using [11C]CH3OTf and isolated by SPE method in 50–70% radiochemical yields at EOB. The specific activity of the target tracers [11C]6, [11C]7 and [11C]9 was in a range of 74–111 GBq/μmol at the end of synthesis (EOS).This paper reports the simple synthesis of new carbon-11 labeled styryl dyes as potential PET RNA-specific, living cell imaging probes.

Fully automated synthesis and initial PET evaluation of [11C]PBR28

Co-reporter:Min Wang, Karmen K. Yoder, Mingzhang Gao, Bruce H. Mock, Xiao-Ming Xu, Andrew J. Saykin, Gary D. Hutchins, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2009 Volume 19(Issue 19) pp:5636-5639

Publication Date(Web):1 October 2009

DOI:10.1016/j.bmcl.2009.08.051

Fully automated synthesis and initial PET evaluation of a TSPO radioligand, [11C]PBR28 (N-(2-[11C]methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide), are reported. These results facilitate the potential preclinical and clinical PET studies of [11C]PBR28 in animals and humans.Fully automated synthesis and initial PET evaluation of a TSPO radioligand [11C]PBR28 are reported.

Synthesis and preliminary biological evaluation of new carbon-11 labeled tetrahydroisoquinoline derivatives as SERM radioligands for PET imaging of ER expression in breast cancer

Co-reporter:Mingzhang Gao, Min Wang, Kathy D. Miller, George W. Sledge, Qi-Huang Zheng

European Journal of Medicinal Chemistry 2008 Volume 43(Issue 10) pp:2211-2219

Publication Date(Web):October 2008

DOI:10.1016/j.ejmech.2008.01.001

The estrogen receptors (ERs) are attractive targets in the treatment of breast cancer and the development of receptor-based breast cancer imaging agents for diagnostic use in biomedical imaging technique positron emission tomography (PET). Tetrahydroisoquinoline derivatives are a class of selective estrogen receptor modulators (SERMs) with high binding affinity and specificity exhibiting up to 50 folds for ERα over ERβ. New carbon-11 labeled tetrahydroisoquinoline derivatives, [11C]methyl 1-(2-(4-(2-(4-fluorophenyl)-6-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenoxy)ethyl)piperidine-4-carboxylate ([11C]10a) and [11C]methyl 1-(2-(4-(2-(4-chlorophenyl)-6-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenoxy)ethyl)piperidine-4-carboxylate ([11C]10b), have been first designed, synthesized and evaluated. The target tracers were prepared by O-[11C]methylation of their corresponding precursors using [11C]CH3OTf and isolated by solid-phase extraction (SPE) purification procedure in 40–60% radiochemical yields, which were decay corrected to the end of bombardment (EOB), based on [11C]CO2. The overall synthesis time was 15–20 min from EOB. The radiochemical purity was >99%, and specific activity was in a range of 74–111 GBq/μmol at the end of synthesis (EOS). Preliminary findings from in vitro biological assay indicate that the synthesized derivatives displayed similar potencies in the MCF-7 human breast cancer cell line in comparison with 4-hydroxytamoxifen, a well-known potent SERM. These results encourage further in vivo evaluation of carbon-11 labeled tetrahydroisoquinoline derivatives as new potential SERM radioligands for PET imaging of ER expression in breast cancer.This paper reports the synthesis and preliminary biological evaluation of new carbon-11 labeled tetrahydroisoquinoline derivatives, potential SERM radioligands for PET imaging of ER expression in breast cancer.

Synthesis of new carbon-11-labeled 7-aroyl-aminoindoline-1-sulfonamides as potential PET agents for imaging of tubulin polymerization in cancers

Co-reporter:Min Wang;Mingzhang Gao;Kathy D. Miller;George W. Sledge;Gary D. Hutchins

Journal of Labelled Compounds and Radiopharmaceuticals 2008 Volume 51( Issue 1) pp:6-11

Publication Date(Web):

DOI:10.1002/jlcr.1462

Abstract

The tubulin polymerization is an attractive target for anticancer therapy and in the development of cancer imaging agents for use in biomedical imaging technique positron emission tomography (PET). 7-Aroyl-aminoindoline-1-sulfonamides are a novel class of potent antitublin agents. Carbon-11-labeled 7-aroyl-aminoindoline-1-sulfonamides have been synthesized as new potential PET agents for imaging of tubulin polymerization in cancers. The target tracers were prepared by O-[¹¹C]methylation of their corresponding precursors using [¹¹C]CH₃OTf and isolated by a simplified solid-phase extraction purification procedure in 40–55% radiochemical yields based on [¹¹C]CO₂ and decay corrected to the end of bombardment (EOB), 15–20 min overall synthesis time from EOB, >98% radiochemical purity, and 74–111 GBq/µmol specific activity at the end of synthesis. Copyright © 2008 John Wiley & Sons, Ltd.

Synthesis and biodistribution of new radiolabeled high-affinity choline transporter inhibitors [11C]hemicholinium-3 and [18F]hemicholinium-3

Co-reporter:Qi-Huang Zheng, Mingzhang Gao, Bruce H. Mock, Shuyan Wang, Toshihiko Hara, Rachid Nazih, Michael A. Miller, Tim J. Receveur, John C. Lopshire, William J. Groh, Douglas P. Zipes, Gary D. Hutchins, Timothy R. DeGrado

Bioorganic & Medicinal Chemistry Letters 2007 Volume 17(Issue 8) pp:2220-2224

Publication Date(Web):15 April 2007

DOI:10.1016/j.bmcl.2007.01.105

The high-affinity choline transporter (CHT1) system is an attractive target for the development of positron emission tomography (PET) biomarkers to probe brain, cardiac, and cancer diseases. An efficient and convenient synthesis of new radiolabeled CHT1 inhibitors [11C]hemicholinium-3 and [18F]hemicholinium-3 by solid-phase extraction (SPE) technique using a cation-exchange CM Sep-Pak cartridge has been well developed. The preliminary evaluation of both tracers through biodistribution studies in 9L-glioma rats has been performed, and the uptakes in the heart and tumor were observed, while very low brain uptake was seen.

Synthesis of carbon-11 labeled sulfonanilide analogues as new potential PET agents for imaging of aromatase in breast cancer

Co-reporter:Min Wang, Gabrielle Lacy, Mingzhang Gao, Kathy D. Miller, George W. Sledge, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2007 Volume 17(Issue 2) pp:332-336

Publication Date(Web):15 January 2007

DOI:10.1016/j.bmcl.2006.10.065

Aromatase is a particularly good target in the treatment of estrogen receptor positive breast cancer. Novel carbon-11 labeled sulfonanilide analogues, N-[11C]methyl-N-(2-alkyloxy-4-nitrophenyl)-methanesulfonamides ([11C]3a–f, alkyl = propyl, isopropyl, 1-ethyl-propyl, cyclopentyl, cyclohexyl, and cyclohexylethyl), were designed and synthesized as potential PET agents for imaging of aromatase in breast cancer.

Synthesis of [11C]Iressa as a new potential PET cancer imaging agent for epidermal growth factor receptor tyrosine kinase

Co-reporter:Ji-Quan Wang, Mingzhang Gao, Kathy D. Miller, George W. Sledge, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2006 Volume 16(Issue 15) pp:4102-4106

Publication Date(Web):1 August 2006

DOI:10.1016/j.bmcl.2006.04.080

Iressa (Gefitinib) is an orally active inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK) involved in cell signal transduction processes critical to proliferation, apoptosis, repair, and angiogenesis of cancer cells. [11C]Iressa was first designed and synthesized as a new potential positron emission tomography (PET) cancer imaging agent for EGFR-TK in 30–40% radiochemical yield with 4.0–6.0 Ci/μmol specific activity at end of bombardment (EOB).

PET imaging and optical imaging with d-luciferin [11C]methyl ester and d-luciferin [11C]methyl ether of luciferase gene expression in tumor xenografts of living mice

Co-reporter:Ji-Quan Wang, Karen E. Pollok, Shanbao Cai, Keith M. Stantz, Gary D. Hutchins, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2006 Volume 16(Issue 2) pp:331-337

Publication Date(Web):15 January 2006

DOI:10.1016/j.bmcl.2005.09.082

New carbon-11 labeled d-luciferin analogs d-luciferin [11C]methyl ester ([11C]LMEster, [11C]1) and d-luciferin [11C]methyl ether ([11C]LMEther, [11C]2) were synthesized in 25–55% radiochemical yield. PET studies with [11C]LMEster and [11C]LMEther demonstrate a lower retention of the C-11 label at 45 min post-injection in luciferase expression tumor. Optical imaging with unlabeled substrate d-luciferin and radiotracers [11C]LMEster and [11C]LMEther gave tumor luciferase images within a few minutes of photon counting.

Synthesis of radiolabeled stilbene derivatives as new potential PET probes for aryl hydrocarbon receptor in cancers

Co-reporter:Mingzhang Gao, Min Wang, Kathy D. Miller, George W. Sledge, Gary D. Hutchins, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2006 Volume 16(Issue 22) pp:5767-5772

Publication Date(Web):15 November 2006

DOI:10.1016/j.bmcl.2006.08.088

New carbon-11 and fluorine-18 labeled stilbene derivatives, cis-3,5-dimethoxy-4′-[11C]methoxystilbene (4′-[11C]8a), cis-3,4′,5-trimethoxy-3′-[11C]methoxystilbene (3′-[11C]8b), trans-3,5-dimethoxy-4′-[11C]methoxystilbene (4′-[11C]10a), trans-3,4′,5-trimethoxy-3′-[11C]methoxystilbene (3′-[11C]10b), cis-3,5-dimethoxy-4′-[18F]fluorostilbene (4′-[18F]12a), and trans-3,5-dimethoxy-4′-[18F]fluorostilbene (4′-[18F]13a), were designed and synthesized as potential PET probes for aryl hydrocarbon receptor (AhR) in cancers.

Synthesis of carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as new potential PET AMPA receptor ligands

Co-reporter:Mingzhang Gao, Deyuan Kong, Abraham Clearfield, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2006 Volume 16(Issue 8) pp:2229-2233

Publication Date(Web):15 April 2006

DOI:10.1016/j.bmcl.2006.01.042

New carbon-11 and fluorine-18 labeled N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential positron emission tomography AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid) receptor ligands to image brain diseases. The single crystal structure of the most potent compound N-acetyl-1-(4′-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5a) is first reported.

Synthesis of 2-amino-6-(4-[11C]methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester as a novel potential PET gene reporter probe for HBV and HSV-tk in cancers

Co-reporter:Ji-Quan Wang, Xiangshu Fei, Thomas A. Gardner, Gary D. Hutchins, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry 2005 Volume 13(Issue 2) pp:549-556

Publication Date(Web):17 January 2005

DOI:10.1016/j.bmc.2004.10.007

Acyclic nucleoside 2-amino-6-(4-methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester (ABE, 1) is a new hepatitis B virus (HBV) specific antiviral reagent and shows high anti-HBV activity. Carbon-11 labeled ABE may serve as a novel reporter probe for positron emission tomography (PET) to image HBV and herpes simplex virus thymidine kinase (HSV-tk) in cancers. The radiolabeling precursors 2-amino-6-(4-hydroxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester (10) and 2-N-Boc protected analogue 2-N-bis(Boc)amino-6-(4-hydroxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester (12), and the reference standard ABE were synthesized from bis(trifluoroethyl) (2-iodoethoxy)methylphosphonate (5), guanine (6), and 2-amino-6-chloropurine (8). The target radiotracer 2-amino-6-(4-[11C]methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester ([11C]ABE, [11C]1) was prepared by O-[11C]methylation of the unprotected HO-precursor 10, or 2-N-Boc protected HO-precursor 12 with [11C]methyl triflate followed by a quick deprotection reaction, and isolated by solid-phase extraction (SPE) purification in 40–55% radiochemical yields.Synthesis of radiolabeled antiviral nucleoside analogue 2-amino-6-(4-[11C]methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester ([11C]ABE) as a novel potential PET reporter probe for hepatitis B virus (HBV) and herpes simplex virus thymidine kinase (HSV-tk) in cancers is reported.

Synthesis and preliminary biological evaluation of O6-[4-(2-[18F]fluoroethoxymethyl)benzyl]guanine as a novel potential PET probe for the DNA repair protein O6-alkylguanine-DNA alkyltransferase in cancer chemotherapy

Co-reporter:Ji-Quan Wang, Emiko L. Kreklau, Barbara J. Bailey, Leonard C. Erickson, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry 2005 Volume 13(Issue 20) pp:5779-5786

Publication Date(Web):15 October 2005

DOI:10.1016/j.bmc.2005.05.061

A novel fluorine-18-labeled O6-benzylguanine (O6-BG) derivative, O6-[4-(2-[18F]fluoroethoxymethyl)benzyl]guanine (O6-[18F]FEMBG, [18F]1), has been synthesized for evaluation as a potential positron emission tomography (PET) probe for the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) in cancer chemotherapy. The appropriate radiolabeling precursor N2,9-bis(p-anisyldiphenylmethyl)-O6-[4-(hydroxymethyl)benzyl]guanine (6) and reference standard O6-[4-(2-fluoroethoxymethyl)benzyl]guanine (O6-FEMBG, 1) were synthesized from 1,4-benzenedimethanol and 2-amino-6-chloropurine in four or six steps, respectively, with moderate to excellent chemical yields. The target tracer O6-[18F]FEMBG was prepared in 20–35% radiochemical yields by reaction of MTr-protected precursor 6 with [18F]fluoroethyl bromide followed by quick deprotection reaction and purification with a simplified Silica Sep-Pak method. Total synthesis time was 60–70 min from the end of bombardment. Radiochemical purity of the formulated product was >95%, with a specific radioactivity of >1.0 Ci/μmol at the end of synthesis. The activity of unlabeled O6-FEMBG was evaluated via an in vitro AGT oligonucleotide assay. Preliminary findings from biological assay indicate that the synthesized analogue has similarly strong inhibiting effect on AGT in comparison with O6-BG and O6-4-fluorobenzylguanine (O6-FBG). The results warrant further in vivo evaluation of O6-[18F]FEMBG as a new potential PET probe for AGT.The synthesis and preliminary biological evaluation of O6-[4-(2-[18F]fluoroethoxymethyl)benzyl]guanine, as a novel potential PET probe for the DNA repair protein O6-alkylguanine-DNA alkyltransferase in cancer chemotherapy, are reported.

Radiosynthesis of carbon-11-labeled camptothecin derivatives as potential positron emission tomography tracers for imaging of topoisomerase I in cancers

Co-reporter:Mingzhang Gao, Kathy D. Miller, George W. Sledge, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters 2005 Volume 15(Issue 17) pp:3865-3869

Publication Date(Web):1 September 2005

DOI:10.1016/j.bmcl.2005.05.108

Four carbon-11-labeled camptothecin derivatives, 9-[11C]methoxy-20(S)-camptothecin ([11C]5), 10-[11C]methoxy-20(S)-camptothecin ([11C]7), 9-nitro-10-[11C]methoxy-20(S)-camptothecin ([11C]9), and 9-[([11C]trimethylamino)methyl]-10-hydroxy-20(S)-camptothecin ([11C]11), have been synthesized as potential positron emission tomography tracers for imaging of topoisomerase I in cancers.

[11C]Choline as a PET biomarker for assessment of prostate cancer tumor models

Co-reporter:Qi-Huang Zheng, Thomas A. Gardner, Sudhanshu Raikwar, Chinghai Kao, K.Lee Stone, Tanya D. Martinez, Bruce H. Mock, Xiangshu Fei, Ji-Quan Wang, Gary D. Hutchins

Bioorganic & Medicinal Chemistry 2004 Volume 12(Issue 11) pp:2887-2893

Publication Date(Web):1 June 2004

DOI:10.1016/j.bmc.2004.03.051

[11C]Choline has been evaluated as a positron emission tomography (PET) biomarker for assessment of established human prostate cancer tumor models. [11C]Choline was prepared by the reaction of [11C]methyl triflate with 2-dimethylaminoethanol (DMAE) and isolated and purified by solid-phase extraction (SPE) method in 60–85% yield based on [11C]CO2, 15–20 min overall synthesis time from end of bombardment (EOB), 95–99% radiochemical purity and specific activity >0.8 Ci/μmol at end of synthesis (EOS). The biodistribution of [11C]choline was determined at 30 min post iv injection in prostate cancer tumor models C4-2, PC-3, CWR22rv, and LNCaP tumor-bearing athymic mice. The results showed the accumulation of [11C]choline in these tumors was 1.0% dose/g in C4-2 mouse, 0.4% dose/g in PC-3 mice, 3.2% dose/g in CWR22rv mice, and 1.4% dose/g in LNCaP mice; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 2.3 (T/M, C4-2), 1.4 (T/M, PC-3), 2.5 (T/M, CWR22rv), 1.2 (T/M, LNCaP) and 2.6 (T/B, C4-2), 2.6 (T/B, PC-3), 7.8 (T/B, CWR22rv), 3.2 (T/B, LNCaP), respectively. The micro-PET imaging of [11C]choline in prostate cancer tumor models was acquired from a C4-2, PC-3, CWR22rv, or LNCaP implanted mouse at 30 min post iv injection of 1 mCi of the tracer using a dedicated high resolution (<3 mm full-width at half-maximum) small FOV (field-of-view) PET imaging system, IndyPET-II scanner, developed in our laboratory, which showed the accumulation of [11C]choline in C4-2, PC-3, CWR22rv, or LNCaP tumor implanted in a nude athymic mouse. The initial dynamic micro-PET imaging data indicated the average T/M ratios were approximately 3.0 (C4-2), 2.1 (PC-3), 3.5 (CWR22rv), and 3.3 (LNCaP), respectively, which showed the tumor accumulation of [11C]choline in all four tumor models is high. These results suggest that there are significant differences in [11C]choline accumulation between these different tumor types, and these differences might offer some useful measure of tumor biological process.In vivo evaluation including biodistribution and micro-PET (positron emission tomography) imaging studies of [11C]choline as a PET biomarker in four established human prostate cancer tumor models C4-2, PC-3, CWR22rv, and LNCaP tumor-bearing athymic mice is reported.

Synthesis, biodistribution and micro-PET imaging of radiolabeled antimitotic agent T138067 analogues

Co-reporter:Xiangshu Fei, Qi-Huang Zheng, Ji-Quan Wang, K.Lee Stone, Tanya D. Martinez, Kathy D. Miller, George W. Sledge, Gary D. Hutchins

Bioorganic & Medicinal Chemistry Letters 2004 Volume 14(Issue 5) pp:1247-1251

Publication Date(Web):8 March 2004

DOI:10.1016/j.bmcl.2003.12.061

Radiolabeled antimitotic agents [11C]T138067 and [18F]T138067 have been synthesized for evaluation as new potential positron emission tomography (PET) biomarkers for cancer imaging. In vivo biodistribution and micro-PET imaging of [11C]T138067 were performed in breast cancer animal models MCF-7 transfected with IL-1α implanted athymic mice and MDA-MB-435 implanted athymic mice. The results suggest that the uptakes of [11C]T138067 in both MCF-7 transfected with IL-1α tumor and MDA-MB-435 tumor are non-specific binding.Graphic

Synthesis of radiolabeled biphenylsulfonamide matrix metalloproteinase inhibitors as new potential PET cancer imaging agents

Co-reporter:Xiangshu Fei, Qi-Huang Zheng, Xuan Liu, Ji-Quan Wang, Hui Bin Sun, Bruce H. Mock, K.Lee Stone, Kathy D. Miller, George W. Sledge, Gary D. Hutchins

Bioorganic & Medicinal Chemistry Letters 2003 Volume 13(Issue 13) pp:2217-2222

Publication Date(Web):7 July 2003

DOI:10.1016/S0960-894X(03)00382-2

Novel matrix metalloproteinase (MMP) inhibitor radiotracers, (S)-3-methyl-2-(2′,3′,4′-methoxybiphenyl-4-sulfonylamino)-butyric acid [11C]methyl ester (1a–c), (S)-3-methyl-2-(2′,3′,4′-fluorobiphenyl-4-sulfonylamino)-butyric acid [11C]methyl ester (1d–f), and (S)-3-methyl-2-(4′-nitrobiphenyl-4-sulfonylamino)-butyric acid [11C]methyl ester (1g), a series of substituted biphenylsulfonamide derivatives, have been synthesized for evaluation as new potential positron emission tomography (PET) cancer imaging agents.Graphic

Synthesis and preliminary biological evaluation of 6-O-[11C]-[(methoxymethyl)benzyl]guanines, new potential PET breast cancer imaging agents for the DNA repair protein AGT

Co-reporter:Xuan Liu, Qi-Huang Zheng, Xiangshu Fei, Ji-Quan Wang, David W Ohannesian, Leonard C Erickson, K.Lee Stone, Gary D Hutchins

Bioorganic & Medicinal Chemistry Letters 2003 Volume 13(Issue 4) pp:641-644

Publication Date(Web):February 2003

DOI:10.1016/S0960-894X(02)01048-X

Novel radiolabeled O6-benzylguanine derivatives, 6-O-[11C]-[(methoxymethyl)benzyl]guanines ([11C]p-O6-MMBG, 1a; [11C]m-O6-MMBG, 1b; ([11C]o-O6-MMBG, 1c), have been synthesized for evaluation as new potential positron emission tomography (PET) breast cancer imaging agents for DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT).Graphic

Synthesis of MMP inhibitor radiotracer [11C]CGS 25966, a new potential pet tumor imaging agent

Co-reporter:Xiangshu Fei;Kathy D. Miller;K. Lee Stone;Ji-Quan Wang;Gary D. Hutchins;George W. Sledge;Xuan Liu

Journal of Labelled Compounds and Radiopharmaceuticals 2003 Volume 46(Issue 4) pp:343-351

Publication Date(Web):19 FEB 2003

DOI:10.1002/jlcr.675

[¹¹C]CGS 25966, a novel radiolabeled matrix metalloproteinase (MMP) inhibitor, has been synthesized for evaluation as new potential positron emission tomography (PET) tumor imaging agent. The precursor was labeled by [¹¹C]methyl triflate through O-[¹¹C]methylation method at the hydroxyl position of phenol under basic conditions and isolated by HPLC purification to produce pure target compound in 15–25% radiochemical yield, based on ¹¹CO₂, decay corrected to end of bombardment. Copyright © 2003 John Wiley & Sons, Ltd.

Synthesis of radiolabeled O6-benzylguanine derivatives as new potential PET tumor imaging agents for the DNA repair protein O6-alkylguanine-DNA alkyltransferase

Co-reporter:Xuan Liu;Xiangshu Fei;Ji-Quan Wang;Leonard C. Erickson;David W. Ohannesian;K. Lee Stone;Kathy D. Miller;Gary D. Hutchins;Tanya D. Martinez

Journal of Labelled Compounds and Radiopharmaceuticals 2002 Volume 45(Issue 14) pp:1239-1252

Publication Date(Web):7 NOV 2002

DOI:10.1002/jlcr.636

Novel radiolabeled O⁶-benzylguanine derivatives, 2-amino-6-O-[¹¹C]-[(methoxymethyl)benzyloxy]-9-benzyl purines ([¹¹C]p-O⁶-AMBP, 1a; [¹¹C]m-O⁶-AMBP, 1b; [¹¹C]o-O⁶-AMBP, 1c), have been synthesized for evaluation as new potential positron emission tomography (PET) tumor imaging agents for the DNA repair protein, O⁶-alkylguanine-DNA alkyltransferase (AGT). The appropriate precursors for radiolabeling were obtained in three steps from starting material 2-amino-6-chloropurine with moderate to excellent chemical yields. Tracers were prepared by O-[¹¹C]methylation of hydroxymethyl precursors using [¹¹C]methyl triflate. Pure target compounds were isolated by solid-phase extraction (SPE) purification procedure in 45–60% radiochemical yields (decay corrected to the end of bombardment), and a synthesis time of 20–25min. Copyright © 2002 John Wiley & Sons, Ltd.

Synthesis of MMP inhibitor radiotracers [11C]methyl-CGS 27023A and its analogs, new potential PET breast cancer imaging agents

Co-reporter:Xiangshu Fei;Gary D. Hutchins;Xuan Liu;K. Lee Stone;Kathy A. Carlson;Bruce H. Mock;Wendy L. Winkle;Barbara E. Glick-Wilson;Kathy D. Miller;Rose S. Fife;George W. Sledge;Hui Bin Sun;Raymond E. Carr

Journal of Labelled Compounds and Radiopharmaceuticals 2002 Volume 45(Issue 6) pp:449-470

Publication Date(Web):27 MAR 2002

DOI:10.1002/jlcr.570

[¹¹C]Methyl-CGS 27023A (1a) and its analogs [¹¹C]methyl-2-picolyl-CGS 27023A (1b), [¹¹C]methyl-benzyl-CGS 27023A (1c), [¹¹C]methyl-2-nitro-CGS 27023A (1d), [¹¹C]methyl-3-nitro-CGS 27023A (1e), and [¹¹C]methyl-4-nitro-CGS 27023A (1f), novel radiolabeled matrix metalloproteinase (MMP) inhibitors, have been synthesized for evaluation as new potential positron emission tomography (PET) breast cancer imaging agents. The appropriate precursors for radiolabeling were obtained in four to five steps from starting material amino acid D-valine with moderate to excellent chemical yields. Precursors were labeled by [¹¹C]methyl triflate through ¹¹C–O-methylation method at the aminohydroxyl position under basic conditions and isolated by solid-phase extraction (SPE) purification to produce pure target compounds in 40–60% radiochemical yields (decay corrected to end of bombardment), in 20–25 min synthesis time. Copyright © 2002 John Wiley & Sons, Ltd.

Simple synthesis of new carbon-11-labeled 1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives for PET imaging of A3 adenosine receptor

Co-reporter:Mingzhang Gao, Andy Chufan Gao, Min Wang, Qi-Huang Zheng

Applied Radiation and Isotopes (September 2014) Volume 91() pp:71-78

Publication Date(Web):September 2014

DOI:10.1016/j.apradiso.2014.05.005

Facile synthesis of carbon-11-labeled cholesterol-based cationic lipids as new potential PET probes for imaging of gene delivery in cancer

Co-reporter:Mingzhang Gao, Min Wang, Kathy D. Miller, George W. Sledge, Gary D. Hutchins, Qi-Huang Zheng

Steroids (October 2010) Volume 75(Issue 10) pp:715-720

Publication Date(Web):1 October 2010

DOI:10.1016/j.steroids.2010.04.009

Gene therapy based on gene delivery is a promising strategy for the treatment of various human diseases such as cancer. Cationic lipids represent one of the important synthetic gene delivery systems. There is a great interest in imaging of gene therapy using the biomedical imaging technique positron emission tomography (PET). Carbon-11-labeled cholesterol-based cationic lipids were first designed and synthesized as new potential PET probes for imaging of gene delivery in cancer. The [11C-methyl]quaternary amine target tracers, N-[11C]methyl-N-[4-(cholest-5-en-3β-yloxycarbonyl)butyl]pyrrolidinium iodide ([11C]4a), N-[11C]methyl-N′-[4-(cholest-5-en-3β-yloxycarbonyl)butyl]imidazolium iodide ([11C]4b), N-[11C]methyl-N-[4-(cholest-5-en-3β-yloxycarbonyl)butyl]piperidinium iodide ([11C]4c), N-[11C]methyl-N-[4-(cholest-5-en-3β-yloxycarbonyl)butyl]-4-methylpiperidinium iodide ([11C]4d), and N-[11C]methyl-N-[4-(cholest-5-en-3β-yloxycarbonyl)butyl]morpholinium iodide ([11C]4e), were prepared from their corresponding tertiary amine precursors with [11C]methyl iodide ([11C]CH3I) through N-[11C]methylation and isolated by a simplified solid-phase extraction (SPE) method using a Silica Sep-Pak cartridge in 50–60% radiochemical yields decay corrected to end-of-bombardment (EOB), based on [11C]CO2, and 111–185 GBq/μmol specific activity at the end of synthesis (EOS).

Synthesis of carbon-11-labeled tricyclic necroptosis inhibitors as new potential PET agents for imaging of tumor necrosis factor α (TNF-α)

Co-reporter:Mingzhang Gao, Christian M. Lola, Min Wang, Kathy D. Miller, George W. Sledge, Gary D. Hutchins, Qi-Huang Zheng

Applied Radiation and Isotopes (October 2010) Volume 68(Issue 10) pp:1950-1958

Publication Date(Web):October 2010

DOI:10.1016/j.apradiso.2010.04.030

Synthesis of new carbon-11 labeled naphthalene-sulfonamides for PET imaging of human CCR8

Co-reporter:Min Wang, Benjamin Cooley, Mingzhang Gao, Kathy D. Miller, George W. Sledge, Gary D. Hutchins, Qi-Huang Zheng

Applied Radiation and Isotopes (October 2008) Volume 66(Issue 10) pp:

Publication Date(Web):1 October 2008

DOI:10.1016/j.apradiso.2008.03.010

Carbon-11 labeled naphthalene-sulfonamides, N-(4-(N-(4-[11C]methoxyphenyl)sulfamoyl)naphthalene-1-yl)benzamide ([11C]5a), N-(4-(N-(4-[11C]methoxyphenyl)sulfamoyl)naphthalene-1-yl)-2-methylbenzamide ([11C]5b), N-(4-(N-(4-[11C]methoxyphenyl)sulfamoyl)naphthalene-1-yl)-3-methylbenzamide ([11C]5c), N-[11C]methyl-N-methyl-4-(4-benzamidonaphthalene-1-sulfonamido)piperidine-1-carboxamide ([11C]9a) and N-[11C]methyl-N-methyl-4-(4-(2-methylbenzamido)naphthalene-1-sulfonamido)piperidine-1-carboxamide ([11C]9b), have been synthesized as new potential positron emission tomography (PET) agents for imaging of human CCR8. The target tracers were prepared by either O-[11C]methylation or N-[11C]methylation of their corresponding precursors using [11C]CH3OTf and isolated by either a simplified solid-phase extraction (SPE) purification procedure or a high pressure liquid chromatography (HPLC) method in 30–50% radiochemical yields decay corrected to end of bombardment (EOB), 20–25 min overall synthesis time, and 74–111 GBq/μmol specific activity at end of synthesis (EOS).

Synthesis of carbon-11 labeled biaryl 1,2,3,4-tetrahydroisoquinoline derivatives and conformationally flexible analogues as new potential PET glioma tumor imaging agents

Co-reporter:Min Wang, Mingzhang Gao, Kathy D. Miller, George W. Sledge, Qi-Huang Zheng

Applied Radiation and Isotopes (October 2007) Volume 65(Issue 10) pp:1152-1159

Publication Date(Web):October 2007

DOI:10.1016/j.apradiso.2007.05.006

Synthesis of [11C]PBR06 and [18F]PBR06 as agents for positron emission tomographic (PET) imaging of the translocator protein (TSPO)

Co-reporter:Min Wang, Mingzhang Gao, Kathy D. Miller, Qi-Huang Zheng

Steroids (November 2011) Volume 76(Issue 12) pp:1331-1340

Publication Date(Web):1 November 2011

DOI:10.1016/j.steroids.2011.06.012

The translocator protein 18 kDa (TSPO) is an attractive target for molecular imaging of neuroinflammation and tumor progression. [18F]PBR06, a fluorine-18 labeled form of PBR06, is a promising PET TSPO radioligand originally developed at NIMH. [11C]PBR06, a carbon-11 labeled form of PBR06, was designed and synthesized for the first time. The standard PBR06 was synthesized from 2,5-dimethoxybenzaldehyde in three steps with 71% overall chemical yield. The radiolabeling precursor desmethyl-PBR06 was synthesized from 2-hydroxy-5-methoxybenzaldehyde in five steps with 12% overall chemical yield. The target tracer [11C]PBR06 was prepared by O-[11C]methylation of desmethyl-PBR06 with [11C]CH3OTf in CH3CN at 80 °C under basic condition and isolated by HPLC combined with SPE purification with 40–60% decay corrected radiochemical yield and 222–740 GBq/μmol specific activity at EOB. On the similar grounds, [18F]PBR06 was also designed and synthesized. The previously described Br-PBR06 precursor was synthesized from 2,5-dimethoxybenzaldehyde in two steps with 78% overall chemical yield. A new radiolabeling precursor tosyloxy-PBR06, previously undescribed tosylate congener of PBR06, was designed and synthesized from ethyl 2-hydroxyacetate, 4-methylbenzene-1-sulfonyl chloride, and N-(2,5-dimethoxybenzyl)-2-phenoxyaniline in four steps with 50% overall chemical yield. [18F]PBR06 was prepared by the nucleophilic substitution of either new tosyloxy-PBR06 precursor or known Br-PBR06 precursor in DMSO at 140 °C with K[18F]F/Kryptofix 2.2.2 for 15 min and HPLC combined with SPE purification in 20–60% decay corrected radiochemical yield, >99% radiochemical purity, 87–95% chemical purity, and 37–222 GBq/μmol specific activity at EOB. Radiosynthesis of [18F]PBR06 using new tosylated precursor gave similar radiochemical purity, and higher specific activity, radiochemical yield and chemical purity in comparison with radiosynthesis using bromine precursor.Highlights► [11C]PBR06 was first designed and synthesized from a new precursor desmethyl-PBR06. ► A new fluorine-18 labeling precursor tosyloxy-PBR06 was discovered. ► Synthesis of [18F]PBR06 via tosyloxy-PBR06 gave better results than via Br-PBR06.

Synthesis of carbon-11 labeled celecoxib derivatives as new candidate PET radioligands for imaging of inflammation

Co-reporter:Mingzhang Gao, Min Wang, Kathy D. Miller, Gary D. Hutchins, Qi-Huang Zheng

Applied Radiation and Isotopes (November 2009) Volume 67(Issue 11) pp:2019-2024

Publication Date(Web):November 2009

DOI:10.1016/j.apradiso.2009.07.022

Facile synthesis of carbon-11-labeled arylpiperazinylthioalkyl derivatives as new PET radioligands for imaging of 5-HT1AR

Co-reporter:Mingzhang Gao, Min Wang, Qi-Huang Zheng

Applied Radiation and Isotopes (March 2012) Volume 70(Issue 3) pp:498-504

Publication Date(Web):March 2012

DOI:10.1016/j.apradiso.2011.11.034

Synthesis of carbon-11-labeled piperidine ring of N-[ω-(6-methoxynaphthalen-1-yl)alkyl] derivatives as new selective PET σ1 receptor probes

Co-reporter:Mingzhang Gao, Min Wang, Gary D. Hutchins, Qi-Huang Zheng

Applied Radiation and Isotopes (March 2010) Volume 68(Issue 3) pp:459-465

Publication Date(Web):March 2010

DOI:10.1016/j.apradiso.2009.12.035

Fully automated synthesis of PET TSPO radioligands [11C]DAA1106 and [18F]FEDAA1106

Co-reporter:Min Wang, Mingzhang Gao, Qi-Huang Zheng

Applied Radiation and Isotopes (June 2012) Volume 70(Issue 6) pp:965-973

Publication Date(Web):June 2012

DOI:10.1016/j.apradiso.2012.03.011

An improved synthesis of dopamine D2/D3 receptor radioligands [11C]fallypride and [18F]fallypride

Co-reporter:Mingzhang Gao, Min Wang, Bruce H. Mock, Barbara E. Glick-Wilson, Karmen K. Yoder, Gary D. Hutchins, Qi-Huang Zheng

Applied Radiation and Isotopes (June 2010) Volume 68(Issue 6) pp:1079-1086

Publication Date(Web):June 2010

DOI:10.1016/j.apradiso.2009.09.071

Synthesis of carbon-11-labeled tariquidar derivatives as new PET agents for imaging of breast cancer resistance protein (ABCG2)

Co-reporter:Min Wang, David X. Zheng, Michael B. Luo, Mingzhang Gao, Kathy D. Miller, Gary D. Hutchins, Qi-Huang Zheng

Applied Radiation and Isotopes (June 2010) Volume 68(Issue 6) pp:1098-1103

Publication Date(Web):June 2010

DOI:10.1016/j.apradiso.2010.02.008

Synthesis of 2-[11C]methoxy-3,17β-O,O-bis(sulfamoyl)estradiol as a new potential PET agent for imaging of steroid sulfatase (STS) in cancers

Co-reporter:Min Wang, Lu Xu, Mingzhang Gao, Kathy D. Miller, George W. Sledge, Qi-Huang Zheng

Steroids (July 2012) Volume 77(Issues 8–9) pp:864-870

Publication Date(Web):1 July 2012

DOI:10.1016/j.steroids.2012.04.007

Steroid sulfatase (STS) catalyzes the hydrolysis of steroid sulfates to estrones, the main source of estrogens in tumors. Carbonic anhydrase II (CAII) is highly expressed in red blood cells through a coordination of the monoanionic form of the sulfamate moiety to the zinc atom in the enzyme active site, and CAII is highly expressed in several tumors. 2-Methoxy-3,17β-O,O-bis(sulfamoyl)estradiol (5) is a dual-function STS-CAII inhibitor inhibited STS with 39 nM IC50 value selectively over CAII with 379 nM IC50 value. This compound exhibited potent antiproferative activity with mean graph midpoint value of 87 nM in the NCI 60-cell-line panel, and antiangiogenic in vitro and in vivo activity in an early-stage Lewis lung model as well. The compound has been recently developed as a multitargeted anticancer agent. Both STS and CAII are over-expressed in cancers and have become attractive targets for cancer treatment and molecular imaging of cancer. Here we report the first design and synthesis of 2-[11C]methoxy-3,17β-O,O-bis(sulfamoyl)estradiol ([11C]5) as a new potential imaging agent for biomedical imaging technique positron emission tomography (PET) to image STS in cancers. The authentic standard 5 was synthesized from 17β-estradiol by published procedures in 5 steps with 40% overall chemical yield. The precursor 2-hydroxy-3,17β-O,O-bis(sulfamoyl)estradiol (14a) for radiolabeling was synthesized from 17β-estradiol in 10 steps with 5% overall chemical yield. The target tracer [11C]5 was prepared from the precursor 14a with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) purification in 40–50% radiochemical yields based on [11C]CO2 and decay corrected to end of bombardment (EOB), with 370–740 GBq/μmol specific activity at EOB.Highlights► New PET tracer 2-[11C]methoxy-3,17β-O,O-bis(sulfamoyl)estradiol was synthesized. ► HPLC combined with solid-phase extraction (SPE) method was used in radiosynthesis. ► New 2-substituted estradiol derivatives were synthesized.

Synthesis of carbon-11-labeled 4-aryl-4H-chromens as new PET agents for imaging of apoptosis in cancer

Co-reporter:Mingzhang Gao, Min Wang, Kathy D. Miller, Gary D. Hutchins, Qi-Huang Zheng

Applied Radiation and Isotopes (January 2010) Volume 68(Issue 1) pp:110-116

Publication Date(Web):January 2010

DOI:10.1016/j.apradiso.2009.09.067

Synthesis of carbon-11 labeled 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium derivatives as new potential PET SKCa channel imaging agents

Co-reporter:Mingzhang Gao, Min Wang, Qi-Huang Zheng

Applied Radiation and Isotopes (February 2008) Volume 66(Issue 2) pp:194-202

Publication Date(Web):February 2008

DOI:10.1016/j.apradiso.2007.08.011

Synthesis of carbon-11-labeled casimiroin analogues as new potential PET agents for imaging of quinone reductase 2 and aromatase expression in breast cancer

Co-reporter:Min Wang, Mingzhang Gao, Kathy D. Miller, George W. Sledge, Gary D. Hutchins, Qi-Huang Zheng

Steroids (December 2010) Volume 75(Issue 12) pp:967-973

Publication Date(Web):1 December 2010

DOI:10.1016/j.steroids.2010.06.004

Carbon-11-labeled casimiroin analogues were first designed and synthesized as new potential PET agents for imaging of quinone reductase (QR) 2 and aromatase expression in breast cancer. [11C]casimiroin (6-[11C]methoxy-9-methyl-[1,3]dioxolo[4,5-h]quinolin-8(9H)-one, [11C]11) and its carbon-11-labeled analogues 5,6,8-trimethoxy-1-[11C]methyl-4-methylquinolin-2(1H)-one ([11C]17), 8-methoxy-1-[11C]methyl-4-methylquinolin-2(1H)-one ([11C]21a), 6,8-dimethoxy-1-[11C]methyl-4-methylquinolin-2(1H)-one ([11C]21b), and 5,8-dimethoxy-1-[11C]methyl-4-methylquinolin-2(1H)-one ([11C]21c), were prepared from their corresponding precursors with [11C]methyl triflate ([11C]CH3OTf) under basic conditions (NaH) through either O- or N-[11C]methylation and isolated by semi-preparative HPLC method in 40–50% radiochemical yields decay corrected to end of bombardment (EOB), based on [11C]CO2, and 111–185 GBq/μmol specific activity at the end of synthesis (EOS).

Synthesis of new carbon-11-labeled carboxamide derivatives as potential PET dopamine D3 receptor radioligands

Co-reporter:Mingzhang Gao, Min Wang, Gary D. Hutchins, Qi-Huang Zheng

Applied Radiation and Isotopes (December 2008) Volume 66(Issue 12) pp:1891-1897

Publication Date(Web):December 2008

DOI:10.1016/j.apradiso.2008.05.010

Facile and high-yield synthesis of N-(4-diethylamino)benzyl-4-[11C]methoxy-N-(p-tolyl)benzenesulfonamide as a new potential PET selective CB2 radioligand

Co-reporter:Mingzhang Gao, Julie Xu, Min Wang, Qi-Huang Zheng

Applied Radiation and Isotopes (August 2014) Volume 90() pp:181-186

Publication Date(Web):August 2014

DOI:10.1016/j.apradiso.2014.03.029

Simple synthesis of carbon-11-labeled chromen-4-one derivatives as new potential PET agents for imaging of DNA-dependent protein kinase (DNA-PK) in cancer

Co-reporter:Mingzhang Gao, Min Wang, Kathy D. Miller, Qi-Huang Zheng

Applied Radiation and Isotopes (August 2012) Volume 70(Issue 8) pp:

Publication Date(Web):1 August 2012

DOI:10.1016/j.apradiso.2012.04.023

Carbon-11-labeled chromen-4-one derivatives were synthesized as new potential PET agents for imaging of DNA repair enzyme DNA-dependent protein kinase (DNA-PK) in cancer. The target tracers, X-[11C]methoxy-2-morpholino-4H-chromen-4-ones (X=8, 7, 6, 5; [11C]4a–d), were prepared from their corresponding precursors, X-hydroxy-2-morpholino-4H-chromen-4-ones (X=8, 7, 6, 5; 5a–d), with [11C]CH3OTf through O-[11C]methylation and isolated by a simplified solid-phase extraction (SPE) method using a C-18 Sep-Pak Plus cartridge. The radiochemical yields decay corrected to end of bombardment (EOB), from [11C]CO2, were 40–60%. The specific activity at end of synthesis (EOS) was 185–370 GBq/μmol.Highlights► New chromen-4-one derivatives were synthesized. ► New carbon-11-labeled chromen-4-one derivatives were synthesized. ► Simple solid-phase extraction (SPE) method was employed in radiosynthesis.

Synthesis of radiolabeled protein disulfide isomerase (PDI) inhibitors as new potential PET agents for imaging of the enzyme PDI in neurological disorders and cancer

Co-reporter:Mingzhang Gao, Qingqing Yang, Min Wang, Kathy D. Miller, George W. Sledge, Qi-Huang Zheng

Applied Radiation and Isotopes (April 2013) Volume 74() pp:61-69

Publication Date(Web):April 2013

DOI:10.1016/j.apradiso.2013.01.003

Synthesis of carbon-11-labeled bivalent β-carbolines as new PET agents for imaging of cholinesterase in Alzheimer's disease

Co-reporter:Min Wang, David X. Zheng, Mingzhang Gao, Gary D. Hutchins, Qi-Huang Zheng

Applied Radiation and Isotopes (April 2011) Volume 69(Issue 4) pp:678-685

Publication Date(Web):April 2011

DOI:10.1016/j.apradiso.2011.01.004

Facile synthesis of new carbon-11 labeled conformationally restricted rivastigmine analogues as potential PET agents for imaging AChE and BChE enzymes

Co-reporter:Min Wang, Ji-Quan Wang, Mingzhang Gao, Qi-Huang Zheng

Applied Radiation and Isotopes (April 2008) Volume 66(Issue 4) pp:506-512

Publication Date(Web):April 2008

DOI:10.1016/j.apradiso.2007.11.005

Synthesis of new carbon-11 labeled cyclofenil derivatives for PET imaging of breast cancer estrogen receptors

Co-reporter:Mingzhang Gao, Min Wang, Bruce H. Mock, Kathy D. Miller, George W. Sledge, Gary D. Hutchins, Qi-Huang Zheng

Applied Radiation and Isotopes (April 2008) Volume 66(Issue 4) pp:523-529

Publication Date(Web):April 2008

DOI:10.1016/j.apradiso.2007.11.006

Design and synthesis of carbon-11-labeled dual aromatase–steroid sulfatase inhibitors as new potential PET agents for imaging of aromatase and steroid sulfatase expression in breast cancer

Co-reporter:Min Wang, Jarrett Mickens, Mingzhang Gao, Kathy D. Miller, George W. Sledge, Gary D. Hutchins, Qi-Huang Zheng

Steroids (4 November 2009) Volume 74(Issue 12) pp:896-905

Publication Date(Web):4 November 2009

DOI:10.1016/j.steroids.2009.06.006

Aromatase and steroid sulfatase (STS) are particularly attractive targets in the treatment of estrogen-receptor-positive breast cancer and the development of enzyme-based cancer imaging agents for the biomedical imaging technique positron emission tomography (PET). New carbon-11-labeled sulfamate derivatives were first designed and synthesized as potential PET dual aromatase–steroid sulfatase inhibitor (DASSI) radiotracers for imaging of aromatase and STS expression in breast cancer. The target tracers 5-(((4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)-2-[11C]methoxyphenyl sulfamate ([11C]8a) and 4-(((4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)-2-[11C]methoxyphenyl sulfamate ([11C]8b) were prepared from their corresponding precursors 5-(((4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)-2-hydroxyphenyl sulfamate (16) and 4-(((4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)-2-hydroxyphenyl sulfamate (21) with [11C]CH3OTf under basic conditions through the O-[11C]methylation and isolated by the reversed-phase high pressure liquid chromatography (HPLC) method in 30–45% radiochemical yields based on [11C]CO2 and decay corrected to end of bombardment (EOB). The specific activity at end of synthesis (EOS) was 111–185 GBq/μmol.

Synthesis of [11C]HG-10-102-01 as a new potential PET agent for imaging of LRRK2 enzyme in Parkinson’s disease

Co-reporter:Min Wang, Mingzhang Gao, Zhidong Xu, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters (15 March 2017) Volume 27(Issue 6) pp:

Publication Date(Web):15 March 2017

DOI:10.1016/j.bmcl.2017.02.019

The reference standard (4-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (HG-10-102-01) and its precursor (4-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-3-hydroxyphenyl)(morpholino)methanone (desmethyl-HG-10-102-01) were synthesized from 2,4,5-trichloropyrimide and 3-methoxy-4-nitrobenzoic acid with overall chemical yield 49% in four steps and 14% in five steps, respectively. The target tracer (4-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-3-[11C]methoxyphenyl)(morpholino)methanone ([11C]HG-10-102-01) was prepared from the precursor desmethyl-HG-10-102-01 with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 45–55% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370–1110 GBq/μmol with a total synthesis time of ∼40-min from EOB.

Synthesis of carbon-11-labeled isonicotinamides as new potential PET agents for imaging of GSK-3 enzyme in Alzheimer’s disease

Co-reporter:Mingzhang Gao, Min Wang, Qi-Huang Zheng

Bioorganic & Medicinal Chemistry Letters (15 February 2017) Volume 27(Issue 4) pp:

Publication Date(Web):15 February 2017

DOI:10.1016/j.bmcl.2017.01.041

The authentic standards 2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide (4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-methoxyphenyl)pyridin-3-yl)isonicotinamide (7a), and their corresponding precursors 2-(cyclopropanecarboxamido)-N-(4-hydroxypyridin-3-yl)isonicotinamide (4b) and 2-(cyclopropanecarboxamido)-N-(4-(4-hydroxyphenyl)pyridin-3-yl)isonicotinamide (7b) were synthesized from methyl 2-aminoisonicotinate and cyclopropanecarbonyl chloride with overall chemical yield 47% in three steps, 22% in four steps, 40% in three steps, and 17% in four steps, respectively. The target tracers 2-(cyclopropanecarboxamido)-N-(4-[11C]methoxypyridin-3-yl)isonicotinamide ([11C]4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-[11C]methoxyphenyl)pyridin-3-yl)isonicotinamide ([11C]7a) were prepared from the precursors (4b and 7b) with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 40–50% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370–1110 GBq/μmol with a total synthesis time of ∼40-min from EOB.

Facile radiosynthesis of new carbon-11-labeled propanamide derivatives as selective androgen receptor modulator (SARM) radioligands for prostate cancer imaging

Co-reporter:Mingzhang Gao, Min Wang, Kathy D. Miller, Qi-Huang Zheng

Steroids (11 December 2011) Volume 76(Issue 13) pp:1505-1512

Publication Date(Web):11 December 2011

DOI:10.1016/j.steroids.2011.08.005

The androgen receptor (AR) is an attractive target for the treatment and molecular imaging of prostate cancer. New carbon-11-labeled propanamide derivatives were first designed and synthesized as selective androgen receptor modulator (SARM) radioligands for prostate cancer imaging using the biomedical imaging technique positron emission tomography (PET). The target tracers, (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(2-[11C]methoxyphenoxy)-2-methylpropanamide ([11C]8a), (S)-2-hydroxy-3-(2-[11C]methoxyphenoxy)-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide ([11C]8e), (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(4-[11C]methoxyphenoxy)-2-methylpropanamide ([11C]8c) and (S)-2-hydroxy-3-(4-[11C]methoxyphenoxy)-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide ([11C]8g), were prepared by O-[11C]methylation of their corresponding precursors, (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(2-hydroxyphenoxy)-2-methylpropanamide (9a), (S)-2-hydroxy-3-(2-hydroxyphenoxy)-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide (9b), (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(4-hydroxyphenoxy)-2-methylpropanamide (9c) and (S)-2-hydroxy-3-(4-hydroxyphenoxy)-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide (9d), with [11C]CH3OTf under basic conditions and isolated by a simplified C-18 solid-phase extraction (SPE) method in 55 ± 5% (n = 5) radiochemical yields based on [11C]CO2 and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 23 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 277.5 ± 92.5 GBq/μmol (n = 5).Highlights► New propanamide derivatives were synthesized. ► New carbon-11-labeled propanamide derivatives were first designed and synthesized. ► Simplified solid-phase extraction (SPE) method was employed in radiosynthesis.