Development, validation and implementation of radio-HPLC methods for the P2X7-receptor-targeted [11C]GSK1482160 radiopharmaceutical.

A radio-analytical RP-HPLC method was developed and validated to support production of the P2X7-receptor-targeted [11C]GSK1482160 radiopharmaceutical. Method validation included characterization of retention times, peak shapes, linearity, accuracy, precision, selectivity, limits of detection and quantitation (UV signal), radiochemical stability, as well as analytical method range and robustness. The validated radio-HPLC method is suitable for the definition of [11C]GSK1482160 radiochemical identity, radiochemical purity, as well as molar activity, and is being employed in support of human studies with [11C]GSK1482160.

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

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 370-1110GBq/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 111-740GBq/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.

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

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

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

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 [(11)C]CX-6258 {(E)-5-chloro-3-((5-(3-(4-[(11)C]methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one, [(11)C]4a} was prepared from N-desmethyl-CX-6258 (5) with [(11)C]CH3OTf under basic condition (2N NaOH) through N-[(11)C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40-50% radiochemical yield based on [(11)C]CO2 and decay corrected to end of bombardment (EOB) with 370-1110GBq/µmol specific activity at EOB.

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

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 [(11)C]AZD8931 {2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-[(11)C]methylacetamide} ([(11)C]11a) was prepared from N-desmethyl-AZD8931 (11b) with [(11)C]CH3OTf under basic condition (NaH) through N-[(11)C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40-50% radiochemical yield based on [(11)C]CO2 and decay corrected to end of bombardment (EOB) with 370-1110GBq/µmol specific activity at EOB.

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.

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 [(11)C]methyl 4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate ([(11)C]10a) and [(11)C]methyl 4-(2-methyl-5-(ethoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate ([(11)C]10b) were prepared from their corresponding precursors with [(11)C]CH3OTf under basic condition through O-[(11)C]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).

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.

The reference standards 4a-b, 6a-b, 7a-c, and desmethylated precursors 9a-b, 10a-b, 8a-c were synthesized from 4-methoxyaniline, ethyl 2-chloro-acetoacetate and substituted benzene-1,2-diamines with 3, 5, 6 steps in 61-67%, 34-41%, 23-31%, and with 4, 6, 7 steps in 49-57%, 28-35%, 20-27% overall chemical yield, respectively. The target tracers [(11)C]4a-b, [(11)C]6a-b, [(11)C]7a-c were synthesized from their corresponding precursors with [(11)C]CH3OTf through O-[(11)C]methylation and isolated by simplified SPE in 40-60% decay corrected radiochemical yields at EOB, with 185-370 GBq/µmol specific activity at EOS.

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.

The reference standard N-(4-diethylamino)benzyl-4-methoxy-N-(p-tolyl)benzenesulfonamide (3c) (CB2, Ki=0.5 nM; CB1, Ki=1297 nM; selectivity CB1/CB2=2594) and its corresponding precursor N-(4-diethylamino)benzyl-4-hydroxy-N-(p-tolyl)benzenesulfonamide (3d) were synthesized from 4-(diethylamino)benzaldehyde and p-toluidine in 3 steps with 75-84% overall chemical yield. The target tracer N-(4-diethylamino)benzyl-4-[(11)C]methoxy-N-(p-tolyl)benzenesulfonamide ([(11)C]3c) was synthesized from the phenol hydroxyl precursor by O-[(11)C]-methylation with [(11)C]CH3OTf, followed by HPLC combined with SPE purification in 40-50% decay corrected radiochemical yields with 370-740 GBq/µmol specific activity at the end of bombardment (EOB).

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

The reference standard 2-fluoro-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoic acid was synthesized from 2,5-dimethyl-2,5-hexanediol and 2-fluoro-4-methylbenzoic acid in 10 steps with 3% overall chemical yield. The precursor 2-nitro-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoic acid was synthesized from 2,5-dimethyl-2,5-hexanediol and dimethyl-2-nitroterephthalate in seven steps with 2% overall chemical yield. The target tracer 2-[(18)F]fluoro-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoic acid was synthesized from its nitro-precursor by the nucleophilic substitution with K[(18)F]F/Kryptofix 2.2.2 and isolated by HPLC combined with solid-phase extraction (SPE) purification in 20-30% radiochemical yield with 37-370GBq/µmol specific activity at end of bombardment (EOB).

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.

(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-[(11)C]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.

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

Carbon-11-labeled substituted ß-tetrahydrocarbolines were prepared from their corresponding phenolic hydroxyl precursors with [(11)C]CH3OTf through O-[(11)C]methylation and isolated by simplified SPE in 50-60% decay corrected radiochemical yields at EOB with 185-370GBq/µmol specific activity at EOS. A fluorine-18-labeled substituted ß-tetrahydrocarboline was prepared from its corresponding halo-precursors (X=Cl, Br, I) with K[(18)F]F/Kryptofix 2.2.2 via the nucleophilic substitution and isolated by HPLC combined with SPE in 25-40% decay corrected radiochemical yield with 37-222GBq/µmol specific activity at EOB.

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-Raf(V600E) in cancers.

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-[(11)C]methoxy-1H-pyrazolo[3,4-b]pyridine-5-yl)-3-(propylsulfonamidio)benzamide was prepared from the precursor with [(11)C]CH(3)OTf through O-[(11)C]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).

The organic arsenic derivative GMZ27 induces PML-RARα-independent apoptosis in myeloid leukemia cells.

Arsenic trioxide (ATO) is an inorganic arsenic derivative that is very effective against acute promyelocytic leukemia. However, organic arsenic derivatives (OAD) have a more favorable toxicity profile than ATO. We herein characterized dipropil-S-glycerol arsenic (GMZ27), a novel OAD. GMZ27 had potent antiproliferative activity against human acute myeloid leukemia (AML) cell lines that was higher than that of ATO. In contrast to ATO, GMZ27 only marginally induced maturation of leukemia cells and had no effect on the cell cycle. The anti-leukemia activity of GMZ27 against AML cells was independent of the presence of the PML-RARα fusion protein. GMZ27 dissipates mitochondrial transmembrane potential, and induces cleavage of caspase 9 and activation of caspase 3 without altering the expression levels of (BCL-2), BAX and BCL-xl. GMZ27 induces the formation of intracellular superoxide, a reactive oxygen species (ROS) which plays a major role in the antileukemia activity of this OAD. In addition to ROS generation, GMZ27 concomitantly reduces intracellular glutathione which markedly weakens the cellular antioxidant capacity, thus enhancing the detrimental intracellular effects of ROS production. These results indicate that GMZ27 induces apoptosis in AML cells in a PML-RARα-independent fashion, through the induction of ROS production. This activity provides the rationale for the testing of GMZ27 in patients with AML.

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.

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-[(11)C]methoxy-2-morpholino-4H-chromen-4-ones (X=8, 7, 6, 5; [(11)C]4a-d), were prepared from their corresponding precursors, X-hydroxy-2-morpholino-4H-chromen-4-ones (X=8, 7, 6, 5; 5a-d), with [(11)C]CH(3)OTf through O-[(11)C]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 [(11)C]CO(2), were 40-60%. The specific activity at end of synthesis (EOS) was 185-370 GBq/µmol.

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

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-3,17ß-O,O-bis(sulfamoyl)estradiol (5) is a dual-function STS-CAII inhibitor inhibited STS with 39 nM IC(50) value selectively over CAII with 379 nM IC(50) 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-[(11)C]methoxy-3,17ß-O,O-bis(sulfamoyl)estradiol ([(11)C]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 17ß-estradiol by published procedures in 5 steps with 40% overall chemical yield. The precursor 2-hydroxy-3,17ß-O,O-bis(sulfamoyl)estradiol (14a) for radiolabeling was synthesized from 17ß-estradiol in 10 steps with 5% overall chemical yield. The target tracer [(11)C]5 was prepared from the precursor 14a with [(11)C]CH(3)OTf through O-[(11)C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) purification in 40-50% radiochemical yields based on [(11)C]CO(2) 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.

GSK2126458 is a highly potent inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) with low picomolar to subnanomolar activity. [(11)C]GSK2126458 and [(18)F]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 37-222GBq/µmol specific activity at end of bombardment (EOB), respectively.

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

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-[(11)C]methoxyphenoxy)-2-methylpropanamide ([(11)C]8a), (S)-2-hydroxy-3-(2-[(11)C]methoxyphenoxy)-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide ([(11)C]8 e), (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(4-[(11)C]methoxyphenoxy)-2-methylpropanamide ([(11)C]8c) and (S)-2-hydroxy-3-(4-[(11)C]methoxyphenoxy)-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide ([(11)C]8 g), were prepared by O-[(11)C]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 (9 c) and (S)-2-hydroxy-3-(4-hydroxyphenoxy)-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide (9 d), with [(11)C]CH(3)OTf under basic conditions and isolated by a simplified C-18 solid-phase extraction (SPE) method in 55 ± 5% (n = 5) radiochemical yields based on [(11)C]CO(2) 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).

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

The translocator protein 18 kDa (TSPO) is an attractive target for molecular imaging of neuroinflammation and tumor progression. [(18)F]PBR06, a fluorine-18 labeled form of PBR06, is a promising PET TSPO radioligand originally developed at NIMH. [(11)C]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 [(11)C]PBR06 was prepared by O-[(11)C]methylation of desmethyl-PBR06 with [(11)C]CH(3)OTf in CH(3)CN 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, [(18)F]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. [(18)F]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[(18)F]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 [(18)F]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.

Synthesis and preliminary in vitro biological evaluation of new carbon-11-labeled celecoxib derivatives as candidate PET tracers for imaging of COX-2 expression in cancer.

The enzyme cyclooxygenase-2 (COX-2) is overexpressed in a variety of malignant tumors. This study was designed to develop new radiotracers for imaging of COX-2 in cancer using biomedical imaging technique positron emission tomography (PET). Carbon-11-labeled celecoxib derivatives, [(11)C]4a-c and [(11)C]8a-d, were prepared by O-[(11)C] methylation of their corresponding precursors using [(11)C]CH(3)OTf under basic conditions and isolated by a simplified solid-phase extraction (SPE) method in 52 ± 2% (n = 5) and 57 ± 3% (n = 5) radiochemical yields based on [(11)C]CO(2) 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). The IC(50) values to block COX-2 for known compounds celecoxib (4d), 4a and 4c were 40, 290 and 8 nM, respectively, and preliminary findings from in vitro biological assay indicated that the synthesized new compounds 4b and 8a-d display similar strong inhibitory effectiveness in the MDA-MB-435 human cancer cell line in comparison with the parent compound 4d. These results encourage further in vivo evaluation of carbon-11-labeled celecoxib derivatives as new potential PET radiotracers for imaging of COX-2 expression in cancer.

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

Vandetanib (ZD6474) and its chlorine analogue chloro-Vandetanib are potent and selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors with low nanomolar IC(50) values. [(11)C]Vandetanib and [(11)C]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 370-555GBq/µmol specific activity at end of bombardment (EOB).