30 years of [11C]methyl triflate.

Some scientific discoveries are well known only to a core group of researchers working on technical subjects. Nevertheless, they open new research directions, allow existing knowledge to be viewed in entirely new and useful ways, or provide a way to make something that was hard or impossible to make before. Carbon-11 methyl triflate ([11C]MeOTf) is one such advance, facilitating the synthesis of many carbon-11 radio tracers and broadening the range of applications of carbon-11 radiochemistry. The year 2022 marked the 30th anniversary of the original paper in Applied Radiation and Isotopes introducing a simple synthesis of [11C]MeOTf from carbon-11 methyl iodide ([11C]MeI) and it also marked the end of the fruitful career and life of the researcher who developed it, Douglas Jewett. It seems fitting to say a few words on how it came to be and how it has helped advance carbon-11 radiochemistry.

Reliability of striatal [¹¹C]raclopride binding in smokers wearing transdermal nicotine patches.

PURPOSE: In studies where [(11)C]raclopride (RAC) positron emission tomography (PET) is used to assess changes in striatal dopamine, it is important to control for cognitive states, such as drug craving, that could alter dopamine levels. In cigarette smokers, transdermal nicotine patches (TNP) can control nicotine craving, but the effects of nicotine patches on RAC binding are unknown. Thus, we sought to determine the test-retest reliability of RAC binding in the presence of nicotine patches. METHODS: Eleven male smokers were scanned twice with RAC on separate days while wearing TNP. RESULTS: Across the striatum, test-retest variability was 7.63 ± 5.88; percent change in binding potential was 1.11 ± 9.83; and the intraclass correlation coefficient was 0.91 (p < 0.0001). CONCLUSION: Baseline RAC binding is highly reproducible in smokers wearing nicotine patches. This suggests that TNP are an acceptable method for controlling cigarette craving during studies that utilize RAC to examine changes in dopamine.

Test-retest variability of [¹¹C]raclopride-binding potential in nontreatment-seeking alcoholics.

Knowledge of the reproducibility of striatal [¹¹C]raclopride (RAC) binding is important for studies that use RAC PET paradigms to estimate changes in striatal dopamine (DA) during pharmacological and cognitive challenges. To our knowledge, no baseline test-retest data exist for nontreatment-seeking alcoholics (NTS). We determined the test-retest reproducibility of baseline RAC binding potential (BP(ND) ) in 12 male NTS subjects. Subjects were scanned twice with single-bolus RAC PET on separate days. Striatal RAC BP (BP(ND) ) for left and right dorsal caudate, dorsal putamen, and ventral striatum was estimated using the Multilinear Reference Tissue Method (MRTM) and Logan Graphical Analysis (LGA) with a reference region. Test-retest variability (TRV), % change in BP(ND) between scan days, and the intraclass correlation coefficient (ICC) were used as metrics of reproducibility. For MRTM, TRV for striatal RAC binding in NTS subjects was ±6.5% and ±7.1% for LGA. Average striatal ICCs were 0.94 for both methods (P < 0.0001). Striatal BP(ND) values were similar to those reported previously for detoxified alcoholics. The results demonstrate that baseline striatal RAC binding is highly reproducible in NTS subjects, with a low variance similar to that reported for healthy control subjects.

Dopamine transporter binding in rat striatum: a comparison of [O-methyl-11C]beta-CFT and [N-methyl-11C]beta-CFT.

INTRODUCTION: Positron emission tomography scanning with radiolabeled phenyltropane cocaine analogs is important for quantifying the in vivo density of monoamine transporters, including the dopamine transporter (DAT). [(11)C]beta-CFT is useful for studying DAT as a marker of dopaminergic innervation in animal models of psychiatric and neurological disorders. [(11)C]beta-CFT is commonly labeled at the N-methyl position. However, labeling of [(11)C]beta-CFT at the O-methyl position is a simpler procedure and results in a shorter synthesis time [desirable in small-animal studies, where specific activity (SA) is crucial]. In this study, we sought to validate that the O-methylated form of [(11)C]beta-CFT provides equivalent quantitative results to that of the more commonly reported N-methyl form. METHODS: Four female Sprague-Dawley rats were scanned twice on the IndyPET II small-animal scanner, once with [N-methyl-(11)C]beta-CFT and once with [O-methyl-(11)C]beta-CFT. DAT binding potentials (BP identical withB'(avail)/K(d)) were estimated for right and left striata with a nonlinear least-squares algorithm, using a reference region (cerebellum) as the input function. RESULTS: [N-Methyl-(11)C]beta-CFT and [O-methyl-(11)C]beta-CFT were synthesized with 40-50% radiochemical yields (HPLC purification). Radiochemical purity was >99%. SA at end of bombardment was 258+/-30 GBq/micromol. Average BP values for right and left striata with [N-methyl-(11)C]beta-CFT were 1.16+/-0.08 and 1.23+/-0.14, respectively. BP values for [O-methyl-(11)C]beta-CFT were 1.18+/-0.08 (right) and 1.22+/-0.16 (left). Paired t tests demonstrated that labeling position did not affect striatal DAT BP. CONCLUSIONS: These results suggest that [O-methyl-(11)C]beta-CFT is quantitatively equivalent to [N-methyl-(11)C]beta-CFT in the rat striatum.

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

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.

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

Carbon-11 labeled cyclofenil derivatives, [(11)C]methyl-2-{4-[bis(4-hydroxyphenyl)methylene]cyclohexyl}acetate ([(11)C]16a), [(11)C]methyl-4-[bis(4-hydroxyphenyl)methylene]cyclohexanecarboxylate ([(11)C]16b), [(11)C]methyl-2-{3-[bis(4-hydroxyphenyl)methylene]cyclohexyl}acetate ([(11)C]18a), and [(11)C]methyl-3-[bis(4-hydroxyphenyl)methylene]cyclohexanecarboxylate ([(11)C]18b), have been synthesized as new potential PET agents for imaging breast cancer estrogen receptors. The target tracers were prepared by O-[(11)C]methylation of their corresponding precursors using [(11)C]CH(3)OTf and isolated by a simplified SPE purification procedure in 35-50% radiochemical yields decay corrected to EOB, 15-20 min overall synthesis time, and 74-111 GBq/micromol specific activity at EOS.

A physiologic imaging pilot study of breast cancer treated with AZD2171.

BACKGROUND: This pilot study combined physiologic imaging, microcomputed tomography, and histologic tumor evaluation with a xenograft model of breast cancer to identify surrogates likely to correlate with response to AZD2171, an inhibitor of the vascular endothelial growth factor (VEGF) receptor tyrosine kinases. EXPERIMENTAL DESIGN: MCF-7 cells transfected with vector (MCF-7neo) or VEGF (MCF(VEGF)) were implanted in the right and left mammary fat pads of 75 athymic mice. Treatment with AZD2171 (5 mg/kg/d) or vehicle control was initiated once tumors were established. Positron emission tomography with [11C]carbon monoxide to measure blood volume, [18F]fluoromethane to measure perfusion, and [18F]fluorodeoxyglucose to measure glucose utilization was done at baseline, and after 24 hours, 72 hours, and 4 weeks of treatment. After imaging, tumors were analyzed for microvessel density, proliferation, and VEGF expression. RESULTS: AZD2171 induced significant inhibition of tumor growth in established MCF-7(neo) xenografts and regression of established MCF-7(VEGF) xenografts. An acute decrease in blood flow was detected in MCF-7(VEGF) tumors at 24 hours (P = 0.05). Tumor blood volume was increased in the MCF-7(VEGF) tumors but correlated with tumor size; blood volume did not change with AZD2171 therapy. Glucose utilization correlated with tumor size and did not change with acute or chronic AZD2171 therapy. Unlike blood flow and blood volume, glucose utilization was similar in MCF-7neo and MCF-7(VEGF) tumors. Microvessel density and proliferation acutely decreased in MCF-7(VEGF) tumors but returned to baseline during chronic therapy. CONCLUSIONS: [18F]Fluoromethane imaging may be a useful surrogate for biological activity of AZD2171 with changes identified within 24 hours of starting therapy.

Synthesis and initial PET imaging of new potential NK1 receptor radioligands 1-[2-(3,5-bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-4-[11C]methyl-piperazine and {4-[2-(3,5-bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazine-1-yl}-acetic acid [11C]methyl ester.

The NK(1) receptor radioligands 1-[2-(3,5-bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-4-[(11)C]methyl-piperazine ([(11)C]BMP, [(11)C]) and {4-[2-(3,5-bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazine-1-yl}-acetic acid [(11)C]methyl ester ([(11)C]BME, [(11)C]) were synthesized for evaluation as new potential PET imaging agents for brain NK(1) receptors. The new tracers [(11)C]BMP and [(11)C]BME were prepared by N-[(11)C]methylation and O-[(11)C]methylation of corresponding precursors 1-[2-(3,5-bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazine and {4-[2-(3,5-bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazine-1-yl}-acetic acid using [(11)C]methyl triflate and isolated by solid-phase extraction (SPE) purification procedure with 40-55% radiochemical yields, decay corrected to end of bombardment, and a synthesis time of 15-20 min. The initial PET dynamic studies of the tracers [(11)C] and [(11)C] in rats were performed using an animal PET scanner, IndyPET-II, developed in our laboratory. The results show the tracer [(11)C]BMP had better uptake in the animal brain than the tracer [(11)C]BME and gave higher quality rat brain images. Blocking studies by intravenous coinjection of hot tracer [(11)C]BMP with cold drug BMP had no effect on [(11)C]BMP-PET rat brain imaging. Likewise, blocking studies by intravenous coinjection of hot tracer [(11)C]BME with cold drug BME also showed no effect on [(11)C]BME-PET rat brain imaging. These results suggest that the localization of [(11)C]BMP and [(11)C]BME in rat brain is mediated by nonspecific processes, and the visualization of [(11)C]BMP-PET and [(11)C]BME-PET on rat brain is related to nonspecific binding.

A facile synthesis of [(11)C]acetylene.

Acetylene is a versatile synthon organic chemistry. The complexity and difficulty of synthesis of [(11)C]acetylene has limited its use as a labeling intermediate for PET radiotracers. A new method for production of [(11)C]acetylene has been developed in our laboratory that simplifies the synthesis procedure allowing for easy automation and implementation. The technique is a modification of Madsen et al. (1981, Phys. Med. Biol. 26(5), 875) that utilized carbon dioxide ((11)C) and barium. First [(11/12)C]CO(2) was trapped at room temperature on barium within a quartz reaction tube, then heated to 900 degrees C under hydrogen flow to release [(11)C]acetylene. Hydrogen gas is apparently oxidized to form water vapor which reacts immediately with the formed carbide to liberate acetylene. Radiochemical yields of 31.4--75.4% and specific activities of 0.11-- 161 mCi/micromol have been obtained with radiochemical purities greater than 99%. This technique provides a new, efficient and very practical synthesis of [(11)C]acetylene that can be utilized as synthon for novel PET radiopharmaceuticals.

[11C]Choline as a potential PET marker for imaging of breast cancer athymic mice.

[11C]Choline has been evaluated as a potential positron emission tomography (PET) marker for imaging of breast cancer. The biodistribution of [11C]choline was determined at 45 min post iv injection in MCF-7's transfected with IL-1alpha implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptake of [11C]choline in these tumors was high, 2.0% dose/g in MCF-7's transfected with IL-1alpha implanted mice and 1.8% dose/g in MDA-MB-435 implanted mice; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 1.7 (T/M, MCF-7's), 2.1 (T/M, MDA-MB-435) and 6.9 (T/B, MCF-7's), 12.5 (T/B, MDA-MB-435), respectively; the tumor/muscle ratios are moderate, and the tumor/blood ratios are high. The micro-PET imaging of [11C]choline in both breast cancer athymic mice was acquired for 15 min from a MCF-7's transfected with IL-1alpha and/or MDA-MB-435 implanted mouse at 45 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, Indy-PET II scanner, developed in our laboratory, which showed the uptake of [11C]choline in MCF-7's transfected with IL-1alpha tumor or MDA-MB-435 tumor implanted in a nude athymic mouse. These results suggest that [11C]choline may be a potential PET breast cancer imaging agent.

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

A series of [11C]methyl-halo-CGS 27023A analogs (2-F, 1a; 4-F, 1b; 2-Cl, 1c; 3-Cl, 1d; 4-Cl, 1e; 2-Br, 1f; 3-Br, 1g; 4-Br, 1h; 4-I, 1i), novel radiolabeled matrix metalloproteinase (MMP) inhibitors, have been synthesized for evaluation as new potential positron emission tomography (PET) breast cancer imaging agents. The precursors halo-CGS 27023A analogs (2-F, 6a; 4-F, 6b; 2-Cl, 6c; 3-Cl, 6d; 4-Cl, 6e; 2-Br, 6f; 3-Br, 6g; 4-Br, 6h; 4-I, 6i) for radiolabeling were obtained in four 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.

Synthesis, biodistribution and micro-PET imaging of a potential cancer biomarker carbon-11 labeled MMP inhibitor (2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid [11C]methyl ester.

(2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid [(11)C]methyl ester ([(11)C]FMAME), a novel carbon-11 labeled matrix metalloproteinase (MMP) inhibitor, has been synthesized for evaluation as new potential positron emission tomography (PET) cancer biomarker. [(11)C]FMAME was prepared by appropriate precursor (2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid (FMA), which was synthesized in six steps from (D)-valine in 71% chemical yield. This acid precursor was labeled by [(11)C]methyl triflate through O-[(11)C]methylation method under basic conditions and isolated by solid-phase extraction (SPE) purification to produce pure target compound in 40-55% radiochemical yield, based on (11)CO(2), decay corrected to end of bombardment, and 15-20 min synthesis time. The biodistribution of [(11)C]FMAME was determined at 30 min post IV injection in breast cancer animal models MCF-7 transfected with IL-1 alpha implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptakes of [(11)C]FMAME in these tumors were 1.13% dose/g in MCF-7 transfected with IL-1 alpha implanted mice and 1.37% dose/g in MDA-MB-435 implanted mice, respectively; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 1.05 +/- 0.29 (T/M, MCF-7's), 0.77 +/- 0.20 (T/B, MCF-7's) and 0.99 +/- 0.35 (T/M, MDA-MB-435), 1.44 +/- 0.69 (T/B, MDA-MB-435), respectively. Pretreatment of MCF-7 transfected with IL-1 alpha tumor-bearing mice with MMP inhibitor FMA had no effect on [(11)C]FMAME biodistribution. Likewise, pretreatment of MDA-MB-435 tumor-bearing mice with FMA also showed no effect on [(11)C]FMAME biodistribution. The micro-PET images were acquired for 15 min from a MCF-7 transfected with IL-1 alpha tumor-bearing mouse or a MDA-MB-435 tumor-bearing mouse at 30 min post IV injection of 1 mCi of [(11)C]FMAME using a dedicated high resolution (<3 mm full-width at half-maximum) PET imaging system (Indy-PET II scanner). The initial dynamic micro-PET images of [(11)C]FMAME in a MCF-7 transfected with IL-1 alpha tumor-bearing mouse during different time periods of 0-15, 15-30, 30-45 and 45-60 min were performed by Indy-PET II. The PET images clearly showed both tumors were visible with [(11)C]FMAME. These results suggest that the localization of [(11)C]FMAME in the tumor is mediated by non-specific processes, and the visualization of [(11)C]FMAME on the tumor using the Indy-PET II scanner is related to non-specific binding.

Striatal D(2)/D(3) receptor availability is inversely correlated with cannabis consumption in chronic marijuana users.

BACKGROUND: Although the incidence of cannabis abuse/dependence in Americans is rising, the neurobiology of cannabis addiction is not well understood. Imaging studies have demonstrated deficits in striatal D(2)/D(3) receptor availability in several substance-dependent populations. However, this has not been studied in currently using chronic cannabis users. OBJECTIVE: The purpose of this study was to compare striatal D(2)/D(3) receptor availability between currently using chronic cannabis users and healthy controls. METHODS: Eighteen right-handed males age 18-34 were studied. Ten subjects were chronic cannabis users; eight were demographically matched controls. Subjects underwent a [(11)C]raclopride (RAC) PET scan. Striatal RAC binding potential (BP(ND)) was calculated on a voxel-wise basis. Prior to scanning, urine samples were obtained from cannabis users for quantification of urine Δ-9-tetrahydrocannabinol (THC) and THC metabolites (11-nor-Δ-9-THC-9-carboxylic acid; THC-COOH and 11-hydroxy-THC;OH-THC). RESULTS: There were no differences in D(2)/D(3) receptor availability between cannabis users and controls. Voxel-wise analyses revealed that RAC BP(ND) values were negatively associated with both urine levels of cannabis metabolites and self-report of recent cannabis consumption. CONCLUSIONS: In this sample, current cannabis use was not associated with deficits in striatal D(2)/D(3) receptor availability. There was an inverse relationship between chronic cannabis use and striatal RAC BP(ND). Additional studies are needed to identify the neurochemical consequences of chronic cannabis use on the dopamine system.

Assessment of i.p. injection of [18F]fallypride for behavioral neuroimaging in rats.

Great progress has been made toward using small animal PET to assess neurochemical changes during behavior. [(18)F]fallypride (FAL) is a D(2)/D(3) antagonist that is sensitive to changes in endogenous dopamine, and, in theory, could be used to assess changes in dopamine during behavioral paradigms. Tail vein injections of tracer require restraint in awake animals, and catheter implantation is invasive and can cause logistical problems. Thus, administering tracer with i.p. injections (which are well-tolerated by rodents) would be preferable. The purpose of this study was to determine whether i.p. injection of FAL would produce striatal uptake similar to that seen with traditional i.v. tail vein injection protocols. Four male Sprague-Dawley rats underwent i.p. injection of FAL, followed by a 30-min uptake and subsequent dynamic image acquisition on the IndyPET III small animal scanner. Three of these rats also received traditional dynamic scanning with i.v. FAL injection via a tail vein. Two rats that received i.p. injection had moderate striatal uptake, with striatum/cerebellum ratios (SUVR) that were only ∼20% lower than ratios from i.v. scans. Two other rats had little to no uptake; SUVR values were ∼70% lower than i.v. SUVR. These latter two animals showed heavy bone uptake, evidence of defluorination of FAL. The results of this pilot study suggest that it may be possible to achieve striatal uptake of FAL after i.p. injection. However, this was not seen consistently across animals. Future studies are needed to validate, and then to optimize, the use of i.p. FAL for behavioral imaging protocols.

An automated SPE-based high-yield synthesis of [11C]acetate and [11C]palmitate: no liquid-liquid extraction, solvent evaporation or distillation required.

INTRODUCTION: An automated method is described for the rapid and high-yield synthesis of two of the most commonly used radioactive fatty acids: [(11)C]acetate and [(11)C]palmitate. METHODS: Reaction of [(11)C]CO(2) with the respective Grignard reagents in diethyl ether solution proceeded for 2 min at 40°C. Quenching of the reaction and liberation of nonreacted [(11)C]CO(2) occurred upon addition of a fourfold molar excess of aqueous 0.1 M HCl (acetate) or nonaqueous HCl/Et(2)O (palmitate). Labeled products were then purified by adsorption to an Alumina-N Sep-Pak Plus cartridge and eluted with either aqueous NaH(2)PO(4) solution (acetate) or 100% ethanol (palmitate). RESULTS: High-performance liquid chromatography analysis confirmed that the radiochemical purity of each product was >98%, and decay-corrected radiochemical yields averaged 33% for [(11)C]palmitate and 40% for [(11)C]acetate. CONCLUSION: The method requires no liquid-liquid extraction, solvent evaporation or distillation capabilities and can be readily adapted to existing radiosynthesis modules.

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

Improved syntheses of dopamine D(2)/D(3) receptor radioligands [(11)C]Fallypride and [(18)F]Fallypride are reported. The phenolic precursor (9) for C-11 labeling and the Fallypride (10) reference standard were synthesized from the starting material 2-hydroxy-3-methoxy-5-(2-propenyl)benzoic acid methyl ester (1) in 7 and 8 steps with 16% and 5% overall chemical yields, respectively. The tosylated precursor (15) for F-18 labeling was synthesized from compound 1 in 5 steps with 32% overall chemical yield. An alternate synthetic approach for Fallypride has been developed using the same starting material 1 in 5 steps with 26% overall chemical yield. [(11)C]Fallypride ([(11)C]10) was prepared by O-[(11)C]methylation of the phenolic precursor with [(11)C]methyl triflate and purified with a semi-preparative HPLC method in 50-60% radiochemical yield, decay corrected to end of bombardment (EOB), based on [(11)C]CO(2), and 370+/-185 GBq/micromol specific radioactivity at EOB. [(18)F]Fallypride ([(18)F]10) was prepared by nucleophilic substitution of the tosylated precursor with K[(18)F]F/Kryptofix 2.2.2 and HPLC combined with solid-phase extraction (SPE) purification in variable (up to 50%) decay corrected radiochemical yield from K[(18)F]F and 111-222 GBq/micromol specific activity at EOB.

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

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 [(11)C]hemicholinium-3 and [(18)F]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.

Evaluation of [11C]hemicholinium-15 and [18F]hemicholinium-15 as new potential PET tracers for the high-affinity choline uptake system in the heart.

[(11)C]Hemicholinium-15 ([(11)C]HC-15) and [(18)F]hemicholinium-15 ([(18)F]HC-15) have been synthesized as new potential PET tracers for the heart high-affinity choline uptake (HACU) system. [(11)C]HC-15 was prepared by N-[(11)C]methylation of the appropriate precursor, 4-methyl-2-phenyl-morpholin-2-ol, using [(11)C]CH(3)OTf in 55-70% radiochemical yield decay corrected to end of bombardment (EOB) and 2-3Ci/mumol specific activity at end of synthesis (EOS). [(18)F]HC-15 was prepared by N-[(18)F]fluoromethylation of the precursor using [(18)F]FCH(2)OTf in 20-30% radiochemical yield decay corrected to EOB and >1.0Ci/mumol specific activity at EOS. The biodistribution of both compounds was determined in rats at 20min post-intravenous injection, and the results show the heart region uptakes 1.32+/-0.75%ID/g in R-ventricle for [(11)C]HC-15 and 1.28+/-0.81%ID/g in L-ventricle for [(18)F]HC-15, respectively. The dynamic PET imaging studies of [(11)C]HC-15 in rats were acquired 60min post-intravenous injection of the tracer using the IndyPET-II scanner. For the blocking experiments, the rats were intravenously pretreated with 3.0mg/kg of unlabeled HC-15 prior to [(11)C]HC-15 injection. [(11)C]HC-15 rat heart PET studies show rapid heart uptake to give clear heart images. The rat heart PET blocking studies found no significant blocking effect. The dynamic PET studies in normal and ablated dogs were performed using Siemens PET scanner with [(13)N]NH(3), [(11)C]HC-15, and [(18)F]HC-15. PET studies in dogs of both [(11)C]HC-15 and [(18)F]HC-15 also show significant heart uptake and give images of the heart. However, there is no significant change in [(11)C]HC-15 L-ventricle uptake following radiofrequency ablation in the dog. These results suggest that the localization of HC-15 tracers in the heart is mediated by non-specific processes, and the visualization of HC-15 tracers on the heart is related to non-specific binding of HACU.

Synthesis of carbon-11 labeled fluorinated 2-arylbenzothiazoles as novel potential PET cancer imaging agents.

Fluorinated 2-arylbenzothiazoles are new potential antitumor drugs, which show potent and selective inhibitory activity against breast, lung, and colon cancer cell lines. Carbon-11 labeled fluorinated 2-arylbenzothiazoles may serve as novel probes for positron emission tomography (PET) to image tyrosine kinase in cancers. The preparation of 4-fluorinated 2-arylbenzothiazoles 4-fluoro-2-(3-benzloxy-4-methoxyphenyl)benzothiazole (6a) and 4-fluoro-2-(3,4-dimethoxyphenyl)benzothiazole (6b) was achieved by a modification of Jacobson thioanilide radical cyclization chemistry. Hydrogenolytic cleavage of the benzyl ether group of compound 6a using H(2)/Pd-C provided the precursor 4-fluoro-2-(3-hydroxy-4-methoxyphenyl)benzothiazole (7) for radiolabeling. Synthesis of radiolabeling precursors and the reference standards 5- and 6-fluorinated arylbenzothiazoles (11c-n) was achieved via the reaction of o-aminothiophenol disulfides with substituted benzaldehydes under reducing conditions. The target radiotracers carbon-11 labeled 4-, 5-, and 6-fluorinated arylbenzothiazoles (3-[(11)C]6b, 4-[(11)C]11c, 3-[(11)C]11c, 5-[(11)C]11f, 4-[(11)C]11f, 4-[(11)C]11i, 3-[(11)C]11i, 5-[(11)C]11l, and 4-[(11)C]11l) were prepared by O-[(11)C]methylation of the phenolic hydroxyl precursors (7, 11d, 11e, 11g, 11h, 11j, 11k, 11m, and 11n) with [(11)C]methyl triflate and isolated by solid-phase extraction (SPE) purification in 30-55% radiochemical yields.

Purification of carbon-11 PET radiotracers from unlabeled precursors by preparative HPLC and SPE.

A general methodology for the rapid purification of carbon-11 positron emission tomography (PET) radiotracers from radiolabeling reaction mixtures has been developed. Preparative HPLC and solid-phase extraction (SPE) techniques are described which can separate some commonly used radiopharmaceuticals such as [(11)C]raclopride, [(11)C]beta-CFT and [(11)C]choline from their unlabeled precursors.