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18F-glutathione conjugate as a PET tracer for imaging tumors that overexpress L-PGDS enzyme.

ABSTRACT: Lipocalin-type prostaglandin D synthase (L-PGDS) has been correlated with the progression of neurological disorders. The present study aimed at evaluating the imaging potency of a glutathione conjugate of fluorine-18-labeled fluorobutyl ethacrynic amide ([18F]FBuEA-GS) for brain tumors. Preparation of [18F]FBuEA-GS has been modified from the -4-tosylate derivative via radiofluorination in 5% radiochemical yield. The mixture of nonradioactive FBuEA-GS derived from a parallel preparation has be resolved to two isomers in a ratio of 9:1 using analytic chiral reversed phase high performance liquid chromatography (RP-HPLC). The two fluorine-18-labeled isomers purified through nonchiral semipreparative RP-HPLC as a mixture were studied by assessing the binding affinity toward L-PGDS through a gel filtration HPLC, by analyzing radiotracer accumulation in C6 glioma cells, and by evaluating the imaging of radiotracer in a C6 glioma rat with positron emission tomography. The inhibition percentage of the production of PGD2 from PGH2 at the presence of 200 µM of FBuEA-GS and 4-Dibenzo[a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)butyl]piperidine (AT-56) were 74.1 ± 4.8% and 97.6 ± 16.0%, respectively. [18F]FBuEA-GS bound L-PGDS (16.3-21.7%) but not the isoform, microsomal prostaglandin E synthase 1. No binding to GST-alpha and GST-pi was observed. The binding strength between [18F]FBuEA-GS and L-PGDS has been evaluated using analytic gel filtration HPLC at the presence of various concentrations of the cold competitor FBuEA-GS. The contrasted images indicated that the radiotracer accumulation in tumor lesions is probably related to the overexpression of L-PGDS.

SUBMITTER: Huang HL

PROVIDER: S-EPMC4128654 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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18F-glutathione conjugate as a PET tracer for imaging tumors that overexpress L-PGDS enzyme.

Huang Ho-Lien HL Huang Ying-Cheng YC Lee Wei-Yuan WY Yeh Chun-Nan CN Lin Kun-Ju KJ Yu Chung-Shan CS

PloS one 20140811 8

Lipocalin-type prostaglandin D synthase (L-PGDS) has been correlated with the progression of neurological disorders. The present study aimed at evaluating the imaging potency of a glutathione conjugate of fluorine-18-labeled fluorobutyl ethacrynic amide ([18F]FBuEA-GS) for brain tumors. Preparation of [18F]FBuEA-GS has been modified from the -4-tosylate derivative via radiofluorination in 5% radiochemical yield. The mixture of nonradioactive FBuEA-GS derived from a parallel preparation has be re ...[more]

PMID: 25111383

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Project description:INTRODUCTION:Our previous work demonstrated that the 99mTc renal tracer, 99mTc(CO)3(FEDA) (99mTc-1), has a rapid clearance comparable in rats to that of 131I-OIH, the radioactive gold standard for the measurement of effective renal plasma flow. The uncharged fluoroethyl pendant group of 99mTc-1 provides a route to the synthesis of a structurally analogous rhenium-tricarbonyl 18F renal imaging agent, Re(CO)3([18F]FEDA) (18F-1). Our goal was to develop an efficient one-step method for the preparation of 18F-1 and to compare its pharmacokinetic properties with those of 131I-OIH in rats. METHODS:18F-1 was prepared by the nucleophilic 18F-fluorination of its tosyl precursor. The labeled compound was isolated by HPLC and subsequently evaluated in Sprague-Dawley rats using 131I-OIH as an internal control and by dynamic PET/CT imaging. Plasma protein binding (PPB) and erythrocyte uptake (RCB) were determined and the urine was analyzed for metabolites. RESULTS:18F-1 was efficiently prepared as a single species with high radiochemical purity (>99%) and it displayed high radiochemical stability in vitro and in vivo. PPB was 87% and RCB was 21%. Biodistribution studies confirmed rapid renal extraction and high specificity for renal excretion, comparable to that of 131I-OIH, with minimal hepatic/gastrointestinal elimination. The activity in the urine, as a percentage of 131I-OIH, was 92% and 95% at 10 and 60 min, respectively. All other organs (heart, spleen, lungs) showed a negligible tracer uptake (<0.4% ID). Dynamic microPET/CT imaging demonstrated rapid transit of 18F-1 through the kidneys and into the bladder; there was no demonstrable activity in bone verifying the absence of free [18F]fluoride. CONCLUSIONS:18F-1 exhibited a high specificity for the kidney, rapid renal excretion comparable to that of 131I-OIH and high in vivo radiochemical stability. Not only is 18F-1 a promising PET renal tracer, but it provides a route to the development of a pair of analogous 18F/99mTc renal imaging agents with almost identical structures and comparable pharmacokinetic properties. These promising in vivo results warrant subsequent evaluation in humans.

Project description:Aim(18)F-DPA-714 is a PET tracer that recognizes macrophage translocator protein (TSPO), and (18)F-Alfatide II ((18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2) is specific for integrin αvβ3. This study aims to apply these two tracers for longitudinal PET imaging of muscular inflammation, and evaluate the value of (18)F-DPA-714 in differentiating inflammation from tumor.MethodsRAW264.7 mouse macrophage cells were used for cell uptake analysis of (18)F-DPA-714. A mouse hind limb muscular inflammation model was established by intramuscular injection of turpentine oil. For the inflammation model, PET imaging was performed at different days using (18)F-DPA-714 and (18)F-Alfatide II. The specificity of the imaging probes was tested by co- or pre-injection of PK11195 or unlabeled RGD (Arg-Gly-Asp) peptide. PET imaging using (18)F-DPA-714 was performed in A549, HT29, U87MG, INS-1, and 4T1 xenograft models. Immunofluorescence staining was performed to evaluate infiltrated macrophages and angiogenesis in inflammation and/or tumors.ResultsUptake of (18)F-DPA-714 in RAW264.7 cells was 45.5% at 1 h after incubation, and could be blocked by PK11195. PET imaging showed increased (18)F-DPA-714 and (18)F-Alfatide II uptake at inflammatory muscles. Peak uptake of (18)F-DPA-714 was seen on day 6 (4.02 ± 0.64 %ID/g), and peak uptake of (18)F-Alfatide II was shown on day 12 (1.87 ± 0.35 %ID/g) at 1 h p.i.. Tracer uptakes could be inhibited by PK11195 for (18)F-DPA-714 or cold RGD for (18)F-Alfatide II. Moreover, macrophage depletion with liposomal clodronate also reduced the local accumulation of both tracers. A549, HT29, U87MG, INS-1, and 4T1 tumor uptakes of (18)F-DPA-714 (0.46 ± 0.28, 0.91 ± 0.08, 1.69 ± 0.67, 1.13 ± 0.33, 1.22 ± 0.55 %ID/g at 1 h p.i., respectively) were significantly lower than inflammation uptake (All P < 0.05).ConclusionPET imaging using (18)F-DPA-714 as a TSPO targeting tracer could evaluate the dynamics of macrophage activation and infiltration in different stages of inflammatory diseases. The concomitant longitudinal PET imaging with both (18)F-DPA-714 and (18)F-Alfatide II matched the causal relationship between macrophage infiltration and angiogenesis. Moreover, we found (18)F-DPA-714 uptake in several types of tumors is significantly lower than that in inflammatory muscles, suggesting (18)F-DPA-714 PET has the potential for better differentiation of tumor and non-tumor inflammation.

Project description:BACKGROUND:Peptides labeled with positron-emitting isotopes are emerging as a versatile class of compounds for the development of highly specific, targeted imaging agents for diagnostic imaging via positron-emission tomography (PET) and for precision medicine via theranostic applications. Despite the success of peptides labeled with gallium-68 (for imaging) or lutetium-177 (for therapy) in the clinical management of patients with neuroendocrine tumors or prostate cancer, there are significant advantages of using fluorine-18 for imaging. Recent developments have greatly simplified such labeling: in particular, labeling of organotrifluoroborates via isotopic exchange can readily be performed in a single-step under aqueous conditions and without the need for HPLC purification. Though an automated synthesis has not yet been explored, microfluidic approaches have emerged for 18F-labeling with high speed, minimal reagents, and high molar activity compared to conventional approaches. As a proof-of-concept, we performed microfluidic labeling of an octreotate analog ([18F]AMBF3-TATE), a promising 18F-labeled analog that could compete with [68Ga]Ga-DOTATATE with the advantage of providing a greater number of patient doses per batch produced. METHODS:Both [18F]AMBF3-TATE and [68Ga]Ga-DOTATATE were labeled, the former by microscale methods adapted from manual labeling, and were imaged in mice bearing human SSTR2-overexpressing, rat SSTR2 wildtype, and SSTR2-negative xenografts. Furthermore, a dosimetry analysis was performed for [18F]AMBF3-TATE. RESULTS:The micro-synthesis exhibited highly-repeatable performance with radiochemical conversion of 50?±?6% (n?=?15), overall decay-corrected radiochemical yield of 16?±?1% (n?=?5) in ~40?min, radiochemical purity >99%, and high molar activity. Preclinical imaging with [18F]AMBF3-TATE in SSTR2 tumor models correlated well with [68Ga]Ga-DOTATATE. The favorable biodistribution, with the highest tracer accumulation in the bladder followed distantly by gastrointestinal tissues, resulted in 1.26?×?10-2?mSv/MBq maximal estimated effective dose in human, a value lower than that reported for current clinical 18F- and 68Ga-labeled compounds. CONCLUSIONS:The combination of novel chemical approaches to 18F-labeling and microdroplet radiochemistry have the potential to serve as a platform for greatly simplified development and production of 18F-labeled peptide tracers. Favorable preclinical imaging and dosimetry of [18F]AMBF3-TATE, combined with a convenient synthesis, validate this assertion and suggest strong potential for clinical translation.

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18F-glutathione conjugate as a PET tracer for imaging tumors that overexpress L-PGDS enzyme.

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18F-glutathione conjugate as a PET tracer for imaging tumors that overexpress L-PGDS enzyme.

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