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Synthesis of fluorine-18 radio-labeled serum albumins for PET blood pool imaging.

ABSTRACT: We sought to develop a practical, reproducible and clinically translatable method of radiolabeling serum albumins with fluorine-18 for use as a PET blood pool imaging agent in animals and man. Fluorine-18 radiolabeled fluoronicotinic acid-2,3,5,6-tetrafluorophenyl ester, [(18)F]F-Py-TFP was prepared first by the reaction of its quaternary ammonium triflate precursor with [(18)F]tetrabutylammonium fluoride ([(18)F]TBAF) according to a previously published method for peptides, with minor modifications. The incubation of [(18)F]F-Py-TFP with rat serum albumin (RSA) in phosphate buffer (pH9) for 15 min at 37-40 °C produced fluorine-18-radiolabeled RSA and the product was purified using a mini-PD MiniTrap G-25 column. The overall radiochemical yield of the reaction was 18-35% (n=30, uncorrected) in a 90-min synthesis. This procedure, repeated with human serum albumin (HSA), yielded similar results. Fluorine-18-radiolabeled RSA demonstrated prolonged blood retention (biological half-life of 4.8 hours) in healthy awake rats. The distribution of major organ radioactivity remained relatively unchanged during the 4 hour observation periods either by direct tissue counting or by dynamic PET whole-body imaging except for a gradual accumulation of labeled metabolic products in the bladder. This manual method for synthesizing radiolabeled serum albumins uses fluorine-18, a widely available PET radionuclide, and natural protein available in both pure and recombinant forms which could be scaled up for widespread clinical applications. These preclinical biodistribution and PET imaging results indicate that [(18)F]RSA is an effective blood pool imaging agent in rats and might, as [(18)F]HSA, prove similarly useful as a clinical imaging agent.

SUBMITTER: Basuli F

PROVIDER: S-EPMC4329020 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Synthesis of fluorine-18 radio-labeled serum albumins for PET blood pool imaging.

Basuli Falguni F Li Changhui C Xu Biying B Williams Mark M Wong Karen K Coble Vincent L VL Vasalatiy Olga O Seidel Jurgen J Green Michael V MV Griffiths Gary L GL Choyke Peter L PL Jagoda Elaine M EM

Nuclear medicine and biology 20141206 3

We sought to develop a practical, reproducible and clinically translatable method of radiolabeling serum albumins with fluorine-18 for use as a PET blood pool imaging agent in animals and man. Fluorine-18 radiolabeled fluoronicotinic acid-2,3,5,6-tetrafluorophenyl ester, [(18)F]F-Py-TFP was prepared first by the reaction of its quaternary ammonium triflate precursor with [(18)F]tetrabutylammonium fluoride ([(18)F]TBAF) according to a previously published method for peptides, with minor modificat ...[more]

PMID: 25533724

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Project description:IntroductionEquilibrium single-photon radionuclide imaging methods for assessing cardiac function and the integrity of the vascular system have long been in use for both clinical and research purposes. However, positron-emitting blood pool agents that could provide PET equivalents to these (and other) clinical procedures have not yet been adopted despite technical imaging advantages offered by PET. Our goal was to develop a PET blood pool tracer that not only meets necessary in vivo biological requirements but can be produced with an uncomplicated and rapid synthesis method which would facilitate clinical translation. Herein, albumin labeled with fluorine-18 was synthesized using a one-pot method and evaluated in vitro and in vivo in rats.MethodsA ligand (NODA-Bz-TFPE), containing NODA attached to a tetrafluorophenylester (TFPE) via a phenyl linker (Bz), was labeled with aluminum fluoride (Al[18F]F). Conjugation of the serum albumin with the ligand (Al[18F]F-NODA-Bz-TFPE), followed by purification (size exclusion chromatography), yielded the final product (Al[18F]F-NODA-Bz-RSA/HSA). In vitro stability was evaluated in human serum albumin by HPLC. Rat biodistributions and whole-body PET imaging over a 4 h time course were used for the in vivo evaluation.ResultsThis synthesis exhibited an overall radiochemical yield of 45 ± 10% (n = 30), a 50-min radiolabeling time, a radiochemical purity >99% and apparent stability up to 4 h in human serum. Blood had the highest retention of Al[18F]F-NODA-Bz-RSA at all times with a blood half-life of 5.2 h in rats. Al[18F]F-NODA-Bz-RSA distribution in most rat tissues remained relatively constant for up to 1 h, indicating that the tissue radioactivity content represents the respective tissue plasma volume. Dynamic whole-body PET images were in agreement with these findings.ConclusionsA new ligand has been developed and radiolabeled with Al[18F]F that allows rapid (50-min) preparation of fluorine-18 serum albumin in one-pot. In addition to increased synthetic efficiency, the construct appears to be metabolically stable in rats. This method could encourage wider use of PET to quantify cardiac function and tissue vascular integrity in both research and clinical settings.

Project description:The accumulation of α-synuclein aggregates (α-syn) in the human brain is an occurrence common to all α-synucleinopathies. Non-invasive detection of these aggregates in a living brain with a target-specific radiotracer is not yet possible. We have recently discovered that the inclusion of a methylenedioxy group in the structure of diarylbisthiazole (DABTA)-based tracers improves binding affinity and selectivity to α-syn. Subsequently, complementary in silico modeling and machine learning (ML) of tracer-protein interactions were employed to predict surface sites and structure-property relations for the binding of the ligands. Based on this observation, we developed a small focused library of DABTAs from which 4-(benzo[d][1,3]dioxol-5-yl)-4'-(3-[18F]fluoro-4-methoxyphenyl)-2,2'-bithiazole [ 18 F]d 2, 6-(4'-(3-[18F]fluoro-4-methoxyphenyl)-[2,2'-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [ 18 F]d 4, 4-(benzo [d][1,3]dioxol-5-yl)-4'-(6-[18F]fluoropyridin-3-yl)-2,2'-bithiazole [ 18 F]d 6, and 6-(4'-(6-[18F]fluoropyridin-3-yl)-[2,2'-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [ 18 F]d 8 were selected based on their high binding affinity to α-syn and were further evaluated. Binding assay experiments carried out with the non-radioactive versions of the above tracers d 2, d 4, d 6, and d 8 showed high binding affinity of the ligands to α-syn: 1.22, 0.66, 1.21, and 0.10 nM, respectively, as well as excellent selectivity over β-amyloid plaques (Aβ) and microtubular tau aggregates (>200-fold selectivity). To obtain the tracers, their precursors were radiolabeled either via an innovative ruthenium-mediated (SNAr) reaction ([ 18 F]d 2 and [ 18 F]d 4) or typical SNAr reaction ([ 18 F]d 6 and [ 18 F]d 8) with moderate-to-high radiochemical yields (13% - 40%), and high molar activity > 60 GBq/μmol. Biodistribution experiments carried out with the tracers in healthy mice revealed that [ 18 F]d 2 and [ 18 F]d 4 showed suboptimal brain pharmacokinetics: 1.58 and 4.63 %ID/g at 5 min post-injection (p.i.), and 1.93 and 3.86 %ID/g at 60 min p.i., respectively. However, [ 18 F]d 6 and [ 18 F]d 8 showed improved brain pharmacokinetics: 5.79 and 5.13 %ID/g at 5 min p.i.; 1.75 and 1.07 %ID/g at 60 min p.i.; and 1.04 and 0.58 %ID/g at 120 min p.i., respectively. The brain uptake kinetics of [ 18 F]d 6 and [ 18 F]d 8 were confirmed in a dynamic PET study. Both tracers also showed no brain radiometabolites at 20 min p.i. in initial in vivo stability experiments carried out in healthy mice. [ 18 F]d 8 seems very promising based on its binding properties and in vivo stability, thus encouraging further validation of its usefulness as a radiotracer for the in vivo visualization of α-syn in preclinical and clinical settings. Additionally, in silico and ML-predicted values correlated with the experimental binding affinity of the ligands.

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Synthesis of fluorine-18 radio-labeled serum albumins for PET blood pool imaging.

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Synthesis of fluorine-18 radio-labeled serum albumins for PET blood pool imaging.

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