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18?F-click labeling and preclinical evaluation of a new 18?F-folate for PET imaging.

ABSTRACT: BACKGROUND:The folate receptor (FR) is a well-established target for tumor imaging and therapy. To date, only a few 18?F-folate conjugates via 18?F-prosthetic group labeling for positron emission tomography (PET) imaging have been developed. To some extent, they all lack the optimal balance between efficient radiochemistry and favorable in vivo characteristics. METHODS:A new clickable olate precursor was synthesized by regioselective coupling of folic acid to 11-azido-3,6,9-trioxaundecan-1-amine at the ?-position of the glutamic acid residue. The non-radioactive reference compound was synthesized via copper-catalyzed azide-alkyne cycloaddition of 3-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)prop-1-yne and ?-(11-azido-3,6,9-trioxaundecanyl)folic acid amide. The radiosynthesis was accomplished in two steps: at first a 18?F-fluorination of 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl-4-methylbenzenesulfonate, followed by a 18?F-click reaction with the ?-azido folate. The in vitro, ex vivo, and in vivo behaviors of the new 18?F-folate were investigated using FR-positive human KB cells in displacement assays and microPET studies using KB tumor-bearing mice. RESULTS:The new 18?F-folate with oligoethylene spacers showed reduced lipophilicity in respect to the previously developed 18?F-click folate with alkyl spacers and excellent affinity (Ki?=?1.6 nM) to the FR. Combining the highly efficient 18?F-click chemistry and a polar oligoethylene-based 18?F-prosthetic group facilitated these results. The overall radiochemical yield of the isolated and formulated product averages 8.7%. In vivo PET imaging in KB tumor-bearing mice showed a tumor uptake of 3.4% ID/g tissue, which could be reduced by FR blockade with native folic acid. Although the new 18?F-oligoethyleneglycole (OEG)-folate showed reduced hepatobiliary excretion over time, a distinct unspecific abdominal background was still observed. CONCLUSIONS:A new 18?F-folate was developed, being available in very high radiochemical yields via a fast and convenient two-step radiosynthesis. The new 18?F-OEG-folate showed good in vivo behavior and lines up with several recently evaluated 18?F-labeled folates.

SUBMITTER: Schieferstein H

PROVIDER: S-EPMC3849131 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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18 F-click labeling and preclinical evaluation of a new 18 F-folate for PET imaging.

Schieferstein Hanno H Betzel Thomas T Fischer Cindy R CR Ross Tobias L TL

EJNMMI research 20130916 1

<h4>Background</h4>The folate receptor (FR) is a well-established target for tumor imaging and therapy. To date, only a few 18 F-folate conjugates via 18 F-prosthetic group labeling for positron emission tomography (PET) imaging have been developed. To some extent, they all lack the optimal balance between efficient radiochemistry and favorable in vivo characteristics.<h4>Methods</h4>A new clickable olate precursor was synthesized by regioselective coupling of folic acid to 11-azido-3,6,9-trioxa ...[more]

PMID: 24041035

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Project description:UnlabelledFolate-receptor-targeted PET radiotracers can potentially serve as versatile imaging agents for the diagnosis, staging, and prediction of response to therapy of patients with folate-receptor (FR)-expressing cancers. Because current FR-targeted PET reagents can be compromised by complex labeling procedures, low specific activities, poor radiochemical yields, or unwanted accumulation in FR negative tissues, we have undertaken to design an improved folate-PET agent that might be more amenable for clinical development. For this purpose, we have synthesized a folate-NOTA-Al(18)F radiotracer and examined its properties both in vitro and in vivo.MethodsRadiochemical synthesis of folate-NOTA-Al(18)F was achieved by incubating (18)F(-) with AlCl3 for 2 min followed by heating in the presence of folate-NOTA for 15 min at 100 °C. Binding of folate-NOTA-Al(18)F to FR was quantitated in homogenates of KB and Cal51 tumor xenografts in the presence and absence of excess folic acid as a competitor. In vivo imaging was performed on nu/nu mice bearing either FR+ve (KB cell) or FR-ve (A549 cell) tumor xenografts, and specific accumulation of the radiotracer in tumor and other tissues was assessed by high-resolution micro-PET and ex vivo biodistribution in the presence and absence of excess folic acid. Image quality of folate-NOTA-Al(18)F was compared with that of (99m)Tc-EC20, a clinically established folate-targeted SPECT imaging agent.ResultsTotal radiochemical synthesis and purification of folate-NOTA-Al(18)F was completed within 37 min, yielding a specific activity of 68.82 ± 18.5 GBq/μmol, radiochemical yield of 18.6 ± 4.5%, and radiochemical purity of 98.3 ± 2.9%. Analysis of FR binding revealed a Kd of ∼1.0 nM, and micro-PET imaging together with ex vivo biodistribution analyses demonstrated high FR-mediated uptake in an FR+ tumor and the kidneys.ConclusionsFolate-NOTA-Al(18)F constitutes an easily prepared FR-targeted PET imaging agent with improved radiopharmaceutical properties and high specificity for folate receptor expressing tumors. Given its improved properties over (99m)Tc-EC20 (i.e., higher resolution, shorter image acquisition time, etc.), we conclude that folate-NOTA-Al(18)F constitutes a viable alternative to (99m)Tc-EC20 for use in identification, diagnosis, and staging of patients with FR-expressing cancers.

Project description:RG7388 (Idasanutlin) is a potent inhibitor of oncoprotein murine double minute 2 (MDM2). Herein we investigated the feasibility of developing 18F-labeled RG7388 as a radiotracer for imaging MDM2 expression in tumors with positron emission tomography (PET). Two fluorinated analogues of RG7388, 6 and 7, were synthesized by attaching a fluoronicotinyl moiety to RG7388 via a polyethylene glycol (PEG3) or a propyl linker. The inhibitory potency (IC50) of 6 and 7 against MDM2 was determined by a fluorescence polarization (FP)-based assay. Next, compound 6 was labeled with 18F using a trimethylammonium triflate precursor to obtain [18F]FN-PEG3-RG7388 ([18F]6), and its properties were evaluated in MDM2 expressing wild-type p53 tumor cell lines (SJSA-1 and HepG2) in vitro and in tumor xenografts in vivo. The FP assays revealed an IC50 against MDM2 of 119 nM and 160 nM for 6 and 7, respectively. 18F-labeling of 6 was achieved in 50.3 ± 7.5% radiochemical yield. [18F]6 exhibited a high uptake (∼70% of input dose) and specificity in SJSA-1 and HepG2 cell lines. Saturation binding assays revealed a binding affinity (Kd) of 128 nM for [18F]6 on SJSA-1 cells. In mice, [18F]6 showed fast clearance from blood with a maximum tumor uptake of 3.80 ± 0.85% injected dose per gram (ID/g) in HepG2 xenografts at 30 min postinjection (p.i.) and 1.32 ± 0.32% ID/g in SJSA-1 xenografts at 1 h p.i. Specificity of [18F]6 uptake in tumors was demonstrated by pretreatment of mice with SJSA-xenografts with a blocking dose of RG7388 (35 mg/kg body weight, i.p.). In vivo stability studies in mice using HPLC showed ∼60% and ∼30% intact [18F]6 remaining in plasma at 30 min and 1 h p.i., respectively, with the remaining activity attributed to polar peaks. Our results suggest that RG7388 is a promising molecular scaffold for 18F-labeled probe development for MDM2. Additional labeling strategies and functionalizing locations on RG7388 are under development to improve binding affinity and in vivo stability of the 18F-labeled compound to make it more amenable for PET imaging of MDM2 in vivo.

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18?F-click labeling and preclinical evaluation of a new 18?F-folate for PET imaging.

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18 F-click labeling and preclinical evaluation of a new 18 F-folate for PET imaging.

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