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New F-18 prosthetic group via oxime coupling.

ABSTRACT: A novel fluorine-18 prosthetic ligand, 5-(1,3-dioxolan-2-yl)-2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)pyridine [(18)F]2, has been synthesized. The prosthetic ligand is formed in high radiochemical yield (rcy = 71 ± 2%, n = 3) with excellent radiochemical purity (rcp = 99 ± 1%, n = 3) in a short reaction time (10 min). [(18)F]2 is a small, neutral, organic complex, easily synthesized in four steps from a readily available starting material. It can be anchored onto a target molecule containing an aminooxy functional group under acidic conditions by way of an oxime bond. We report herein two examples [(18)F]23 and [(18)F]24, potential imaging agents for ?-amyloid plaques, which were labeled with this prosthetic group. This approach could be used for labeling proteins and peptides containing an aminooxy group. Biodistribution in male ICR mice for both oxime labeled complexes [(18)F]23 and [(18)F]24 were compared to that of the known ?-amyloid plaque indicator, [(18)F]-AV-45, florbetapir 1. Oximes [(18)F]23 and [(18)F]24 are larger in size and therefore should reduce the blood-brain barrier (BBB) penetration. The brain uptake for oxime [(18)F]23 appeared to be reduced, but still retained some capability to cross the BBB. Oxime [(18)F]24 showed promising results after 2 min post injection (0.48% dose/gram); however, the uptake increased after 30 min post injection (0.92% dose/gram) suggesting an in vivo decomposition/metabolism of compound [(18)F]24. We have demonstrated a general protocol for the fluoride-18 labeling with a new prosthetic ligand [(18)F]2 that is tolerant toward several functional groups and is formed via chemoselective oxime coupling.

SUBMITTER: Carberry P

PROVIDER: S-EPMC3086766 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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New F-18 prosthetic group via oxime coupling.

Carberry Patrick P Lieberman Brian P BP Ploessl Karl K Choi Seok R SR Haase Danniebelle N DN Kung Hank F HF

Bioconjugate chemistry 20110331 4

A novel fluorine-18 prosthetic ligand, 5-(1,3-dioxolan-2-yl)-2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)pyridine [(18)F]2, has been synthesized. The prosthetic ligand is formed in high radiochemical yield (rcy = 71 ± 2%, n = 3) with excellent radiochemical purity (rcp = 99 ± 1%, n = 3) in a short reaction time (10 min). [(18)F]2 is a small, neutral, organic complex, easily synthesized in four steps from a readily available starting material. It can be anchored onto a target molecule containing an ami ...[more]

PMID: 21452846

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Project description:In a previous study, we evaluated a HER2-specific single domain antibody fragment (sdAb) 2Rs15d labeled with 18F via conjugation of a residualizing prosthetic agent that was synthesized by copper-catalyzed azide-alkyne cycloaddition (CuAAC). In order to potentially increase overall efficiency and decrease the time required for labeling, we now investigate the use of a strain-promoted azide-alkyne cycloaddition (SPAAC) between the 2Rs15d sdAb, which had been pre-derivatized with an azide-containing residualizing moiety, and an 18F-labeled aza-dibenzocyclooctyne derivative. The HER2-targeted sdAb 2Rs15d and a nonspecific sdAb R3B23 were pre-conjugated with a moiety containing both azide- and guanidine functionalities. The thus derivatized sdAbs were radiolabeled with 18F using an 18F-labeled aza-dibenzocyclooctyne derivative ([18F]F-ADIBO) via SPAAC, generating the desired conjugate ([18F]RL-II-sdAb). For comparison, unmodified 2Rs15d was labeled with N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB), the prototypical residualizing agent for radioiodination. Radiochemical purity (RCP), immunoreactive fraction (IRF), HER2-binding affinity and cellular uptake of [18F]RL-II-2Rs15d were assessed in vitro. Paired label biodistribution of [18F]RL-II-2Rs15d and [125I]SGMIB-2Rs15d, and microPET/CT imaging of [18F]RL-II-2Rs15d and the [18F]RL-II-R3B23 control sdAb were performed in nude mice bearing HER2-expressing SKOV-3 xenografts. A radiochemical yield of 23.9?±?6.9% (n?=?8) was achieved for the SPAAC reaction between [18F]F-ADIBO and azide-modified 2Rs15d and the RCP of the labeled sdAb was >95%. The affinity (Kd) and IRF for the binding of [18F]RL-II-2Rs15d to HER2 were 5.6?±?1.3?nM and 73.1?±?22.5% (n?=?3), respectively. The specific uptake of [18F]RL-II-2Rs15d by HER2-expressing BT474M1 breast carcinoma cells in vitro was 14-17% of the input dose at 1, 2, and 4?h, slightly higher than seen for co-incubated [125I]SGMIB-2Rs15d. The uptake of [18F]RL-II-2Rs15d in SKOV-3 xenografts at 1?h and 2?h p.i. were 5.54?±?0.77% ID/g and 6.42?±?1.70% ID/g, respectively, slightly higher than those for co-administered [125I]SGMIB-2Rs15d (4.80?±?0.78% ID/g and 4.78?±?1.39% ID/g). MicroPET/CT imaging with [18F]RL-II-2Rs15d at 1-3?h p.i. clearly delineated SKOV-3 tumors while no significant accumulation of activity in tumor was seen for [18F]RL-II-R3B23. With the exception of kidneys, normal tissue levels for [18F]RL-II-2Rs15d were low and cleared rapidly. To our knowledge, this is the first time SPAAC method has been used to label an sdAb with 18F, especially with residualizing functionality.

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New F-18 prosthetic group via oxime coupling.

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New F-18 prosthetic group via oxime coupling.

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