Labeling a TCO-functionalized single domain antibody fragment with 18F via inverse electron demand Diels Alder cycloaddition using a fluoronicotinyl moiety-bearing tetrazine derivative.

Labeling a TCO-functionalized single domain antibody fragment with 18F via inverse electron demand Diels Alder cycloaddition using a fluoronicotinyl moiety-bearing tetrazine derivative. Bioorg Med Chem. 2020 Sep 01;28(17):115634 Authors: Zhou Z, Zalutsky MR, Vaidyanathan G Abstract Single domain antibody fragments (sdAbs) exhibit a rapid tumor uptake and fast blood clearance amenable for labeling with 18F (t½ = 110 min) but suffer from high kidney accumulation. Previously, we developed a method for 18F-labeling of sdAbs via trans-cyclooctene (TCO)-tetrazine (Tz) inverse electron demand Diel's Alder cycloaddition reaction (IEDDAR) that incorporated a renal brush border enzyme (RBBE)-cleavable linker. Although >15 fold reduction in kidney activity levels was achieved, tumor uptake was compromised. Here we investigate whether replacing the [18F]AlF-NOTA moiety with [18F]fluoronicotinyl would rectify this problem. Anti-HER2 sdAb 5F7 was first derivatized with a TCO-containing agent that included the RBBE-cleavable linker GlyLys (GK) and a PEG chain, and then subjected to IEDDAR with 6-[18F]fluoronicotinyl-PEG4-methyltetrazine to provide [18F]FN-PEG4-Tz-TCO-GK-PEG4-5F7 ([18F]FN-GK-5F7). For comparisons, a control lacking GK linker and 5F7 labeled using residualizing N-succinimidyl 3-guanidinomethyl-5-[125I]iodobenzoate (iso-[125I]SGMIB) also were synthesized. Radiochemical purity, affinity (KD) and immunoreactive fraction of [18...
Source: Bioorganic and Medicinal Chemistry - Category: Chemistry Authors: Tags: Bioorg Med Chem Source Type: research