Fluorine-18 Radiolabeled Single-Chain Antibody Variable Fragment 1F4 Targets α1-Subunit Gamma-Aminobutyric Acid Type A Receptors in Mice

Gamma-aminobutyric
acid type A (GABA-A) receptors are the principal
inhibitory neurotransmitter receptors in the central nervous system
(CNS), but their functions in the peripheral nervous system (PNS)
and organs such as the heart remain poorly understood. These receptors
comprise various subtypes based on subunit composition with differential
brain and heart expression linked to distinct pathologies. Current
positron emission tomography (PET) imaging protocols use radioligands
lacking subtype specificity. To address this, we developed a PET tracer
targeting the α1 subunit. The α1-specific single-chain
variable fragment (scFv) 1F4 was engineered from the variable domains
of monoclonal antibody (mAb) 1F4. It was efficiently 18F-labeled under mild conditions via biorthogonal inverse electron
demand Diels–Alder (iEDDA) ligation. PET biodistribution in
mice showed favorable pharmacokinetics for [18F]F-Tz-TCO-scFv
1F4 with specific α1 subunit binding in the brain, heart, and
lungs. This tracer promises to evaluate GABA-A α1 distribution
and expression in peripheral organs, particularly the heart.