Fast ¹⁸F Labeling of a Near-Infrared Fluorophore Enables Positron Emission Tomography and Optical Imaging of Sentinel Lymph Nodes

Abstract

We combine a novel boronate trap for F− with a near-infrared fluorophore into a single molecule. Attachment to targeting ligands enables localization by positron emission tomography (PET) and near-infrared fluorescence (NIRF). Our first application of this generic tag is to label Lymphoseek (tilmanocept), an agent designed for receptor-specific sentinel lymph node (SLN) mapping. The new conjugate incorporates 18F− in a single, aqueous step, targets mouse SLN rapidly (1 h) with reduced distal lymph node accumulation, permits PET or scintigraphic imaging of SLN, and enables NIRF-guided excision and histological verification even after 18F decay. This embodiment is superior to current SLN mapping agents such as nontargeted [99mTc]sulfur colloids and Isosulfan Blue, as well as the phase III targeted ligand [99mTc]SPECT Lymphoseek counterpart, species that are visible by SPECT or visible absorbance separately. Facile incorporation of 18F into a NIRF probe should promote many synergistic PET and NIRF combinations.

Optimization via specific fluorescence brightness of a receptor-targeted probe for optical imaging and positron emission tomography of sentinel lymph nodes

“…After radiolabeling tilmanocept with 68 Ga, a generator-produced positron-emitting radionuclide, canine pelvic SLNs were imaged 1 h after a transrectal injection into the prostate gland. 21 Covalent attachment of Cy7, a cyanine fluorescent dye, to tilmanocept resulted in an NIR fluorescent-tagged tilmanocept, 22,23 which retained the properties exhibited by tilmanocept without the fluorescent tag. Fluorescent-labeled tilmanocept exhibited sub-nanomolar receptor affinity (K D < 1 nM) to a macrophage cell line that expresses the receptor (CD206), as well as in vivo behavior consistent with SLN receptor-mediated accumulation.…”

18F-positron-emitting/fluorescent labeled erythrocytes allow imaging of internal hemorrhage in a murine intracranial hemorrhage model

“…These agents are visible by PET, 31,32 are stable in vivo, 33,34 and bear a reactive group for RBCmembrane labeling.…”

Emerging lymphatic imaging technologies for mouse and man

“…Clinical approaches proposed for improved SLNM include intraoperative use of ICG (94) and a recently approved, macrophagetargeted, radiolabeled sugar (tilmanocept) (95,96) that has also been labeled with a NIRF dye (97) or a radionuclide/NIRF conjugate (98). Other investigational approaches for SLNM conducted in preclinical studies have employed QDots (99), MR lymphangiography with Gadolinium-based contrast agents (100), and gold nanorods that were tracked using photoacoustic imaging (101).…”