Targeted Dual-Modal PET/SPECT-NIR Imaging: From Building Blocks and Construction Strategies to Applications

Abstract

Molecular imaging is an emerging non-invasive method to qualitatively and quantitively visualize and characterize biological processes. Among the imaging modalities, PET/SPECT and near-infrared (NIR) imaging provide synergistic properties that result in deep tissue penetration and up to cell-level resolution. Dual-modal PET/SPECT-NIR agents are commonly combined with a targeting ligand (e.g., antibody or small molecule) to engage biomolecules overexpressed in cancer, thereby enabling selective multimodal visualization of primary and metastatic tumors. The use of such agents for (i) preoperative patient selection and surgical planning and (ii) intraoperative FGS could improve surgical workflow and patient outcomes. However, the development of targeted dual-modal agents is a chemical challenge and a topic of ongoing research. In this review, we define key design considerations of targeted dual-modal imaging from a topological perspective, list targeted dual-modal probes disclosed in the last decade, review recent progress in the field of NIR fluorescent probe development, and highlight future directions in this rapidly developing field.

Keywords: PET/SPECT imaging; dual-modal imaging; fluorescence-guided surgery; heptamethine.

Figure 1

(a) General schematic of dual-modal imaging. (b) SPECT-CT and fluorescence imaging of ccRCC using ¹¹¹In-DOTA-girentuximab-IR-800CW (girentuximab mAb targets carbonic anhydrase IX, CA-IX) [19]. (c) CT, PET-CT, and FGS using ⁶⁸Ga-NOTA-BBN-IR-800CW (BBN targets GRPR) [20]. Images used according to permissions from respective journals.

Figure 2

Classification of targeted-bifunctional (chelator/radionuclide and fluorophore) probes into four generic classes based on connectivity logic: class I—bifunctional fluorophores, class II—bifunctional chelators, class III—bifunctional ligands, and class IV—trifunctional linker connecting chelators, fluorophores, and targeting ligands.

Figure 3

Overview of recent developments of fluorophores with absorbance/emission maxima in the (a) near-infrared and (b) short-wavelength IR regions. Blue, red, and green colors indicate cationic, anionic, and conjugable functional groups, respectively.

Figure 4

(a) FRET-quenched bifunctional probe targeting MMP-14. (b) Fluorogenic heptamethine cyanine based on self-immolative linker chemistry. (c) PSMA-targeted probe containing IR700-DX and ¹¹¹In-labeled DOTA.