New Developments in Carbonic Anhydrase IX-Targeted Fluorescence and Nuclear Imaging Agents

Abstract

Carbonic anhydrase IX (CAIX) is a tumor-specific and hypoxia-induced biomarker for the molecular imaging of solid malignancies. The nuclear- and optical-imaging of CAIX-expressing tumors have received great attention due to their potential for clinical applications. Nuclear imaging is a powerful tool for the non-invasive diagnosis of primary and metastatic CAIX-positive tumors and for the assessment of responses to antineoplastic treatment. Intraoperative optical fluorescence imaging provides improved visualization for surgeons to increase the discrimination of tumor lesions, allowing for safer surgical treatment. Over the past decades, many CAIX-targeted molecular imaging probes, based on monoclonal antibodies, antibody fragments, peptides, and small molecules, have been reported. In this review, we outline the recent development of CAIX-targeted probes for single-photon emission computerized tomography (SPECT), positron emission tomography (PET), and near-infrared fluorescence imaging (NIRF), and we discuss issues yet to be addressed.

Keywords: PET; SPECT; cancer; carbonic anhydrase IX; fluorescence imaging; imaging agents.

Figure 1

PET/CT imaging of a patient with a ccRCC tumor in the left kidney (red arrow) after injection of [⁸⁹Zr]Zr-girentuximab. The patient received a mass dose of 10 mg of girentuximab and was imaged at 0.5 to 168 h PA. Tumor-to-background ratio was increased over time.

Figure 2

MicroPET/CT images acquired at 1 h PI of [¹⁸F]F-CaIX-P1-4-10 in HT-29 colorectal cancer xenograft-bearing mice. Arrows indicate high-count density regions in the tumor. The units of the bar scale are standard uptake values (SUVs).

Figure 3

Chemical structures of BSA-based CAIX probes.

Figure 4

Chemical structures of AAZ-based CAIX probes.

Figure 5

(A) Tumor accumulation and circulation half-life of HypoxyFluor-1 (12) in CAIX positive HT-29 tumor-bearing mice. (B) The tracer was eliminated from blood within 1 h.

Figure 6

SPECT/CT scan with [^99mTc]Tc-PHC-102 (13) in SKRC-52-bearing mouse at 4 h PI (A) Maximum-intensity projection (MIP) and (B) sagittal, coronal, and trans-axial projections. Int = intestine; Ki = kidney; Tu = tumor.

Figure 7

(A) Chemical structure of 16 and 17. (B) Comparison of the fluorescence intensity of HypoxyFluor-1 (12) and HypoxyFluor-2 (16) in HT-29 tumor-bearing mice. (C) PET image analysis of free ⁶⁸Ga, [⁶⁸Ga]Ga-NOTA, and [⁶⁸Ga]Ga-NOTA-SAC 17 at 30, 60, 90, min PI, respectively.

Figure 8

Chemical structures of IS-based CAIX imaging probes.

Figure 9

Coronal SPECT/CT images of an HT-29 tumor-bearing mouse obtained at 24 h PI using IS-[¹¹¹In]In-DO2A-ALB1 and [¹¹¹In]In-DO3A-IS1.

Figure 10

Chemical structures of published multivalent CAIX ligands.

Figure 11

Chemical structures of the dual-motif CAIX-targeted probes.

Figure 12

Micro-PET images of orthotopic U87MG xenografts of [⁶⁴Cu]Cu-XYIMSR-06 (34) at 8 h PI.