Spectral Properties of Pro‐multimodal Imaging Agents Derived from a NIR Dye and a Metal Chelator

Abstract

Monomolecular multimodal imaging agents (MOMIAs) are able to provide complementary diagnostic information of a target diseased tissue. We developed a convenient solid-phase approach to construct two pro-MOMIAs (before incorporating radiometal) derived from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and cypate, a near-infrared (NIR) fluorescent dye analogous to indocyanine green (ICG). The possible interaction between d orbitals of transition metal DOTA complexes or free metals and the p orbitals of cypate chromophore could quench the fluorescence of pro-MOMIAs. However, we did not observe significant changes in the spectral properties of cypate upon conjugation with DOTA and subsequent chelation with metals. The fluorescence intensity of the chelated and nonmetal-chelated PRO-MOMIAs remained fairly the same in dilute 20% aqueous dimethylsulfoxide (DMSO) solution (1 x 10(-6) M). Significant reduction in the fluorescence intensity of pro-MOMIAs occurred in the presence of a large excess of metal ions (>1 molar ratio for indium and 20-fold for a copper relative to pro-MOMIA). This study suggests the feasibility of using MOMIAs for combined optical and radioisotope imaging.

Molecular imaging with optics: primer and case for near-infrared fluorescence techniques in personalized medicine

“…Using cypate (which is structurally similar to ICG) conjugated to a DOTA chelating moiety, Zhang and Achilefu26 demonstrated that the fluorescent properties can be retained in dual-labeled agents, a finding that is also substantiated by the invivo imaging work described earlier. Similar to the study by Sampath et al,25 Xu et al27 dual-labeled trastuzumab with a red-excitable dye, Cy5.5, as well as with chelating moiety for eventual use in preclinical studies.…”

Multimodal Fluorescence-Mediated Tomography and SPECT/CT for Small-Animal Imaging

“…DOTA-Gly-Ser-Gly-Lys(Cypate)-E-Ahx-NH2,LS444, was synthesized and radiolabeled with 111 InCl 3 (MSD-Nordion, Kanata, ON, Canada, 3.0 microcuries (µCi)) in aqueous buffer (190µl, 0.4 M sodium acetate, pH 4.5, 30 min, 98 °C) as described previously (6, 7). Labeling efficiency and radiochemical purity were checked by HPLC (Supelcosil ABZ + PLUS, HPLC Column, 15cm X 4mm, 5µm) with a gradient of H 2 O and acetonitrile containing 0.1% TFA.…”

“…Alternatively mutliple molecular contrasts might be joined through specific links (4–6). For example optical methods have unique activation contrast mechanisms, which are complementary to PET/SPECT information and the information available to both nuclear and optical contrasts can be harnessed directly using monomolecular optical multimodality imaging agent’s (MOMIA) (4–7). Imaging of MOMIA agents requires suitable instrumentation and algorithms.…”

“…MOMIAs are being developed to address these pharmacokinetic issues. Recent work has demonstrated the use of this approach for SPECT/optical (15–17), PET/Optical (6, 7, 18), and MRI/optical (19–21) imaging. The last challenge is determining how to merge the anatomical or functional information from multiple technologies into a single imaging output that leverages the respective strengths of each modality and provide new insight into biological processes relevant to cancer diagnosis and therapy monitoring (4, 11).…”

Dual-Labeling Strategies for Nuclear and Fluorescence Molecular Imaging: A Review and Analysis

“…The findings should build upon the existing knowledge and make significant strides towards validating multimodal imaging platforms for clinical use. Innovative chemistry strategies to combine chelators and NIRF dyes into a single “reactive” unit have been shown and offer great promise to simplify agent synthesis and broaden the use of multimodal probes [67–70]. Given the importance of mAb-based targeting approaches, such platforms may help mitigate the loss of immunoreactivity that can occur following multistep conjugations at random sites on mAbs or mAb fragments.…”