Dual‐isotope ¹¹¹In/¹⁷⁷Lu SPECT imaging as a tool in molecular imaging tracer design

Abstract

The synthesis, design and subsequent pre-clinical testing of new molecular imaging tracers are topic of extensive research in healthcare. Quantitative dual-isotope SPECT imaging is proposed here as a tool in the design and validation of such tracers, as it can be used to quantify and compare the biodistribution of a specific ligand and its nonspecific control ligand, labeled with two different radionuclides, in the same animal. Since the biodistribution results are not blurred by experimental or physiological inter-animal variations, this approach allows determination of the ligand's net targeting effect. However, dual-isotope quantification is complicated by crosstalk between the two radionuclides used and the radionuclides should not influence the biodistribution of the tracer. Here, we developed a quantitative dual-isotope SPECT protocol using combined (111)Indium and (177)Lutetium and tested this tool for a well-known angiogenesis-specific ligand (cRGD peptide) in comparison to a potential nonspecific control (cRAD peptide). Dual-isotope SPECT imaging of the peptides showed a similar organ and tumor uptake to single-isotope studies (cRGDfK-DOTA, 1.5 ± 0.8%ID cm(-3); cRADfK-DOTA, 0.2 ± 0.1%ID cm(-3)), but with higher statistical relevance (p-value 0.007, n = 8). This demonstrated that, for the same relevance, seven animals were required in case of a single-isotope test design as compared with only three animals when a dual-isotope test was used. Interchanging radionuclides did not influence the biodistribution of the peptides. Dual-isotope SPECT after simultaneous injection of (111)In and (177)Lu-labeled cRGD and cRAD was shown to be a valuable method for paired testing of the in vivo target specificity of ligands in molecular imaging tracer design.

Imaging of Tumor Spheroids, Dual-Isotope SPECT, and Autoradiographic Analysis to Assess the Tumor Uptake and Distribution of Different Nanobodies

“…In our case, the use of only four mice per group (per couple of NBs to investigate) led to unambiguous data because of the elimination of interanimal variations. In contrast, standard biodistributions studies would generally require six mice per tracer and per time point [14,19].…”

“…This imaging technique allows distinction of radiolabeled compounds both in space and over time, making possible the simultaneous detection of multiple tracers in a single subject. Importantly, dualisotope indium-111/lutetium-177 SPECT has been already used as a tool to evaluate small peptide tracers in the preclinical setting [14], and its use is extended to the NB field in the present study.…”

A targeted approach to cancer imaging and therapy

“…At present, image-guided drug delivery is primarily used for preclinical optimization of the pharmacokinetics and biodistribution profiles of nanoparticles rather than the drugs they carry. In principle, it is possible to use dual-isotope SPECT to quantify and compare the biodistribution of nanocarriers and their drug payload 59 . Drug release and nanoparticle stability may also be assessed by optical imaging based on the quenching-dequenching phenomenon 60,61 .…”

Advance of Molecular Imaging Technology and Targeted Imaging Agent in Imaging and Therapy

“…Based on the isotope-specific energies of the emitted photons (e.g., [ 111 In] indium: 171 and 245 keV; [ 177 Lu] lutetium: 202 and 307 keV), SPECT can distinguish different radioisotopes, therefore making it possible to image different targets simultaneously. Hijnen et al [23] took advantage of this characteristic and devised a dual-isotope experiment on a micro-SPECT system. In their study, they quantified the biodistribution and tumor uptake of the angiogenesis tracer cRGD via SPECT (Figure 1).…”

“…(a) The mice were imaged 1 h after coinjection of 1.32 nmol 177 Lu—DOTA—cRGDfK (yellow-green colormap) and 1.32 nmol 111 In—DOTA—cRADfK (blue-purple colormap); (b) the mice were imaged 1 h after coinjection of 1.32 nmol 111 In—DOTA—cRGDfK (blue-purple colormap) and 1.32 nmol 177 Lu—DOTA—cRADfK (yellow-green colormap). The white arrows indicate the locations of tumor [23]. …”