Evaluation of a 68Ga-Labeled DOTA-Tetrazine as a PET Alternative to 111In-SPECT Pretargeted Imaging

Abstract

The bioorthogonal reaction between a tetrazine and strained trans-cyclooctene (TCO) has garnered success in pretargeted imaging. This reaction was first validated in nuclear imaging using an 111In-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-linked bispyridyl tetrazine (Tz) ([111In]In-DOTA-PEG11-Tz) and a TCO functionalized CC49 antibody. Given the initial success of this Tz, it has been paired with TCO functionalized small molecules, diabodies, and affibodies for in vivo pretargeted studies. Furthermore, the single photon emission tomography (SPECT) radionuclide, 111In, has been replaced with the β-emitter, 177Lu and α-emitter, 212Pb, both yielding the opportunity for targeted radiotherapy. Despite use of the ‘universal chelator’, DOTA, there is yet to be an analogue suitable for positron emission tomography (PET) using a widely available radionuclide. Here, a 68Ga-labeled variant ([68Ga]Ga-DOTA-PEG11-Tz) was developed and evaluated using two different in vivo pretargeting systems (Aln-TCO and TCO-CC49). Small animal imaging and ex vivo biodistribution studies were performed and revealed target specific uptake of [68Ga]Ga-DOTA-PEG11-Tz in the bone (3.7 %ID/g, knee) in mice pretreated with Aln-TCO and tumor specific uptake (5.8 %ID/g) with TCO-CC49 in mice bearing LS174 xenografts. Given the results of this study, [68Ga]Ga-DOTA-PEG11-Tz can serve as an alternative to [111In]In-DOTA-PEG11-Tz.

Evaluation of [64Cu]Cu-NOTA-PEG7-H-Tz for Pretargeted Imaging in LS174T Xenografts—Comparison to [111In]In-DOTA-PEG11-BisPy-Tz

“…The uptake in tumor tissue as well as in other organs of [ 64 Cu]Cu-NOTA-PEG 7 -H-Tz ( 1 ) was slightly lower than those previously found when evaluating [ 111 In]In-DOTA-PEG 11 -BisPy-Tz ( 2 ), using the same setup ( Figure 3 C,D) [ 11 ]. Significant amounts of activity of 2.9 ± 0.5% ID/g were also found in the heart (surrogate for the blood activity) after 2 h, which slightly decreased over the next 20 h to 2.3 ± 0.1% ID/g, resulting in tumor-to-blood (T/B) ratios of 1.1 and 3.3, respectively ( Figure 3 D).…”

“…Significant amounts of activity of 2.9 ± 0.5% ID/g were also found in the heart (surrogate for the blood activity) after 2 h, which slightly decreased over the next 20 h to 2.3 ± 0.1% ID/g, resulting in tumor-to-blood (T/B) ratios of 1.1 and 3.3, respectively ( Figure 3 D). These values are significantly lower than those observed for [ 111 In]In-DOTA-PEG 11 -BisPy-Tz ( 2 ), and indicate that [ 64 Cu]Cu-NOTA-PEG 7 -H-Tz ( 1 ) is excreted at a faster rate [ 11 ]. This also results in higher tumor-to-background ratios ( Figure 3 D).…”

“…Many groups have continuously worked to improve pretargeting strategies based on the tetrazine ligation. For example, we have recently used the same experimental setup to compare the performance of [ 111 In]In-DOTA-PEG 11 -BisPy-Tz ( 2 ) to a 68 Ga-labeled variant of the tracer [ 11 ]. In general, it is usually difficult to compare the performance of different tetrazine-based molecular imaging probes, because factors such as animal strain, tumor models, pretargeting vectors, and evaluation time points are varied [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ].…”

“…In this study, we evaluated [ 64 Cu]Cu-NOTA-PEG 7 -H-Tz ( 1 ) in mice bearing LS174T tumor xenografts, using CC49-TCO as a pretargeting vector. The same setup that was previously used for the evaluation of [ 111 In]In-DOTA-PEG 11 -BisPy-Tz ( 2 ) by us and others [ 3 , 4 , 11 ], and allows us to compare the in vivo performance of [ 64 Cu]Cu-NOTA-PEG 7 -H-Tz to previous results [ 11 ]. Figure 1 displays both tetrazines used in this study.…”

Carbon Nanomaterials for Sorption of 68Ga for Potential Using in Positron Emission Tomography

“…Among radionuclides suitable for PET, 68 Ga is one of the most promising isotopes for widespread use [ 23 , 24 , 25 ]. It has a suitable set of nuclear physical characteristics (T 1/2 = 68 min, 100% β + ) and high availability, as it can be obtained from a 68 Ge/ 68 Ga generator.…”