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Twins in spirit - episode I: comparative preclinical evaluation of [(68)Ga]DOTATATE and [(68)Ga]HA-DOTATATE.

Schottelius M, Šimeček J, Hoffmann F, Willibald M, Schwaiger M, Wester HJ - EJNMMI Res (2015)

Bottom Line: Recently, an intra-patient comparison demonstrated that the somatostatin (sst) ligand [(68)Ga]HA-DOTATATE ([(68)Ga]DOTA-3-iodo-Tyr(3)-octreotate) provides PET images comparable to or superior to those obtained with [(68)Ga]DOTATATE.The present preclinical data fully confirm the general biodistribution pattern and excellent in vivo sst-targeting characteristics previously observed for [(68)Ga]HA-DOTATATE in patients.Thus, [(68)Ga]HA-DOTATATE represents a fully adequate, freely available substitute for [(68)Ga]DOTATATE and, given the superb sst-targeting characteristics of [(177)Lu]HA-DOTATATE in vitro, potential applicability for sst-targeted PRRT.

View Article: PubMed Central - PubMed

Affiliation: Pharmaceutical Radiochemistry, Technical University Munich, Walther-Meissner-Strasse 3, 85748 Garching, Germany.

ABSTRACT

Background: Recently, an intra-patient comparison demonstrated that the somatostatin (sst) ligand [(68)Ga]HA-DOTATATE ([(68)Ga]DOTA-3-iodo-Tyr(3)-octreotate) provides PET images comparable to or superior to those obtained with [(68)Ga]DOTATATE. To provide a comprehensive basis for nevertheless observed slight differences in tracer biodistribution and dosimetry, the characteristics of [(68)Ga]HA-DOTATATE were investigated in a detailed preclinical study.

Methods: Affinities of (nat)Ga-HA-DOTATATE and (nat)Ga-DOTATATE to sst1-5 were determined using membrane preparations and [(125)I]SST-28 as radioligand. Internalization into AR42J cells was studied in dual-tracer studies with [(125)I]TOC as internal reference. Biodistribution was investigated using AR42J tumor-bearing CD1 mice, and specificity of tracer uptake was confirmed in competition studies by coinjection of 0.8 mg TOC/kg.

Results: Sst2 affinities (IC50) of [(nat)Ga]HA-DOTATATE (1.4 ± 0.8 nM, logP: -3.16) and [(nat)Ga]DOTATATE (1.2 ± 0.6 nM, logP: -3.69) were nearly identical. Both compounds displayed IC50 > 1 μM for sst1,3,4, while sst5 affinity was markedly increased for (nat)Ga-HA-DOTATATE (102 ± 65 nM vs >1 μM for (nat)Ga-DOTATATE). [(nat)Lu]HA-DOTATATE and [(nat)Lu]DOTATATE showed slightly lower, identical sst2 affinities (2.0 ± 1.6 and 2.0 ± 0.8 nM, respectively) and sst3 affinities of 93 ± 1 and 162 ± 16 nM. Internalization of [(68)Ga]HA-DOTATATE was tenfold higher than that of [(125)I]TOC but only sixfold higher for [(68)Ga]DOTATATE and [(177)Lu]HA-DOTATATE. While [(68)Ga]HA-DOTATATE and [(68)Ga]DOTATATE had shown similar target- and non-target uptake in patients, biodistribution studies in mice at 1 h post injection (n = 5) revealed slightly increased non-specific uptake of [(68)Ga]HA-DOTATATE in the blood, liver, and intestines (0.7 ± 0.3, 1.0 ± 0.2, and 4.0 ± 0.7 %iD/g vs 0.3 ± 0.1, 0.5 ± 0.1, and 2.7 ± 0.8 %iD/g for [(68)Ga]DOTATATE). However, sst-mediated accumulation of [(68)Ga]HA-DOTATATE in the pancreas, adrenals, and tumor was significantly enhanced (36.6 ± 4.3, 10.8 ± 3.2, and 33.6 ± 10.9 %iD/g vs 26.1 ± 5.0, 5.1 ± 1.4, and 24.1 ± 4.9 %iD/g, respectively). Consequently, tumor/background ratios for [(68)Ga]HA-DOTATATE in the AR42J model are comparable or slightly increased compared to [(68)Ga]DOTATATE.

Conclusions: The present preclinical data fully confirm the general biodistribution pattern and excellent in vivo sst-targeting characteristics previously observed for [(68)Ga]HA-DOTATATE in patients. The effect of slightly enhanced lipophilicity on background accumulation and normal organ dose is compensated by the high uptake of [(68)Ga]HA-DOTATATE in tumor. Thus, [(68)Ga]HA-DOTATATE represents a fully adequate, freely available substitute for [(68)Ga]DOTATATE and, given the superb sst-targeting characteristics of [(177)Lu]HA-DOTATATE in vitro, potential applicability for sst-targeted PRRT.

No MeSH data available.


Related in: MedlinePlus

Tumor-to-organ ratios of [68Ga]DOTATATE and [68Ga]HA-DOTATATE. Biodistribution experiments were carried out in AR42J tumor-bearing nude mice (60 min p.i.). Data are means ± SD (n = 5).
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Fig4: Tumor-to-organ ratios of [68Ga]DOTATATE and [68Ga]HA-DOTATATE. Biodistribution experiments were carried out in AR42J tumor-bearing nude mice (60 min p.i.). Data are means ± SD (n = 5).

Mentions: Again, the preclinical mouse data obtained in this study parallel the findings from our human PET studies, where [68Ga]HA-DOTATATE showed somewhat improved sst-targeting efficiency compared to [68Ga]DOTATATE, reflected by a slight increase in SUVmean for the spleen and pituitary [8]. However, while the mouse biodistribution data in this study reveal fundamental differences between both the general biodistribution and sst-mediated tissue accumulation of [68Ga]HA-DOTATATE and [68Ga]DOTATATE, respectively, these opposed effects were not observed to the same extent in the human studies. For example, tracer uptake (SUVmean) in normal organs such as the liver and kidney as well as in primary tumors and their metastases were found to be nearly identical for both radioligands in patients [8]. Obviously, tissue distribution of [68Ga]HA-DOTATATE and [68Ga]DOTATATE in humans is mainly dominated by the very similar tracer pharmacokinetics of both compounds, whereas in mice, the respective influence of both the increased sst-targeting efficiency and of the slightly enhanced lipophilicity of [68Ga]HA-DOTATATE on tracer biodistribution is much more pronounced. Interestingly, the comparable in vivo performance of [68Ga]HA-DOTATATE and [68Ga]DOTATATE in patients is well reflected by the very similar tumor-to-background ratios (Figure 4) obtained for the two compounds in the AR42J xenograft model. Here, the high sst-targeting efficiency of [68Ga]HA-DOTATATE is counterbalanced by the enhanced tracer accumulation in non-target organs occasioned by the delayed clearance kinetics of [68Ga]HA-DOTATATE. It is important to note that, given the early time point after tracer injection (1 h p.i.), these data certainly do not display the full sst-targeting potential of [68Ga]HA-DOTATATE. Its increased blood activity levels at 1 h p.i. may lead to improved bioavailability and even higher tumor uptake at later time points, which might prove advantageous for PRRT using [177Lu]HA-DOTATATE. However, longer circulation times also might entail increased hematotoxicity, and therefore, it needs to be carefully evaluated in preclinical therapeutic studies, to what extent the differences between [177Lu]DOTATATE and [177Lu]HA-DOTATATE will have an impact on the therapeutic effects of the compounds.Figure 4


Twins in spirit - episode I: comparative preclinical evaluation of [(68)Ga]DOTATATE and [(68)Ga]HA-DOTATATE.

Schottelius M, Šimeček J, Hoffmann F, Willibald M, Schwaiger M, Wester HJ - EJNMMI Res (2015)

Tumor-to-organ ratios of [68Ga]DOTATATE and [68Ga]HA-DOTATATE. Biodistribution experiments were carried out in AR42J tumor-bearing nude mice (60 min p.i.). Data are means ± SD (n = 5).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4402678&req=5

Fig4: Tumor-to-organ ratios of [68Ga]DOTATATE and [68Ga]HA-DOTATATE. Biodistribution experiments were carried out in AR42J tumor-bearing nude mice (60 min p.i.). Data are means ± SD (n = 5).
Mentions: Again, the preclinical mouse data obtained in this study parallel the findings from our human PET studies, where [68Ga]HA-DOTATATE showed somewhat improved sst-targeting efficiency compared to [68Ga]DOTATATE, reflected by a slight increase in SUVmean for the spleen and pituitary [8]. However, while the mouse biodistribution data in this study reveal fundamental differences between both the general biodistribution and sst-mediated tissue accumulation of [68Ga]HA-DOTATATE and [68Ga]DOTATATE, respectively, these opposed effects were not observed to the same extent in the human studies. For example, tracer uptake (SUVmean) in normal organs such as the liver and kidney as well as in primary tumors and their metastases were found to be nearly identical for both radioligands in patients [8]. Obviously, tissue distribution of [68Ga]HA-DOTATATE and [68Ga]DOTATATE in humans is mainly dominated by the very similar tracer pharmacokinetics of both compounds, whereas in mice, the respective influence of both the increased sst-targeting efficiency and of the slightly enhanced lipophilicity of [68Ga]HA-DOTATATE on tracer biodistribution is much more pronounced. Interestingly, the comparable in vivo performance of [68Ga]HA-DOTATATE and [68Ga]DOTATATE in patients is well reflected by the very similar tumor-to-background ratios (Figure 4) obtained for the two compounds in the AR42J xenograft model. Here, the high sst-targeting efficiency of [68Ga]HA-DOTATATE is counterbalanced by the enhanced tracer accumulation in non-target organs occasioned by the delayed clearance kinetics of [68Ga]HA-DOTATATE. It is important to note that, given the early time point after tracer injection (1 h p.i.), these data certainly do not display the full sst-targeting potential of [68Ga]HA-DOTATATE. Its increased blood activity levels at 1 h p.i. may lead to improved bioavailability and even higher tumor uptake at later time points, which might prove advantageous for PRRT using [177Lu]HA-DOTATATE. However, longer circulation times also might entail increased hematotoxicity, and therefore, it needs to be carefully evaluated in preclinical therapeutic studies, to what extent the differences between [177Lu]DOTATATE and [177Lu]HA-DOTATATE will have an impact on the therapeutic effects of the compounds.Figure 4

Bottom Line: Recently, an intra-patient comparison demonstrated that the somatostatin (sst) ligand [(68)Ga]HA-DOTATATE ([(68)Ga]DOTA-3-iodo-Tyr(3)-octreotate) provides PET images comparable to or superior to those obtained with [(68)Ga]DOTATATE.The present preclinical data fully confirm the general biodistribution pattern and excellent in vivo sst-targeting characteristics previously observed for [(68)Ga]HA-DOTATATE in patients.Thus, [(68)Ga]HA-DOTATATE represents a fully adequate, freely available substitute for [(68)Ga]DOTATATE and, given the superb sst-targeting characteristics of [(177)Lu]HA-DOTATATE in vitro, potential applicability for sst-targeted PRRT.

View Article: PubMed Central - PubMed

Affiliation: Pharmaceutical Radiochemistry, Technical University Munich, Walther-Meissner-Strasse 3, 85748 Garching, Germany.

ABSTRACT

Background: Recently, an intra-patient comparison demonstrated that the somatostatin (sst) ligand [(68)Ga]HA-DOTATATE ([(68)Ga]DOTA-3-iodo-Tyr(3)-octreotate) provides PET images comparable to or superior to those obtained with [(68)Ga]DOTATATE. To provide a comprehensive basis for nevertheless observed slight differences in tracer biodistribution and dosimetry, the characteristics of [(68)Ga]HA-DOTATATE were investigated in a detailed preclinical study.

Methods: Affinities of (nat)Ga-HA-DOTATATE and (nat)Ga-DOTATATE to sst1-5 were determined using membrane preparations and [(125)I]SST-28 as radioligand. Internalization into AR42J cells was studied in dual-tracer studies with [(125)I]TOC as internal reference. Biodistribution was investigated using AR42J tumor-bearing CD1 mice, and specificity of tracer uptake was confirmed in competition studies by coinjection of 0.8 mg TOC/kg.

Results: Sst2 affinities (IC50) of [(nat)Ga]HA-DOTATATE (1.4 ± 0.8 nM, logP: -3.16) and [(nat)Ga]DOTATATE (1.2 ± 0.6 nM, logP: -3.69) were nearly identical. Both compounds displayed IC50 > 1 μM for sst1,3,4, while sst5 affinity was markedly increased for (nat)Ga-HA-DOTATATE (102 ± 65 nM vs >1 μM for (nat)Ga-DOTATATE). [(nat)Lu]HA-DOTATATE and [(nat)Lu]DOTATATE showed slightly lower, identical sst2 affinities (2.0 ± 1.6 and 2.0 ± 0.8 nM, respectively) and sst3 affinities of 93 ± 1 and 162 ± 16 nM. Internalization of [(68)Ga]HA-DOTATATE was tenfold higher than that of [(125)I]TOC but only sixfold higher for [(68)Ga]DOTATATE and [(177)Lu]HA-DOTATATE. While [(68)Ga]HA-DOTATATE and [(68)Ga]DOTATATE had shown similar target- and non-target uptake in patients, biodistribution studies in mice at 1 h post injection (n = 5) revealed slightly increased non-specific uptake of [(68)Ga]HA-DOTATATE in the blood, liver, and intestines (0.7 ± 0.3, 1.0 ± 0.2, and 4.0 ± 0.7 %iD/g vs 0.3 ± 0.1, 0.5 ± 0.1, and 2.7 ± 0.8 %iD/g for [(68)Ga]DOTATATE). However, sst-mediated accumulation of [(68)Ga]HA-DOTATATE in the pancreas, adrenals, and tumor was significantly enhanced (36.6 ± 4.3, 10.8 ± 3.2, and 33.6 ± 10.9 %iD/g vs 26.1 ± 5.0, 5.1 ± 1.4, and 24.1 ± 4.9 %iD/g, respectively). Consequently, tumor/background ratios for [(68)Ga]HA-DOTATATE in the AR42J model are comparable or slightly increased compared to [(68)Ga]DOTATATE.

Conclusions: The present preclinical data fully confirm the general biodistribution pattern and excellent in vivo sst-targeting characteristics previously observed for [(68)Ga]HA-DOTATATE in patients. The effect of slightly enhanced lipophilicity on background accumulation and normal organ dose is compensated by the high uptake of [(68)Ga]HA-DOTATATE in tumor. Thus, [(68)Ga]HA-DOTATATE represents a fully adequate, freely available substitute for [(68)Ga]DOTATATE and, given the superb sst-targeting characteristics of [(177)Lu]HA-DOTATATE in vitro, potential applicability for sst-targeted PRRT.

No MeSH data available.


Related in: MedlinePlus