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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 sst 1–5  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  Sst 2  affinities (IC 50 ) of [ nat Ga]HA-DOTATATE (1.4 ± 0.8 nM, log P : −3.16) and [ nat Ga]DOTATATE (1.2 ± 0.6 nM, log P : −3.69) were nearly identical. Both compounds displayed IC 50  > 1 μM for sst 1,3,4 , while sst 5  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 sst 2  affinities (2.0 ± 1.6 and 2.0 ± 0.8 nM, respectively) and sst 3  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.

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