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

Background: Recently, an intra-patient comparison demonstrated that the somatostatin (sst) ligand [Ga-68]HA-DOTATATE ([Ga-68]DOTA-3-iodo-Tyr(3)-octreotate) provides PET images comparable to or superior to those obtained with [Ga-68]DOTATATE. To provide a comprehensive basis for nevertheless observed slight differences in tracer biodistribution and dosimetry, the characteristics of [Ga-68]HA-DOTATATE were investigated in a detailed preclinical study. Methods: Affinities of Ga-nat-HA-DOTATATE and Ga-nat-DOTATATE to sst(1-5) were determined using membrane preparations and [I-125]SST-28 as radioligand. Internalization into AR42J cells was studied in dual-tracer studies with [I-125]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 (IC50) of [Ga-nat]HA-DOTATATE (1.4 +/- 0.8 nM, logP: -3.16) and [Ga-nat]DOTATATE (1.2 +/- 0.6 nM, logP: -3.69) were nearly identical. Both compounds displayed IC50 > 1 mu M for sst(1,3,4), while sst(5) affinity was markedly increased for Ga-nat-HA-DOTATATE (102 +/- 65 nM vs > 1 mu M for Ga-nat-DOTATATE). [Lu-nat]HA-DOTATATE and [Lu-nat]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 [Ga-68]HA-DOTATATE was tenfold higher than that of [I-125] TOC but only sixfold higher for [Ga-68]DOTATATE and [Lu-177]HA-DOTATATE. While [Ga-68]HA-DOTATATE and [Ga-68]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 [Ga-68]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 [Ga-68]DOTATATE). However, sst-mediated accumulation of [Ga-68]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 [Ga-68]HA-DOTATATE in the AR42J model are comparable or slightly increased compared to [Ga-68]DOTATATE. Conclusions: The present preclinical data fully confirm the general biodistribution pattern and excellent in vivo sst-targeting characteristics previously observed for [Ga-68]HA-DOTATATE in patients. The effect of slightly enhanced lipophilicity on background accumulation and normal organ dose is compensated by the high uptake of [Ga-68]HA-DOTATATE in tumor. Thus, [Ga-68]HA-DOTATATE represents a fully adequate, freely available substitute for [Ga-68]DOTATATE and, given the superb sst-targeting characteristics of [Lu-177]HA-DOTATATE in vitro, potential applicability for sst-targeted PRRT.