Comparative evaluation of 68Ga-labelled TATEs: the impact of chelators on imaging

Background Ga-68-labelled peptides targeting somatostatin receptor 2 (SSTR2) have demonstrated encouraging results in managing patients with neuroendocrine tumours (NETs). In addition to metal chelation, bifunctional chelators have also been found to impact imaging outcomes due to their differences in stability, charge, hydrophilicity, etc. In the present work, a comparative pharmacokinetic evaluation and imaging characteristics were performed between Ga-68-labelled somatostatin analogues (TATE) using NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) and DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) as bifunctional chelating agents (BFCAs). Results Both Ga-68-NOTA-TATE and Ga-68-DOTA-TATE were obtained with high radiochemical purity. Ga-68-NOTA-TATE demonstrated higher in vitro stability (>= 99%) than Ga-68-DOTA-TATE (>= 95%) after 3 h of incubation. The water solubilities (partition coefficients, - 1.76 +/- 0.06 vs. - 2.72 +/- 0.16) and plasma protein binding rates (12.12% vs. 30.6%) were lower for Ga-68-NOTA-TATE than for Ga-68-DOTA-TATE. Differential pharmacokinetics and comparable tumour affinities (within 1 h) were observed in AR42J tumour-bearing mice. Healthy volunteer imaging studies showed comparable distribution patterns of these two imaging agents. However, the maximum standardized uptake values (SUVmax) of the two tracers varied in each organ. The two PET agents demonstrated almost identical SUVmax values in the kidneys. Ga-68-NOTA-TATE did have a lower SUVmax in most other organs compared with Ga-68-DOTA-TATE, including the liver (4.2 vs. 10.1), potentially due to the lower protein binding rate. Conclusion Ga-68-NOTA-TATE and Ga-68-DOTA-TATE demonstrated comparable tumour uptake in an AR42J mouse model. An initial clinical study revealed that Ga-68-NOTA-TATE may have reduced background uptake in the major organs such as the liver. Although the subject numbers were limited, further investigation of Ga-68-NOTA-TATE is warranted for detecting SSTR2-positive neuroendocrine tumours.