Instant kit preparation of (68)Ga-radiopharmaceuticals via the hybrid chelator DATA: clinical translation of [(68)Ga]Ga-DATA-TOC

PURPOSE: The widespread use of (68)Ga for positron emission tomography (PET) relies on the development of radiopharmaceutical precursors that can be radiolabelled and dispensed in a simple, quick, and convenient manner. The DATA (6-amino-1,4-diazapine-triacetate) scaffold represents a novel hybrid chelator architecture possessing both cyclic and acyclic character that may allow for facile access to (68)Ga-labelled tracers in the clinic. We report the first bifunctional DATA chelator conjugated to [Tyr(3)]octreotide (TOC), a somatostatin subtype 2 receptor (SST(2))-targeting vector for imaging and functional characterisation of SSTR(2) expressing tumours. METHODS: The radiopharmaceutical precursor, DATA-TOC, was synthesised as previously described and used to complex (nat)Ga(III) and (68)Ga(III). Competition binding assays of [(nat)Ga]Ga-DATA-TOC or [(nat)Ga]Ga-DOTA-TOC against [(125)I-Tyr(25)]LTT-SS28 were conducted in membranes of HEK293 cells transfected to stably express one of the hSST(2,3,5) receptor subtypes (HEK293-hSST(2/3/5) cells). First in vivo studies were performed in female NMRI-nude mice bearing SST(2)-positive mouse phaeochromocytoma mCherry (MPC-mCherry) tumours to compare the in vivo SST(2)-specific tumour-targeting of [(68)Ga]Ga-DATA-TOC and its overall pharmacokinetics versus the [(68)Ga]Ga-DOTA-TOC reference. A direct comparison of [(68)Ga]Ga-DATA-TOC with the well-established PET radiotracer [(68)Ga]Ga-DOTA-TOC was additionally performed in a 46-year-old male patient with a well-differentiated NET (neuroendocrine tumour), representing the first in human administration of [(68)Ga]Ga-DATA-TOC. RESULTS: DATA-TOC was labelled with (68)Ga with a radiolabelling efficiency of > 95% in less than 10 min at ambient temperature. A molar activity up to 35 MBq/nmol was achieved. The hSST(2)-affinities of [(nat)Ga]Ga-DATA-TOC and [(nat)Ga]Ga-DOTA-TOC were found similar with only sub-nanomolar differences in the respective IC(50) values. In mice, [(68)Ga]Ga-DATA-TOC was able to visualise the tumour lesions, showing standardised uptake values (SUVs) similar to [(68)Ga]Ga-DOTA-TOC. Direct comparison of the two PET tracers in a NET patient revealed very similar tumour uptake for the two (68)Ga-radiotracers, but with a higher tumour-to-liver contrast for [(68)Ga]Ga-DATA-TOC. CONCLUSION: [(68)Ga]Ga-DATA-TOC was prepared, to a quality appropriate for in vivo use, following a highly efficient kit type process. Furthermore, the novel radiopharmaceutical was comparable or better than [(68)Ga]Ga-DOTA-TOC in all preclinical tests, achieving a higher tumour-to-liver contrast in a NET-patient. The results illustrate the potential of the DATA-chelator to facilitate the access to and preparation of (68)Ga-radiotracers in a routine clinical radiopharmacy setting. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13550-019-0516-7) contains supplementary material, which is available to authorized users.