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

Purpose: The widespread use of 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 Ga-labelled tracers in the clinic. We report the first bifunctional DATA chelator conjugated to [Tyr]octreotide (TOC), a somatostatin subtype 2 receptor (SST)-targeting vector for imaging and functional characterisation of SSTR expressing tumours.

Methods: The radiopharmaceutical precursor, DATA-TOC, was synthesised as previously described and used to complex Ga(III) and Ga(III). Competition binding assays of [Ga]Ga-DATA-TOC or [Ga]Ga-DOTA-TOC against [I-Tyr]LTT-SS28 were conducted in membranes of HEK293 cells transfected to stably express one of the hSST receptor subtypes (HEK293-hSST cells). First in vivo studies were performed in female NMRI-nude mice bearing SST-positive mouse phaeochromocytoma mCherry (MPC-mCherry) tumours to compare the in vivo SST-specific tumour-targeting of [Ga]Ga-DATA-TOC and its overall pharmacokinetics versus the [Ga]Ga-DOTA-TOC reference. A direct comparison of [Ga]Ga-DATA-TOC with the well-established PET radiotracer [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 [Ga]Ga-DATA-TOC.

Results: DATA-TOC was labelled with 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-affinities of [Ga]Ga-DATA-TOC and [Ga]Ga-DOTA-TOC were found similar with only sub-nanomolar differences in the respective IC values. In mice, [Ga]Ga-DATA-TOC was able to visualise the tumour lesions, showing standardised uptake values (SUVs) similar to [Ga]Ga-DOTA-TOC. Direct comparison of the two PET tracers in a NET patient revealed very similar tumour uptake for the two Ga-radiotracers, but with a higher tumour-to-liver contrast for [Ga]Ga-DATA-TOC.

Conclusion: [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 [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 Ga-radiotracers in a routine clinical radiopharmacy setting.