Development of radiopharmaceuticals to target neurotensin receptors based on ⁶⁸Ga and ¹⁷⁷Lu

Objectives The study aims to develop new theranostic agents for systemic cancer radiotherapy and follow up. The 68 min half-life of the ⁶⁸Ga matches the pharmacokinetics of neurotensin peptide - rapid diffusion, localization at the target and fast blood clearance. ¹⁷⁷Lu is a therapeutic counterpart of ⁶⁸Ga, giving highly destructive β emissions.

Methods The purified eluate from a ⁶⁸Ge/⁶⁸Ga generator and a solution of ¹⁷⁷LuCl₃ respectivelly were used for radiolabelling of neurotensin (DOTA-NT). at pH 4, 950C, in non-ionic buffer. Automated synthesis and postpurification was performed. Analytical testing and biological in vitro and in vivo evaluation of ⁶⁸Ga/¹⁷⁷Lu-DOTA-NT was done in tumor animal models. Real-time quantification of biomolecular interactions was determined: on- and off-rates, affinity of DOTA-NT to tumor cell-surface receptors.

Results Nanomoles of DOTA-NT were radiolabelled with a yield of 90% while the radiochemical purity of ⁶⁸Ga/¹⁷⁷Lu-DOTA-NT, after SPE purification was >98%. The biodistribution pattern shows high and stable tumor uptake up to 8.6% ID/g. The blood clearance is fast, the renal elimination is rapid and high tumor to background ratios was observed. Binding to receptors is achieved in the first 3 min of incubation and remains stable for 30 min.

Conclusions The radiolabelling with ⁶⁸Ga and ¹⁷⁷Lu of very promising candidates for imaging targets of interest in cancer diagnosis and therapy follow-up such as neurotensin receptors, were successfully adapted on the automated module, reducing reaction time and operator exposure. The biological evaluation of ⁶⁸Ga/¹⁷⁷Lu-DOTA-NT show a high and stable tumor uptake of both compounds.Promising preliminary biological evaluation is recommending further investigations of ⁶⁸Ga-DOTA-NT1 as potential tracer in PET imaging and ¹⁷⁷Lu-DOTA-NT1 as systemic radiotehrapy agent.

Research Support The work has been funded by the Sectoral Operational Programme Human Resources Development 2007-2013 of the Ministry of European Funds through the Financial Agreement POSDRU/159/1.5/S/134398 and Partnership Programme in priority areas - PN II, MEN - UEFISCDI, contract 228/2014.