AAZTA⁵-BN as a Versatile Probe for Radiometal Labelling, Nuclear Imaging and Radionuclide Therapy of Gastrin Releasing Peptide Positive Tumors

Ziel/Aim The present study aims at investigating the influence of the versatile bifunctional chelator AAZTA⁵ on a Gastrin Releasing Peptide receptor (GRPr)-based antagonist and assessing its potential in serving as theranostic compound for GRPr-positive tumors.

Methodik/Methods The GRPr-based antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH₂ was functionalized with the spacer 4-amino-1-carboxymethyl-piperidine (Pip) and the chelator 6-[Bis(carboxymethyl)amino]-1,4-bis(carboxymethyl)-6-methyl-1,4-diazepane (AAZTA⁵). The obtained precursor, named LF1, was labelled with gallium-68 (PET), lutetium-177 (therapy/SPECT) and indium-111 (SPECT/intraoperative applications). Furthermore, the stability, lipophilicity, protein binding, K_d and B_max, the internalization rate of the three generated radiotracers and the potential of the ¹⁷⁷Lu-labelled LF1 in serving as theranostic compound were assessed.

Ergebnisse/Results LF1 was labelled within 5 min at RT with a radiochemical purity of >98 % for the ¹⁷⁷Lu- and ¹¹¹In-labelled conjugates and approximately 90 % for the ⁶⁸Ga-laballed conjugate. The radiotracers were stable over 4 h post labelling, exhibiting a logD_octanol/PBS of approx. -3 and protein binding to human serum proteins of approx. 10 %. High affinities for PC3 cells were observed for the three radiotracers, with K_d values between 5 and 16 nM, while the number of GRPr per cell was approx. 4 x 10⁵. The internalization studies showed that the total specific cell surface uptake always exceeded the internalized activity. Our preliminary in vitro therapy data showed that combination therapy with rapamycin was slightly more effective compared to monotherapy with ¹⁷⁷Lu-labelled LF1.

Schlussfolgerungen/Conclusions LF1 labelled lutetium-177 and indium-111 appears to have a considerable potential to serve as a versatile probe suitable for SPECT, therapy and intraoperative applications. The promising acquired in vitro data prompt us to further continue on the evaluation of this precursor in tumor models.

Publikationsverlauf

Artikel online veröffentlicht:
08. April 2021