First-in-human experience with GRPR antagonist [68Ga]Ga-NOTA-PEG2-RM26 in prostate and breast cancer patients using PET/CT

thoroughly using different radionuclides for PET and Single Photon Emission Computed Tomography [5].[ 68 Ga]Ga-RM2 and [ 68 Ga]Ga-NeoBOMB1 are two of the most well-studied GRPR antagonists labelled to gallium-68 [6].GRPR antagonists based on the peptide d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 , hereafter referred to as RM26, have shown high affinity towards GRPR and favourable biodistribution with low absorbed doses to healthy organs [7].Radionuclides are bound using macrocyclic chelators such as NOTA, NODAGA, DOTA, and DOTAGA.In this setting, 68 Ga-labelled RM26 NOTA has shown favourable characteristics [7].A molecular spacer sequence prevents interference with the binding site [8].Coupling the radiometal-chelator complex using two to six polyethylene glycol (PEG) spacer lengths affects hydrophilicity, slightly shifting the excretion route from hepatic to renal.However, the conjugate with the shortest PEG linker, NOTA-PEG 2 -RM26, demonstrated the best association rate, k a , and the best halfmaximal inhibitory concentration (IC50), translating into higher activity uptake in GRPR-expressing tissues.Still, variations were minor, with all four conjugates tested, as demonstrated by Varasteh et al. [9].Two RM26 tracers, namely [ 68 Ga]Ga-NOTA-PEG 3 -RM26 and [ 99m Tc]Tc-maSSS-PEG 2 -RM26, have already been tested in humans and proven safe [10,11].We hypothesised that conjugates with shorter linkers could have slightly different distribution profiles due to smaller size, different lipophilicity, and better