Optimized bombesin analogues as nuclear imaging and therapy agents for gastrin-releasing peptide receptor positive neoplasms

The gastrin-releasing peptide receptor (GRPR) is a G-protein coupled receptor that regulates a series of gastrointestinal and central nervous system functions. Its overexpression in numerous cancers has made it a valuable target for imaging these cancers with radioactive bombesin analogues using positron emission tomography (PET) and single photon emission computed tomography (SPECT). GRPR targeted radiopeptide therapy has yet to garner much success due to significant endogenous overexpression of GRPR in the pancreas and gastrointestinal tract. Our laboratory has recently demonstrated that it is possible to target GRPR on tumours without significant accumulation in healthy tissue to enable radiopeptide therapy and improve tumour visualization. We hypothesize that the previously reported GRPR antagonist ProBOMB1 could be optimized for clinical translation by replacing the current neutral pABzA-DIG spacer for a positively charged spacer molecule to improve tumour uptake and tumour contrast, and to demonstrate the importance of Leu¹³ψPro¹⁴ bond for GRPR affinity. In Chapter 3, we synthesized ProBOMB2, which couples the ProBOMB1 peptide sequence with a cationic Pip spacer to evaluate tumour uptake and biodistribution in vivo when labelled with ⁶⁸Ga or ¹⁷⁷Lu using a preclinical cancer model that overexpresses GRPR. Both ProBOMB2 radiotracers had high specific tumour uptake with significantly improved tumour-to-organ ratios. In Chapter 4, we synthesized IB01075 and TacBOMB2, which contain standard amide bonds between Leu¹³ and AA¹⁴. TacBOMB2 contains a terminal Tac residue while IB01075 uses a standard Pro. We found that the introduction of the amide bond at Leu¹³AA¹⁴ significantly reduces GRPR affinity and functionalizes the precursor as an agonist as opposed to an antagonist. Additionally, GRPR affinity can be significantly improved by utilizing a terminal Tac residue as opposed to a Pro (i.e., TacBOMB2). [⁶⁸Ga]Ga-TacBOMB2 demonstrated high specific tumour uptake with good contrast. In ProBOMB2, we were able to create a GRPR specific radiotracer and demonstrate its improved pharmacokinetics and tumour uptake in a preclinical GRPR-positive cancer model when radiolabeled with either ⁶⁸Ga or ¹⁷⁷Lu. We also elucidated the importance of the Leu¹³ψPro¹⁴ for dictating bioactivity and GRPR affinity and developed a novel GRPR agonist radiotracer for imaging GRPR positive cancers.Medicine, Faculty ofGraduat