Pharmacokinetic Investigations of Ghrelin(1-8) Analogues Towards Development of PET Imaging Probes for Prostate Cancer

The growth hormone secretagogue receptor 1a (GHSR), known as the ghrelin receptor, is differentially expressed in various diseases and cancer types, including pancreatic, breast, and prostate.¹ A ghrelin-based analogue was previously discovered with exceptional receptor affinity, however, in vivo evaluation revealed an unfavourable pharmacokinetics with rapid clearance and accumulation in the liver and intestines.² Stability investigations revealed a metabolic soft spot between amino acids Leu⁵ and Ser⁶.³ Subsequently, a library of analogues were synthesized and evaluated for their in vitro stability, revealing two analogues with improved metabolic stability with retained receptor affinity. In this investigation, three analogues are being radiolabelled with a fluorine-18 6-fluoro-2-naphtyl (6-FN) prosthetic group and evaluated in vivo to assess their pharmacokinetic profiles. Peptides were synthesized using Fmoc solid-phase peptide synthesis, purified by preparative HPLC, and characterized by high-resolution mass spectrometry. An iodonium ylide precursor was synthesized and radiolabelled with fluorine-18 to yield the ¹⁸F-prosthetic group, which was then conjugated to the peptides. The probes are being evaluated in a prostate cancer xenograft model to assess varying pharmacokinetic profiles. This study demonstrates the intricate radiopharmaceutical optimization pathway, accounting for affinity, stability and biodistribution, towards the development of a peptide-based ghrelin-targeted PET probe for prostate cancer imaging.