Novel Synthetic Strategies for the Development of Peptides and Peptidomimetics in Alzheimer's Disease and Prostate Cancer

Peptides are attractive therapeutic agents due to their high target affinity and specificity. However, their clinical application is often limited by poor metabolic stability, rapid renal clearance and low bioavailability, necessitating chemical modifications to generate viable drug candidates. This thesis addresses these challenges through the development of safer synthetic methods and the design of modified peptides targeting two clinically relevant proteins: the insulin-regulated aminopeptidase (IRAP) in Alzheimer’s disease and the gastrin-releasing peptide receptor (GRPR) in prostate cancer. The first part focuses on method development for the safer generation of diazomethane, a key reagent in peptide modification, particularly for the synthesis of β3-amino acids via α-diazoketones in the Arndt-Eistert homologation. However, diazomethane is explosive and carcinogenic, limiting its practical use. In Paper I, we report a method for the in situ generation of diazomethane through a click and release reaction between an enamine and a sulfonyl azide, thereby eliminating the hazardous handling of diazomethane. This strategy enabled the synthesis of α-diazoketones and methyl esters of carboxylic acids under mild, base-free conditions. The second part investigates structure–activity relationships (SAR) of modified peptides targeting IRAP and GRPR. In Paper II, twelve novel analogues of the macrocyclic IRAP inhibitor HA08 were synthesised via a new divergent route focusing on C-terminal modifications. IRAP inhibition has shown cognitive benefits in preclinical models of Alzheimer’s disease. Thus, inhibitors like HA08 are potential cognitive enhancers. However, this peptidomimetic suffers from poor metabolic stability, necessitating further structural modifications. The SAR study revealed that aromaticity and correct spatial orientation at the C-terminus were crucial for IRAP inhibition. Papers III and IV focus on the development of GRPR antagonists for imaging and therapy in early-stage prostate cancer. GRPR is overexpressed in prostate tumour cells but minimally expressed in healthy tissues, making it a valuable molecular target for theranostic application. In Paper III, the influence of rigidity and lipophilicity of aromatic linkers in 68Ga-labelled radiopeptides for PET imaging was explored. Moderate lipophilicity improved tumour uptake and imaging contrast, suggesting that fine-tuning linker properties can optimise radioligand pharmacokinetics. Finally, therapeutic application of GRPR antagonists requires enhancement of circulatory half-life to prolong tumour irradiation. In paper IV, albumin-binding moieties (ABMs) were incorporated into 117Lu-labelled radiopeptides, which extended circulatory half-life for all conjugates and increased GRPR-mediated uptake. The position and lipophilicity of the ABM strongly influenced biodistribution profile of the radioconjugates, with [177Lu]Lu-CA6356 and [177Lu]Lu-CA6357 showing the most favourable profile.