Neurotensin analogs by fluoroglycosylation at Nω-carbamoylated arginines for PET imaging of NTS1-positive tumors.

Since neurotensin (NT) receptors of subtype-1 (NTS1) are expressed by different types of malignant tumors, such as pancreatic adenocarcinoma, colorectal and prostate carcinoma, they represent an interesting target for tumor imaging by positron emission tomography (PET) and endoradiotherapy. Previously reported neurotensin-derived NTS1 ligands for PET were radiolabeled by modification and prelongation of the N-terminus of NT(8-13) peptide analogs. In this study, we demonstrate that modifying Arg8 or Arg9 by Nω-carbamoylation and subsequent fluoroglycosylation provides a suitable approach for the development of NT(8-13) analogs as PET imaging agents. The Nω-carbamoylated and fluoroglycosylated NT(8-13) analogs retained high NTS1 affinity in the one-digit nanomolar range as well as high metabolic stability in vitro. In vivo, the radioligand [18F]21 demonstrated favorable biokinetics in HT-29 tumor-bearing mice with high tumor uptake and high retention, predominantly renal clearance, and fast wash-out from blood and other non-target tissues. Therefore, [18F]21 has the potential to be used as molecular probe for the imaging of NTS1-expressing tumors by PET.

An Alkyne-functionalized Arginine for Solid-Phase Synthesis Enabling "Bioorthogonal" Peptide Conjugation.

Lately, amino-functionalized N ω-carbamoylated arginines were introduced as arginine surrogates enabling peptide labeling. However, this approach is hardly compatible with peptides also containing lysine or cysteine. Here, we present the synthesis of an alkyne-functionalized, N ω-carbamoylated arginine building block (7), which is compatible with Fmoc-strategy solid-phase peptide synthesis. The alkynylated arginine was incorporated into three biologically active linear hexapeptides and into a cyclic pentapeptide. Peptide conjugation to an azido-functionalized fluorescent dye via "click" chemistry was successfully demonstrated. In the case of a peptide also containing lysine besides the alkyne-functionalized arginine, this was feasible in a "bioorthogonal" manner.