Diagnosis of Prostate Cancer with a Neurotensin-Bombesin Radioligand Combination-First Preclinical Results.

The concept of radiotheranostics relies on the overexpression of a biomolecular target on malignant cells to direct diagnostic/therapeutic radionuclide-carriers specifically to cancer lesions. The concomitant expression of more than one target in pathological lesions may be elegantly exploited to improve diagnostic sensitivity and therapeutic efficacy. Toward this goal, we explored a first example of a combined application of [Tc]Tc-DT11 (DT11, N-Lys(MPBA-PEG4)-Arg-Arg-Pro-Tyr-Ile-Leu-OH; NTSR-specific) and [Tc]Tc-DB7(DB7, N-PEG2-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt; GRPR-specific) in prostate cancer models.

Bis(Disulfide)-Bridged Somatostatin-14 Analogs and Their [In]In-Radioligands: Synthesis and Preclinical Profile.

The overexpression of one or more somatostatin receptors (SSTR) in human tumors has provided an opportunity for diagnosis and therapy with somatostatin-like radionuclide carriers. The application of "pansomatostatin" analogs is expected to broaden the clinical indications and upgrade the diagnostic/therapeutic efficacy of currently applied SSTR-prefering radioligands. In pursuit of this goal, we now introduce two bicyclic somatostatin-14 (SS14) analogs, AT5S (DOTA-Ala-Gly-c[Cys-Lys-Asn-c[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-Ser-Cys]) and AT6S (DOTA-Ala-Gly-c[Cys-Lys-c[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-Ser-Cys]), suitable for labeling with trivalent radiometals and designed to sustain in vivo degradation.

Side-Chain Modified [Tc]Tc-DT1 Mimics: A Comparative Study in NTSR-Positive Models.

Radiolabeled neurotensin analogs have been developed as candidates for theranostic use against neurotensin subtype 1 receptor (NTSR)-expressing cancer. However, their fast degradation by two major peptidases, neprilysin (NEP) and angiotensin-converting enzyme (ACE), has hitherto limited clinical success. We have recently shown that palmitoylation at the -amine of Lys in [Tc]Tc-[Lys]DT1 (DT1, N-Gly-Arg-Arg-Pro-Tyr-Ile-Leu-OH, N = 6-(carboxy)-1,4,8,11-tetraazaundecane) led to the fully stabilized [Tc]Tc-DT9 analog, displaying high uptake in human pancreatic cancer AsPC-1 xenografts but unfavorable pharmacokinetics in mice.

Toward Stability Enhancement of NTSR-Targeted Radioligands: Structural Interventions on [Tc]Tc-DT1.

The neurotensin subtype 1 receptor (NTSR) is overexpressed in a number of human tumors, thereby representing a valid target for cancer theranostics with radiolabeled neurotensin (NT) analogs like [Tc]Tc-DT1 (DT1, N-Gly-NT(8-13)). Thus far, the fast degradation of intravenously injected NT-radioligands by neprilysin (NEP) and angiotensin-converting enzyme (ACE) has compromised their clinical applicability. Aiming at metabolic stability enhancements, we herein introduce (i) DT7 ([DAsn]DT1) and (ii) DT8 ([β-Homoleucine]DT1), modified at the C-terminus, along with (iii) DT9 ([(palmitoyl)Lys]DT1), carrying an albumin-binding domain (ABD) at Lys.

Nonpeptidic Z360-Analogs Tagged with Trivalent Radiometals as Anti-CCKR Cancer Theranostic Agents: A Preclinical Study.

(1) Background: Theranostic approaches in the management of cholecystokinin subtype 2 receptor (CCKR)-positive tumors include radiolabeled gastrin and CCK motifs. Moving toward antagonist-based CCKR-radioligands instead, we herein present three analogs of the nonpeptidic CCKR-antagonist Z360, GAS1/2/3. Each was conjugated to a different chelator (DOTA, NODAGA or DOTAGA) for labeling with medically relevant trivalent radiometals (e.