Thesis defense – Adrien Chastel

Lieu : Salle des soutenances
Service de radiologie, Tripode CHU de Bordeaux, Place Amélie Raba Léon

Adrien Chastel
INCIA – Equipe TEP

Exploration of new approaches to targeted radionuclide therapy with neuropeptide analogs

Abstract

Targeted Radionuclide Therapy (TRT) uses radionuclides coupled to carrier molecules (radiopharmaceuticals) capable of targeting receptors overexpressed by tumor cells or their microenvironment. Among the approaches used in TRT, the one based on analogs of radiolabeled peptides, such as [¹⁷⁷Lu]Lu-DOTATATE or [¹⁷⁷Lu]Lu-PSMA, is in full expansion. These treatments are part of a personalized theranostic approach, where a companion molecule labeled with a positron emitter such as ⁶⁸Ga is used for PET imaging as a preamble to TRT. This Thesis work explores the potential offered by the targeting of two neuropeptide receptors, the neurotensin receptor NTS₁ and the neuropeptide Y receptor Y₁R, known to be overexpressed in several cancers.

Regarding the targeting of NTS₁, the design of peptide radiopharmaceuticals is difficult due to the short half-life of the endogenous neurotensin peptide. In the first part of this work, we explored the impact of unnatural amino acids in neurotensin analogs, radiolabelled with ⁶⁸Ga. Insertion of a silylated alanine in the N-terminal position stabilized the [⁶⁸Ga]Ga-JMV6659 peptide while maintaining a good affinity and selectivity profile. In vivo, the analog [⁶⁸Ga]Ga-JMV6659 showed excellent tumor uptake in nude mice carrying an HT-29 xenograft making this compound a good candidate for PET imaging.

Future development of TRT requires increasing the dose deposited to the tumor to better control the cancerous pathology. An emerging strategy, little explored today, consists of the nuclear targeting of therapeutic short-course emitters such as terbium-161, rich in Auger electrons. With this in mind, we explored the feasibility of nuclear addressing via the Y₁R receptor of an agonist analogue of the modified neuropeptide Y, using a cleavage sequence by endosomal cathepsin B subsequently releasing a nuclear localization sequence (NLS) supported by cytoplasmic importins providing transport to the nucleus. Thus, the compound Pb12 was studied after radiolabelling with ¹¹¹In, as a substitute for ¹⁶¹Tb. Results obtained on MCF7 breast cancer cells expressing Y₁R showed that this multi-step nuclear addressing technology works, opening promising prospects with other short-range therapeutic emitters such as alpha emitters.

Keywords: Targeted radionuclide therapy, NTS₁, Y₁R, radiopharmaceuticals

Jury

– Pr Elif Hindié (Directeur de thèse)

– Pr Laurence Bordenave (Présidente du jury)

– Dr David Kryza (Rapporteur)

– Dr David Taïeb (Rapporteur)

– Dr Clément Morgat (Invité)

Publications

– Morgat C, Chastel A, Molinie V, Schollhammer R, Macgrogan G, Vélasco V, Malavaud B, Fernandez P, Hindié E ; Neurotensin Receptor-1 Expression in Human Prostate Cancer: A Pilot Study on Primary Tumors and Lymph Node Metastases ; International Journal of Molecular Sciences, 20(7). pii: E1721, 2019

– Chastel A, Worm D J, Alves I D, Vimont D, Petrel M, Fernandez S, Garrigue P, Fernandez P, Hindié E, Beck-Sickinger A G, Morgat C ; Design, synthesis, and biological evaluation of a multifunctional neuropeptide-Y conjugate for selective nuclear delivery of radiolanthanides, EJNMMI Res, 10(1):16, 2020

– Fanelli R, Chastel A, Previti S, Hindié E, Vimont D, Zanotti-Fregonara P, Fernandez P, Garrigue P, Lamare F, Schollhammer R, Balasse L, Guillet B, Rémond E, Morgat C, Cavelier F ; Silicon-Containing Neurotensin Analogues as Radiopharmaceuticals for NTS1-Positive Tumors Imaging ; Bioconjugate Chemistry, sous presse