PhD Position (36 months) “ALPHACAGE: Advanced Azamacrocyclic-Based Chelators for Next-Generation Therapeutic Radiometals in Nuclear Medicine”

Laboratoire CEMCA – UMR CNRS 6521
Université de Bretagne Occidentale (UBO), Brest, France

Team Chimie Organique, Santé et Molécules (COSM)
Group Macrocycles Azotés et Coordination

Project

Targeted radionuclide therapy is currently experiencing an unprecedented expansion, driven by the clinical success of therapeutic alpha-emitting radiometals such as ²¹²Pb/²¹²Bi, ²²⁵Ac and ²²³Ra. These radionuclides combine high therapeutic efficacy with reduced irradiation of healthy tissues and are expected to play a major role in precision oncology over the coming decade.

However, their full clinical potential critically depends on the availability of highly stable bifunctional chelators, capable of tightly coordinating large metal ions while preserving their integrity under physiological conditions. For generator systems such as ²¹²Pb/²¹²Bi, an additional challenge consists in retaining the daughter radionuclide after radioactive decay. Likewise, the development of robust ligands for actinium, lead, bismuth and radium cations remains one of the major scientific bottlenecks in targeted alpha therapy.

Over the last fifteen years, our group has developed a recognized expertise in the chemistry of azamacrocyclic-based metal-chelators, leading to numerous contributions in transition-, heavy-metal and lanthanide coordination chemistry, molecular imaging and radiopharmaceutical sciences. Building upon these achievements, the present PhD project aims at extending this platform toward the coordination of the next generation of therapeutic radiometals.

Beyond Pb²⁺ and Bi³⁺, particular attention will also be devoted to Ba²⁺ as a non-radioactive structural surrogate of radium, Ra²⁺, and Ac³⁺, allowing the establishment of structure-property relationships across several classes of medically relevant radionuclides.

The project combines organic synthesis, coordination chemistry, structural characterization, thermodynamic and kinetic studies, radiochemistry, and radiopharmaceutical development, offering a multidisciplinary environment at the interface between chemistry, nuclear medicine and molecular imaging.

In parallel with the academic consortium, the project is expected to benefit from interactions with a major industrial partner active in the radiopharmaceutical field, providing additional perspectives toward translational research and future clinical applications.

Scientific objectives

The doctoral project will focus on several complementary aspects:

• Design and synthesis of new pyclen-based macrocyclic ligands;
• Development of innovative picolinate and picolinamide architectures based on HSAB concepts;
• Coordination chemistry of Pb²⁺, Bi³⁺, Ba²⁺, Ra²⁺ and Ac³⁺;
• Thermodynamic, kinetic and structural investigations;
• Radiolabelling with therapeutic radionuclides (²⁰³Pb/²¹²Pb, ²¹²Bi and, depending on project progress, the other medically relevant radionuclides cited above);
• Development of bifunctional chelators for peptide or antibody conjugation;
• Evaluation of radiochemical stability and preparation of next-generation radiopharmaceutical building blocks.

Scientific environment

The PhD student will join the COSM team of the CEMCA laboratory (UMR CNRS 6521), which has internationally recognized expertise in macrocyclic ligand design, coordination chemistry and radiometal chelation.

The project will be carried out in close interaction with (academic and industrial) collaborators in radiochemistry, structural chemistry and nuclear medicine, providing access to advanced analytical, spectroscopic and radiochemical facilities.

References:

[1] M. Dash, M. R. Knapp, M. R. A. Pillai, Targeted Radionuclide Therapy – An Overview, Curr. Radiopharm. 2013, 6, 152–180; D. A. Milenic, M. W. Brechbiel, Targeting of Cancer by Alpha-Particle-Emitting Radionuclides: Clinical Studies, Clin. Cancer Res. 2004, 10, 5015S–5021S.

[2] S. Poty, L. C. Francesconi, M. R. McDevitt, M. J. Morris, J. S. Lewis, Alpha-Emitters for Radiotherapy: From Basic Radiochemistry to Clinical Studies, Nat. Rev. Clin. Oncol. 2018, 15, 593–607.

[3] M. Tosato, L. Lazzari, V. Di Marco, The Coordination Chemistry of Lead(II): A Challenge for Targeted Alpha Therapy, ACS Omega 2022, 7, 15596–15602.

[4] M. Le Fur, M. Beyler, E. Molnár, O. Fougère, D. Esteban-Gómez, G. Tircsó, C. Platas-Iglesias, N. Lepareur, O. Rousseaux, R. Tripier, The Role of the Capping Bond Effect on Pyclen natY3+/90Y3+ Chelates: Full Control of the Regiospecific N-Functionalization Makes the Difference, Chem. Commun. 2017, 53, 9534–9537; G. Nizou, C. Favaretto, F. Borgna, P. V. Grundler, N. Saffon-Merceron, C. Platas-Iglesias, O. Fougère, O. Rousseaux, N. P. van der Meulen, C. Müller, M. Beyler, R. Tripier, Expanding the Scope of Pyclen-Picolinate Lanthanide Chelates to Potential Theranostic Applications, Inorg. Chem. 2020, 59, 11736–11748.

[5] L. M. P. Lima, M. Beyler, F. Oukhatar, P. Le Saëc, A. Faivre-Chauvet, C. Platas-Iglesias, R. Delgado, R. Tripier, Pyclen-Based Ligands for Stable Lead(II) Complexation, Chem. Commun. 2014, 50, 12371–12374; L. M. P. Lima, M. Beyler, R. Delgado, C. Platas-Iglesias, R. Tripier, Lead(II) Complexation by Picolinate-Pyclen Ligands: Thermodynamic Stability and Solution Structure, Inorg. Chem. 2015, 54, 7074–7087.

[6] E. Boros, P. Comba, J. W. Engle, C. Harriswangler, S. E. Lapi, J. S. Lewis, S. Mastroianni, L. M. Mirica, C. Platas-Iglesias, R. Tripier, C. F. Ramogida, M. Tosato, Chemical Tools to Characterize the Coordination Chemistry of Radionuclides for Radiopharmaceutical Applications, Chem. Rev. 2025, 125, 12030–12068.

[7] I. Merdžo, C. Brossard, N. Lepareur, C. Platas-Iglesias, G. Balducci, R. Tripier, E. Alessio, F. Battistin, Impact of Bipyridine and Phenanthroline Incorporation into the Macropa Scaffold on Ba(II)/Ra(II) Chelation, Inorg. Chem. 2026, DOI: 10.1021/acs.inorgchem.6c02747.

Starting: possible from 01/10/2026 to 04/01/2027

Salary: Gross salary: €2,300/month (approximately €1,876 net/month)

About the research group

The Nitrogen Macrocycles & Coordination group is part of the COSM Team (Organic Chemistry, Health and Materials) within the CEMCA Laboratory (UMR CNRS 6521) at the University of Brest (France). The group brings together academic staff (2 Pr and 3 MCF), CNRS researchers (1), engineers (1), postdoctoral fellows (2) and PhD students (5) working at the interface of organic chemistry, coordination chemistry, radiochemistry and molecular imaging.

Our research focuses on the design, synthesis and physicochemical characterization of polyazamacrocyclic ligands and their metal complexes. We develop innovative synthetic methodologies for the regioselective functionalization of macrocyclic platforms and investigate their coordination properties through thermodynamic, kinetic, structural and spectroscopic studies.

Building on these fundamental studies, we design next-generation chelators for applications in nuclear medicine (PET, SPECT and targeted radionuclide therapy), MRI, optical imaging, catalysis, molecular materials and environmental chemistry. Particular emphasis is placed on the rational relationship between molecular structure, metal coordination and functional performance.

The group benefits from state-of-the-art analytical facilities (NMR, X-ray diffraction, EPR, mass spectrometry) and maintains numerous collaborations with leading academic, radiochemistry, clinical and industrial partners across Europe and beyond, providing a highly interdisciplinary and international research environment.

Candidate profile

We are looking for a highly motivated candidate holding a Master's degree in:

• Organic Chemistry;
• Coordination Chemistry;
• Medicinal Chemistry;
• Radiochemistry (or strong interest in this field).

Experience in organic synthesis is highly appreciated. Knowledge of coordination chemistry, NMR, mass spectrometry or radiochemistry would be advantageous but is not mandatory.

Curiosity, scientific autonomy and willingness to work in an interdisciplinary environment are essential.