& Imaging Agents DMAP-BODIPY Alkynes: A Convenient Tool for Labeling Biomolecules for Bimodal PET–Optical Imaging** Bertrand Brizet, [a, b] Victor Goncalves, [a] Claire Bernhard, [a] Pierre D. Harvey, [b] Franck Denat,* [a] and Christine Goze* [a] Abstract: Several new boron dipyrromethene/N,N-dimethy- laminopyridine (BODIPY-DMAP) assemblies were synthesized as precursors for bimodal imaging probes (optical imaging, OI/positron emission tomography, PET). The photophysical properties of the new compounds were also studied. The first proof-of-concept was obtained with the preparation of several new BODIPY-labeled bombesins and evaluation of the affinity for bombesin receptors by using a competition binding assay. Fluorination reactions were investigated on DMAP-BODIPY precursors as well as on DMAP-BODIPY-la- beled bombesins. Chemical modifications on the BODIPY core were also performed to obtain luminescent dyes emit- ting in the therapeutic window (650–900 nm), suitable for in vivo imaging, making these compounds promising precur- sors for PET/optical dual-modality imaging agents. Introduction Molecular imaging is a highly promising field of research and innovation with huge potential in a wide range of applications including prognostic, diagnostic, drug discovery, and develop- ment of theranostics. It enables real-time visualization of bio- chemical events at the cellular and molecular levels within the cells, tissues, and intact subjects. [1] In this area of research, nu- clear imaging, namely positron emission tomography (PET), en- ables non-invasive diagnosis with high sensitivity by providing in vivo distribution of radiolabeled biovectors, thus facilitating detection of cancers. Among the radioelements available for PET imaging, 18 F has become the radionuclide of choice, in a similar way to 99m Tc in gamma scintigraphy. [2] This is due to its optimal nuclear and chemical properties, that is, low energy, high abundance of positrons, and relatively long half- life (109.7 min) in comparison with the 11 C technique. [3] Fluorescence imaging is a valuable technique for small animal imaging. The optical agents also provide the opportuni- ty to perform histological studies based on the fluorescent signal to evidence molecular targeting. Clinical applications are unfortunately more limited owing to their poor penetrability in the tissues. Nevertheless, recent advances in fluorescence imaging instrumentation and probe developments promise new opportunities, highlighting the emerging performances of this technique, especially for fluorescence guided-surgery with targeted molecular imaging. [4] Together, PET and fluorescence imaging presents comple- mentary features, for example, the high penetrability of the 511 keV photons of PET and the high spatial and temporal res- olution of fluorescence. These are some of the reasons why dual-modality PET/optical imaging could strongly be beneficial for preclinical and clinical applications. [5] In this context, the preparation of MonoMolecular Imaging Agents (MOMIA), which combine a fluorescent probe and a radioisotope into a single molecule, showed marked advantages compared with the conventional approach (i.e., sequential coupling of a chela- tor and a NIR fluorophore). [6] Notably, the modification of bio- molecules on one single attachment point simplifies the dual- labeling process and minimizes the loss of affinity for the tar- geted receptors. [7] Among the fluorescent dyes, BODIPY derivatives are highly suitable candidates for the design of bimodal agents because they generally provide high fluorescence quantum yields, [8] high thermal and photochemical stability, and a high degree of tunable emission into the red-NIR region from a simple var- iation of the molecular structure. [8b, 9] Moreover, the BODIPY core bears two fluorine atoms onto its boron center (BF 2 unit), an ideal site for radiofluorination, considering the strength of the B F bond (> 730 kJ mol 1 ), which is one of the most ther- modynamically stable covalent bonds known. [10] Beyond medi- cal imaging, the concept of bimodality can be extended to other important areas. Indeed, promising work on applications of fluorinated BODIPY systems as bimodal XPS-fluorescence labels for the detection of amino groups on SiO 2 supports has recently been reported. [11] [a] Dr. B. Brizet, Dr. V. Goncalves, Dr. C. Bernhard, Prof. F. Denat, Dr. C. Goze Institut de Chimie MolØculaire de l’UniversitØ de Bourgogne, UMR 6302 9, avenue Alain Savary, 21078 Dijon (France) Fax: (+ 33) 380-39-61-17 E-mail : franck.denat@u-bourgogne.fr christine.goze@u-bourgogne.fr [b] Dr. B. Brizet, Prof. P. D. Harvey DØpartment de Chimie UniversitØ de Sherbrooke UniversitØ de Sherbrooke, QuØbec, J1K 2R1 (Canada) [**] DMAP = N,N-dimethylaminopyridine ; BODIPY = boron dipyrromethene; PET = positron emission tomography. Supporting information for this article is available on the WWW under http ://dx.doi.org/10.1002/chem.201402379. Chem. Eur. J. 2014, 20, 12933 – 12944  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 12933 Full Paper DOI: 10.1002/chem.201402379