Gallium Complexation, Stability, and Bioconjugation of 1,4,7-Triazacyclononane Derived Chelators with Azaheterocyclic Arms

We have recently introduced a 1,4,7-triazacyclononane (TACN) based chelating system with additional five-membered azaheterocyclic substituents for complexation of radioactive Cu²⁺ ions. In this work, we investigated the complexation properties of these novel chelators with Ga³⁺. In labeling experiments, we could show that the penta- and hexadentate imidazole derivatives NODIA-Me <b>4</b> and NOTI-Me <b>1</b> can be labeled with ⁶⁸Ga in specific activities up to ∼30 MBq nmol^–1, while the corresponding thiazole derivative NOTThia <b>2</b> did not label satisfactorily under identical conditions. NMR studies on the Ga complexes of <b>1</b> and the model compound NODIA-Me-NH-Me <b>5</b> revealed formation of rigid 1:1 chelates with a slow macrocyclic interconversion and inert Ga–N bonds to the methylimidazole residues on the NMR time scale. The TACN-derived bifunctional chelator NODIA-Me was furthermore conjugated to a prostate-specific membrane antigen (PSMA) targeting moiety to give the corresponding bioconjugate NODIA-Me-PSMA <b>7</b>. Serum stability and ligand challenge experiments of ⁶⁸Ga-<b>7</b> confirmed formation of a stable complex for up to 4 h. The remaining coordination site of five-coordinate Ga complexes was found to be occupied by monodentate ligands including hydroxide and chloride anions depending on the conditions. According to density functional theory calculations, coordination of monodentate ligands as well as of the amide group for the bioconjugated ligand are energetically plausible. Finally, the labeled bioconjugate ⁶⁸Ga-<b>7</b> exhibited rapid renal clearance in biodistribution studies performed by small animal PET imaging with no indication of transchelation/demetalation in vivo. Altogether, our results provide strong evidence for a stable Ga complexation of our novel TACN-based chelators bearing imidazole arms. Despite the formation of two complexes incorporating different monodentate ligands in vitro, the imidazole type ligands show promise as chelating agents for the future development of gallium based radiopharmaceuticals

Effect of the Prosthetic Group on the Pharmacologic Properties of ¹⁸F‑Labeled Rhodamine B, a Potential Myocardial Perfusion Agent for Positron Emission Tomography (PET)

We recently reported the development of the 2-[¹⁸F]­fluoroethyl ester of rhodamine B as a potential positron emission tomography (PET) tracer for myocardial perfusion imaging. This compound, which was prepared using a [¹⁸F]­fluoroethyl prosthetic group, has significant uptake in the myocardium in rats but also demonstrates relatively high liver uptake and is rapidly hydrolyzed in vivo in mice. We have now prepared ¹⁸F-labeled rhodamine B using three additional prosthetic groups (propyl, diethylene glycol, and triethylene glycol) and found that the prosthetic group has a significant effect on the in vitro and in vivo properties of these compounds. Of the esters prepared to date, the diethylene glycol ester is superior in terms of in vitro stability and pharmacokinetics. These observations suggest that the prosthetic group plays a significant role in determining the pharmacological properties of ¹⁸F-labeled compounds. They also support the value of continued investigation of ¹⁸F-labeled rhodamines as PET radiopharmaceuticals for myocardial perfusion imaging