Since the demonstration in 2005 by Ahrens et al.¹ that cells can be labeled with a perfluorocarbon (PFC) and tracked in vivo by ¹⁹F MRI, there has been heightened interest over the past decade to develop ¹⁹F MRI contrast agents for molecular imaging purposes. To date most of the effort has been focused on PFCs and perfluoropolyethers (PFPEs).² Unfortunately, these molecules have low aqueous solubility (limiting formulation to water emulsions with surfactants), and magnetically diverse (resulting in chemical shift artifacts and diffuse images). PFCs and PFPEs are very poor substrates for physiological enzymes due to the robust C-F bond and their high hydrophobicity. For this reason, they are thought to be biologically safe and have shown very little to no in vivo toxicity due to metabolic degradation. However, the exact mechanism of their elimination especially those with high molecular weights are not well understood. Such compounds may tend to accumulate in internal organs and their long term effects are unclear. We have designed, synthesized and characterized several small hydrophilic organofluorine compounds amenable to facile and highly stable aqueous core liposome nanoparticle formulations which can be targeted either passively or actively as 19F MRI molecular imaging probes. Our hypothesis is that small hydrophilic organofluorine molecules with magnetically equivalent fluorine atoms loaded in the aqueous core of liposome nanoparticles will generate ¹⁹F MRI molecular imaging probes with superior particle stability and versatility than PFCs and PTFEs. Molecular design employed simple non-ionic but highly hydrophilic moieties including glycerol, triglycerol and glucose attached covalently to chemically and magnetically equivalent fluorinated moieties to generate highly water-soluble monomer units. These monomer units were then condensed to obtain dimers, trimers and tetramers with high ¹⁹F content using ‘click chemistry’. Molecular structures were confirmed by ¹H-, ¹³C-, and ¹⁹F NMR. Aqueous core liposome encapsulation of these molecules was achieved using standard liposome formulation protocols: hydrating lipids in 500 mM – 1.0 M aqueous solution on the molecule followed by extrusion to reduce particle size to ~150 nm and dial filtration to remove unencapsulated materials. The ¹⁹F content of the liposome formulations was determined by UV absorbance and confirmed by comparison of ¹⁹F NMR integrals against a standard and particle size of the formulations was determined by dynamic light scattering (DLS). ¹⁹F MRI scans were performed using a TurboRARE 3D scan sequence on a 9.4 T Bruker small animal MR scanner equipped with a ¹H/¹⁹F dual-tunable volume RF coil.We have succeeded to prepare three different stable formulations bearing three distinct hydrophilic organofluorine molecular payloads for both targeted (folate) and passive delivery purposes. The average particle size is 150 ± 10 nm and polydispersity of 0.07, for all three formulations and the average concentration of ¹⁹F nuclei ranges from 750 mM to 4 M. This number depends on the number of ¹⁹F atoms per molecule (4 to 24). Phantom dilution studies show that we can detect ¹⁹F MRI signal in solution at 50 mM concentration of ¹⁹F nuclei. Further results from phantom studies (Figure 1) show that the broad spectrum of organic ¹⁹F species (chemical shift range >350 ppm), enables facile incorporation of chemically and magnetically distinct ¹⁹F species into different formulations for spectral ¹⁹F MRI assessment of multiple targets within the same subject simultaneously. This study demonstrates a versatile, facile, and highly reproducible approach to prepare stable liposome nanoparticle formulations with ¹⁹F MRI contrast payload and has the potential to make meaningful impact on ¹⁹F MR molecular imaging.