Intrinsically radiolabelled [(59)Fe]-SPIONs for dual MRI/radionuclide detection.

Towards the development of iron oxide nanoparticles with intrinsically incorporated radionuclides for dual Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) and more recently of Single Photon Emission Computed Tomography/Magnetic Resonance Imaging (SPECT/MRI), we have developed intrinsically radiolabeled [(59)Fe]-superparamagnetic iron oxide nanoparticles ([(59)Fe]-SPIONs) as a proof of concept for an intrinsic dual probe strategy. (59)Fe was incorporated into Fe3O4 nanoparticle crystal lattice with 92±3% efficiency in thermal decomposition synthesis. Multidentate poly(acrylic acid)-dopamine-poly(ethylene-glycol-2000) (PAA-DOP-PEG) ligands were designed and synthesized based on facile EDC chemistry and utilized to functionalize the [(59)Fe]-SPIONs. The transverse relaxivity of [(59)Fe]-SPIONs (97±3 s(-1)mM(-1)) was characterized and found to be similar to non-radioactive SPIONs (72±10 s(-1)mM(-1)), indicating that (59)Fe incorporation does not alter the SPIONs' MRI contrast properties. [(59)Fe]-SPIONs were used to evaluate the nanoparticle biodistribution by ex vivo gamma counting and MRI. Nude mice (n=15) were injected with [(59)Fe]-SPIONs and imaged at various time points with 7T small animal MRI scanner. Ex vivo biodistribution was evaluated by tissue-based gamma counting. MRI signal contrast qualitatively correlates with the %ID/g of [(59)Fe]-SPIONs, with high contrast in liver (45±6%), medium contrast in kidneys (21±5%), and low contrast in brain (4±6%) at 24 hours. This work demonstrates the synthesis and in vivo application of intrinsically radiolabeled [(59)Fe]-SPIONs for bimodal detection and provides a proof of concept for incorporation of both gamma- and positron-emitting inorganic radionuclides into the core of metal based MRI contrast agent nanoparticles.

Microfluidic radiosynthesis and biodistribution of [18 F] 2-(5-fluoro-pentyl)-2-methyl malonic acid.

Microfluidics technology has emerged as a powerful tool for the radiosynthesis of positron emission tomography (PET) and single-photon emission computed tomography radiolabeled compounds. In this work, we have exploited a continuous flow microfluidic system (Advion, Inc., USA) for the [(18) F]-fluorine radiolabeling of the malonic acid derivative, [(18) F] 2-(5-fluoro-pentyl)-2-methyl malonic acid ([(18) F]-FPMA), also known as [(18) F]-ML-10, a radiotracer proposed as a potential apoptosis PET imaging agent. The radiosynthesis was developed using a new tosylated precursor. Radiofluorination was initially optimized by manual synthesis and served as a basis to optimize reaction parameters for the microfluidic radiosynthesis. Under optimized conditions, radio-thin-layer chromatography analysis showed 79% [(18) F]-fluorine incorporation prior to hydrolysis and purification. Following hydrolysis, the [(18) F]-FPMA was purified by C18 Sep-Pak, and the final product was analyzed by radio-HPLC (high-performance liquid chromatography). This resulted in a decay-corrected 60% radiochemical yield and ≥98% radiochemical purity. Biodistribution data demonstrated rapid blood clearance with less than 2% of intact [(18) F]-FPMA radioactivity remaining in the circulation 60 min post-injection. Most organs showed low accumulation of the radiotracer, and radioactivity was predominately cleared through kidneys (95% in 1 h). Radio-HPLC analysis of plasma and urine samples showed a stable radiotracer at least up to 60 min post-injection.

2-aminoethoxydiphenyl borate as a prototype drug for a group of structurally related calcium channel blockers in human platelets.

We have synthesized a series of 2-aminoethoxydiphenyl borate (2-APB, 2,2-diphenyl-1,3,2-oxazaborolidine) analogs and tested their ability to inhibit thrombin-induced Ca(2+) influx in human platelets. The analogs were either synthesized by adding various substituents to the oxazaborolidine ring (methyl, dimethyl, tert-butyl, phenyl, methyl phenyl, and pyridyl) or increasing the size of the oxazaborolidine ring to seven- and nine-membered rings. NMR analysis of the boron-containing analogs suggests that each of them exist as a ring structure through the formation of an N-->B coordinate bond (except for the hexyl analog). The possibility that these boron-containing compounds formed dimers was also considered. All compounds dose-dependently inhibited thrombin-induced Ca(2+) influx in human platelets, with the 2,2-diphenyl-1,3,2-oxazaborolidine-5-one derivative having the weakest activity at 100 microM, whereas the (S)-4-benzyl and (R)-4-benzyl derivatives of 2-APB were approximately 10 times more potent than the parent 2-APB. Two nonboron analogs (3-methyl and 3-tert-butyl 2,2-diphenyl-1,3-oxazolidine) were synthesized; they had approximately the same activity as 2-APB, and this implies that the presence of boron was not necessary for inhibitory activity. All of the compounds tested were also able to inhibit thrombin-induced calcium release. We concluded that extensive modifications of the oxazaborolidine ring in 2-APB can be made, and Ca(2+)-blocking activity was maintained.