Novel Carbohydrate‐Appended Metal Complexes for Potential Use in Molecular Imaging

Seven discrete sugar‐pendant diamines were complexed to the {M(CO)₃}⁺ (^99mTc/Re) core: 1,3‐diamino‐2‐propyl β‐D ‐glucopyranoside ( L ¹ ), 1,3‐diamino‐2‐propyl β‐D ‐xylopyranoside ( L ² ), 1,3‐diamino‐2‐propyl α‐D ‐mannopyranoside ( L ³ ), 1,3‐diamino‐2‐propyl α‐D ‐galactopyranoside ( L ⁴ ), 1,3‐diamino‐2‐propyl β‐D ‐galactopyranoside ( L ⁵ ), 1,3‐diamino‐2‐propyl β‐(α‐D ‐glucopyranosyl‐(1,4)‐D ‐glucopyranoside) ( L ⁶ ), and bis(aminomethyl)bis[(β‐D ‐glucopyranosyloxy)methyl]methane ( L ⁷ ). The Re complexes [Re( L ¹ – L ⁷ )(Br)(CO)₃] were characterized by ¹H and ¹³C 1D/2D NMR spectroscopy which confirmed the pendant nature of the carbohydrate moieties in solution. Additional characterization was provided by IR spectroscopy, elemental analysis, and mass spectrometry. Two analogues, [Re( L ² )(CO)₃Br] and [Re( L ³ )(CO)₃Br], were characterized in the solid state by X‐ray crystallography and represent the first reported structures of Re organometallic carbohydrate compounds. Conductivity measurements in H₂O established that the complexes exist as [Re( L ¹ – L ⁷ )(H₂O)(CO)₃]Br in aqueous conditions. Radiolabelling of L ¹ – L ⁷ with [^99mTc(H₂O)₃(CO)₃]⁺ afforded in high yield compounds of identical character to the Re analogues. The radiolabelled compounds were determined to exhibit high in vitro stability towards ligand exchange in the presence of an excess of either cysteine or histidine over a 24 h period.     

Modified Preparation of 99mTe-Iron Hydroxide Macroaggregate (99mTe-Fe-(OH)2MA)

A modified method for preparing ^99mTc-FHMA for pulmonary studies is elabrated. It includes a new antioxidant sodium metabisulphite. The optimum conditions for the reparation are given. A simple and rapid procedure with a yield more than 98% is described which eliminates a further purification step.     

A Resin‐Linker‐Vector Approach to Radiopharmaceuticals Containing 18F: Application in the Synthesis of O‐(2‐[18F]‐Fluoroethyl)‐L‐tyrosine

A Resin‐linker‐vector (RLV) strategy is described for the radiosynthesis of tracer molecules containing the radionuclide ¹⁸F, which releases the labelled vector into solution upon nucleophilic substitution of a polystyrene‐bound arylsulfonate linker with [¹⁸F]‐fluoride ion. Three model linker‐vector molecules 7 a – c containing different alkyl spacer groups were assembled in solution from (4‐chlorosulfonylphenyl)alkanoate esters, exploiting a lipase‐catalysed chemoselective carboxylic ester hydrolysis in the presence of the sulfonate ester as a key step. The linker‐vector systems were attached to aminomethyl polystyrene resin through amide bond formation to give RLVs 8 a – c with acetate, butyrate and hexanoate spacers, which were characterised by using magic‐angle spinning (MAS) NMR spectroscopy. On fluoridolysis, the RLVs 8 a , b containing the longer spacers were shown to be more effective in the release of the fluorinated model vector (4‐fluorobutyl)phenylcarbamic acid tert‐butyl ester ( 9 ) in NMR kinetic studies and gave superior radiochemical yields (RCY≈60 %) of the ¹⁸F‐labelled vector. The approach was applied to the synthesis of the radiopharmaceutical O‐(2‐[¹⁸F]‐fluoroethyl)‐L ‐tyrosine ([¹⁸F]‐FET), delivering protected [¹⁸F]‐FET in >90 % RCY. Acid deprotection gave [¹⁸F]‐FET in an overall RCY of 41 % from the RLV.     

Preliminary Study of a 1,5-Benzodiazepine-Derivative Labelled with Indium-111 for CCK-2 Receptor Targeting

The cholecystokinin-2 receptor (CCK-2R) is overexpressed in several human cancers but displays limited expression in normal tissues. For this reason, it is a suitable target for developing specific radiotracers. In this study, a nastorazepide-based ligand functionalized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator (IP-001) was synthesized and labelled with indium-111. The radiolabeling process yielded >95% with a molar activity of 10 MBq/nmol and a radiochemical purity of >98%. Stability studies have shown a remarkable resistance to degradation (>93%) within 120 h of incubation in human blood. The in vitro uptake of [¹¹¹In]In-IP-001 was assessed for up to 24 h on a high CCK-2R-expressing tumor cell line (A549) showing maximal accumulation after 4 h of incubation. Biodistribution and single photon emission tomography (SPECT)/CT imaging were evaluated on BALB/c nude mice bearing A549 xenograft tumors. Implanted tumors could be clearly visualized after only 4 h post injection (2.36 ± 0.26% ID/cc), although a high amount of radiotracer was also found in the liver, kidneys, and spleen (8.25 ± 2.21%, 6.99 ± 0.97%, and 3.88 ± 0.36% ID/cc, respectively). Clearance was slow by both hepatobiliary and renal excretion. Tumor retention persisted for up to 24 h, with the tumor to organs ratio increasing over-time and ending with a tumor uptake (1.52 ± 0.71% ID/cc) comparable to liver and kidneys.     

A Highly Efficient Copper‐Mediated Radioiodination Approach Using Aryl Boronic Acids

A convenient and quantitative radioiodination method by copper‐mediated cross‐coupling of aryl boronic acids was developed. The mild labeling conditions, ready availability of the boronic acid substrate, simple operation, broad functional group tolerance and excellent radiochemical yield (RCY) make this a practical strategy for radioiodine labeling without further purification.