Reagents for Astatination of Biomolecules. 3. Comparison ofcloso-Decaborate(2-) andcloso-Dodecaborate(2-) Moieties as Reactive Groups for Labeling with Astatine-211

Abstract

In vivo deastatination has been a major problem in the development of reagents for therapeutic applications of the α-particle emitting radionuclide 211 At. Our prior studies demonstrated that the use of a closo-decaborate(2-) ([closo-B 10 H 9 R] 2− ) moiety for 211 At labeling of biomolecules provides conjugates that are stable to in vivo deastatination. In this investigation, the closo-decaborate(2-) moiety was compared with the structurally similar closo-dodecaborate(2-) ([closo-B 12 H 11 R] 2− ) to determine if one has more favorable properties than the other for use in pendant groups as 211 At labeling molecules. To determine the differences, two sets of structurally identical molecules, with the exception that they contained either a closo-decaborate(2-) or a closo-dodecaborate(2-) moiety, were compared with regards to their synthesis, radiohalogenation, stability to in vivo deastatination and tissue distribution. Quite different rates of reaction were noted in the synthetic steps for the two closo-borate(2-) moieties, but ultimately the yields were similar, making these differences of little importance. Differences in radiohalogenation rates were also noted between the two closo-borate(2-) moieties, with the more electrophilic closo-decaborate(2-) reacting more rapidly. This resulted in somewhat higher yields of astatinated closo-decaborate(2-) derivatives (84% vs 53%), but both cage moieties gave good radioiodination yields (e.g. 79-96%). Importantly, both closo-borate(2-) cage moieties were shown to have high stability to in vivo deastatination. The largest differences between pairs of compounds containing the structurally similar boron cage moieties were in their in vivo tissue distributions. I]1b, was evaluated, the route of excretion appeared to be hepatobiliary rather than renal. Identical biotin derivatives containing the two closo-borate(2-) cage moieties had similar tissue distributions, except the closo-decaborate(2-) derivative had lower concentrations in kidney (1h, 19.9%ID/g; 4h, 24.4%ID/g vs. 1h, 38.9%ID/g; 4h, 40.6%ID/g). In summary, the higher reactivity, faster tissue clearance, and lower kidney concentrations make the closo-decaborate(2-) more favorable for further studies using them in reactive groups for 211 At labeling of biomolecules.

New functionalized mercaptoundecahydrododecaborate derivatives for potential application in boron neutron capture therapy: Synthesis, characterization and dynamic visualization in cells

“…The 1 H and 13 1073-1057 cm -1 ) [43], indicating that intracluster bonding was not perturbed by functionalization of the icosahedron.…”

“…The advantage of this binary approach is in the differential dose that can be established between the tumor and its surrounding normal tissue, provided the compound which carries the target atom, is avidly taken up in tumor, yielding a high tumor to normal tissue ratio. Dodecaborates are undergoing a renaissance in the literature due to their unique structural and electronic properties and potential use in creating new diagnostics, therapeutics and electronically tunable materials [12][13][14]. In regards to compounds for use in BNCT, the mercaptoundecahydro-closo-dodecaborate disodium salt (Na 2 B 12 H 11 SH, "BSH") exhibits a strong biological advantage over the related dicarba-closo-docedaborane (C 2 B 10 H 12 , "carborane") compounds as it possesses a higher percentage of boron, is ionic in nature, and is significantly lower in toxicity based on its boron content.…”

“…Boron-containing lipids constitute very interesting building blocks for the construction of boron-containing liposomes and several approaches toward the synthesis of such lipids have been developed in our laboratory and others[22][23][24][25][26][27][28][29][30][35][36][37][38]. Following the successful preparation of 12, the versatile BSH-carboxylic acid 3 was treated with 1,2-O-distearoyl-sn-3-glycerol(13) in the presence of DMAP and DCC at 40 This yielded the target BSH-lipid ester 14 in 89 % yield. In this case, a higher temperature(40 °C) was necessary to dissolve the lipid 13 in DMF.…”

Production of [211At]-Astatinated Radiopharmaceuticals and Applications in Targeted α-Particle Therapy

“…14). 94 Alternatively, Lindegren's group investigated biotinylated polylysines conjugated to SAB in a pretargeting strategy. In the first study, the poly-l-lysines had molecular weights of 13, 38, and 363 kDa with excellent avidin binding in vitro.…”

Stability and in vivo behavior of Rh[16aneS 4 -diol] 211 At complex: A potential precursor for astatine radiopharmaceuticals

“…This instability can be explained by the rate and mode of metabolism of the carrier molecule and by the low strength of the carbon-astatine bond [22]. Due to the higher strength of boron-astatine bonds, the use of nido -carborane and closo -dodecaborate (2-) for 211 At labeling has been investigated [23,24]. Although good in vivo stability was achieved with decaborate derivatives, some protein pharmacokinetic modifications also have been observed.…”