title: Synthesis and biological evaluation of a novel 99mTc cyclopentadienyl tricarbonyl complex ([(Cp-R)99mTc(CO)3]) for sigma-2 receptor tumor imaging.
abstract: We report the design, synthesis and biological evaluation of a novel (99m)Tc 4-(4-cyclohexylpiperazine-1-yl)-butan-1-one-1-cyclopentadienyltricarbonyl technetium ([(99m)Tc]5) as a potential SPECT tracer for imaging of σ(2) receptors in tumors. [(99m)Tc]5 was prepared in 25±5% isolated radiochemical yield with radiochemical purity of >99% via double-ligand transfer (DLT) reaction from the ferrocene precursor 2b (4-(4-cyclohexylpiperazine-1-yl)-1-ferrocenylbutan-1-one). The corresponding Re-complex 4 and the ferrocenyl complex 2b showed relatively high affinity towards σ(2) receptors in in vitro competition binding assay (K(i) values of 4 and 2b were 64.4±18.5 nM and 43.6±21.3 nM, respectively) and moderate to high selectivity versus σ(1) receptors (K(i)σ(1)/K(i)σ(2) ratios were 12.5 and 95.5, respectively). The logD value of [(99m)Tc]5 was determined to be 2.52±0.33. Biodistribution studies in mice revealed comparably high initial brain uptake of [(99m)Tc]5 and slow washout. Administration of haloperidol 5 min prior to injection of [(99m)Tc]5 significantly reduced the radiotracer uptake in brain, heart, lung, and spleen by 40-50% at 2h p.i.. Moreover, [(99m)Tc]5 showed high uptake in C6 glioma cell lines (8.6%) after incubation for 1h. Blocking with haloperidol to compete with [(99m)Tc]5 significantly reduced the cell uptake. Preliminary blocking study in C6-brain-tumor bearing rats showed that [(99m)Tc]5 binds to σ receptors in the brain-tumor specifically. These results are encouraging for further exploration of (99m)Tc-labeled probes for σ(2) receptor tumor imaging in vivo.
authors.affiliation: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Meng-Chao
authors.initials: MC
authors.lastname: Cui
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.forename: Ying-Feng
authors.initials: YF
authors.lastname: Tu
authors.forename: Teng
authors.initials: T
authors.lastname: Ma
authors.forename: Ying
authors.initials: Y
authors.lastname: Xie
authors.forename: Bing
authors.initials: B
authors.lastname: Jia
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.forename: Bo-Li
authors.initials: BL
authors.lastname: Liu
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Jia
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000378:metabolism; D045744:Cell Line, Tumor; D005910:Glioma / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D051379:Mice; D015609:Organotechnetium Compounds / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000032:analysis* / Q000378:metabolism; D013667:Technetium / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D015609:Organotechnetium Compounds; D017480:Receptors, sigma; C116453:cyclopentadienyl tricarbonyl technetium; C106107:sigma-2 receptor; D013667:Technetium