Radioiodination and preclinical evaluation of 4-benzyl-1-(3-[125I]-iodobenzylsulfonyl)piperidine as a breast tumor imaging tracer in mouse.
OBJECTIVE
4-Benzyl-1-(3-iodobenzylsulfonyl)piperidine, 4-B-IBSP, has shown high-binding affinity to both sigma (σ) receptors in our previous work. In current study, radiolabeling and preclinical evaluation of 4-benzyl-1-(3-[125I]-iodobenzylsulfonyl)piperidine, 4-B-[125I]IBSP, in human ductal breast carcinoma (T47D) cells and in breast adenocarcinoma-bearing BALB/c mice are described.


METHODS
Radioiodination of this new σ ligand was performed by a palladium-catalyzed stannylation approach followed by oxidative iododestannylation reaction using Iodo-Gen. Competition-binding assays for binding of 4-B-[125I]IBSP to guinea pig brain membranes and to T47D cells were performed with known σ ligands. The selectivity and binding characteristics (Bmaxand Kd) were analyzed. In vitro stability and in vivo blood metabolism studies were also evaluated. Moreover, biodistribution studies were performed in normal and into the tumor-bearing mice at interval time points post-injection (p.i.). Both in vitro and in vivo blockade experiments were done in the presence of the σ receptors blocking agents.


RESULTS
Radioiodinated ligand was obtained in high yield and high specific activity. The σ inhibition constants (Ki, nM) for 4-(3-iodobenzyl)-1-(benzylsulfonyl)piperazine (4-IBBSPz), (+)-pentazocine, haloperidol, DTG, and 4-B-IBSP were 1.37 ± 0.19, 3.90 ± 0.77, 2.69 ± 0.33, 30.62 ± 2.01, and 0.61 ± 0.05, respectively. 4-B-[125I]IBSP bound to σ receptor sites preferably to very high-affinity binding sites on T47D cells. The radioligand showed acceptable in vitro and in vivo stabilities in the blood pool. However, in vivo biodistribution studies in normal Swiss albino mice revealed fast clearance of 4-B-[125I]IBSP from blood and the other normal organs. Biodistribution experiments of 4-B-[125I]IBSP in breast adenocarcinoma tumor-bearing BALB/c mice showed a relatively high tumor uptake at 30 min p.i. (4.13 ± 0.95) that reaches to 1.57 ± 0.24 even after 240 min p.i. A pre-injection of 4-B-IBSP and haloperidol with 4-B-[125I]IBSP resulted in 36-57% decrease in activity in the tumor, liver, and brain at 60 min p.i.


CONCLUSIONS
The high affinity of 4-B-[125I]IBSP to σ receptor-binding sites, its relatively high uptake, and preferential retention in the tumor as well as an increasing trend observed in the tumor to blood and in the tumor to muscle ratios suggests that an iodine-123 labeled counterpart, 4-B-[123I]IBSP, would be a promising σ radioligand for pursuing further studies to assess its potential for breast tumors imaging with SPECT.
Radiation Application Research School, Nuclear Science and Technology Research Institute, AEOI, P.O.Box: 11365-3486, Tehran, Iran. msadeghzadeh@aeoi.org.ir.
Masoud
http://orcid.org/0000-0002-6844-6637
M
Sadeghzadeh
Radiation Application Research School, Nuclear Science and Technology Research Institute, AEOI, P.O.Box: 11365-3486, Tehran, Iran.
Behrouz
B
Alirezapour
Radiation Application Research School, Nuclear Science and Technology Research Institute, AEOI, P.O.Box: 11365-3486, Tehran, Iran.
Ghorban Ali
GA
Charkhlooie
Radiation Application Research School, Nuclear Science and Technology Research Institute, AEOI, P.O.Box: 11365-3486, Tehran, Iran.
Maryam Keshavarz
MK
Baghery
Radiation Application Research School, Nuclear Science and Technology Research Institute, AEOI, P.O.Box: 11365-3486, Tehran, Iran.
Amir
A
Khorouti
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000000981:diagnostic imaging* / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011786:Quality Control; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D017480:Receptors, sigma / Q000378:metabolism; D013449:Sulfonamides / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
C000599409:4-benzyl-1-(3-iodobenzylsulfonyl)piperidine; D010880:Piperidines; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D013449:Sulfonamides
Breast cancer; Preclinical evaluation; Sigma receptors, 4-Benzyl-1-(3-[125I]-iodobenzylsulfonyl)piperidine; Tumor imaging agent