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Evaluation of phenylpiperazines as targeting agents for neuroblastoma
J W Babich1, W A Graham, A J Fischman
1Department of Radiology, Massachusetts General Hospital, Boston, USA.
Abstract:
The potential of radiolabelled phenylpiperazines as agents for the detection and therapy of tumours of neural crest origin was evaluated by in vitro pharmacological studies with human neuroblastoma cell lines [SK-N-SH and SK-N-BE(2C)], and in vivo by biodistribution measurements. The ability of phenylpiperazines: 4-phenyl-piperazine (PP), 1-carboxamidino-4-phenyl-piperazine (CAPP), [4-(3-chlorophenyl)-piperazine (mCPP), 4-(3-trifluoro methyl phenyl)-piperazine (TFMPP), and (1,1-dimethyl-4-phenyl)-piperazinium hydrochloride (DMPP) and chlorophenyl hydroxypiperidine [CP(OH)P], to inhibit MIBG uptake by neuroblastoma cells was determined by incubation with [125I]MIBG (0.1 microM) for 2 h in the presence of varying concentrations (10(-8)-10(-3) M) of ligand. For measuring uptake, cells were incubated with [125I]IPP (0.1 microM) and cell-associated radioactivity was measured at various times. Retention was studied by incubating cells in the presence of [125I]IPP (0.1 microM) for 2 h, followed by replacement with drug-free medium and determination of cell-bound radioactivity. Selectivity of [125I]IPP uptake was studied by inhibition studies with MIBG, DMI, 5HT and phenylpiperazines. The biodistribution of [125I]IPP was measured in normal rats at 0.083, 0.5, 1, 2 and 24 h (six animals per group). The IC50S (microM) for inhibition of [125I]MIBG uptake were: PP, 1.5; CPP, 2.5; CAPP, 2.5; DMPP, 5; CP(OH)P, 30 and TFMPP, 65. The rate of cellular uptake of [125I]IPP was greatest between 0 and 60 min and decreased after 60 min, similar to MIBG. After an initial rapid washout of approximately 50% of the radioactivity, retention remained constant for 3 h. The IC50S (microM) for inhibition of [125I]IPP uptake were: MIBG, 18-25; DMI, 0.6-1.5; 5HT, > 100; IPP, 1.8-2.5; CPP, 7.0-9.0 and TFMPP, > or = 20. The in vivo studies demonstrated a pattern of distribution similar to MIBG. The results demonstrate that phenylpiperazines display significant affinity for neuroblastoma with uptake and retention characteristics similar to MIBG.
Insights
Radiolabeled phenylpiperazines show promise for detecting and treating neural crest tumors like neuroblastoma. These compounds exhibit similar uptake and retention properties to MIBG, suggesting their potential as diagnostic and therapeutic agents.
Area of Science:
- Nuclear medicine
- Oncology
- Pharmacology
Background:
- Neuroblastoma and other neural crest tumors are significant challenges in pediatric oncology.
- Radiolabeled agents like MIBG are used for diagnosis and therapy, but novel agents are needed.
- Phenylpiperazines are a class of compounds with potential pharmacological activity.
Purpose of the Study:
- To evaluate radiolabeled phenylpiperazines as potential agents for detecting and treating neural crest tumors.
- To assess the in vitro pharmacological properties and in vivo biodistribution of specific phenylpiperazine derivatives.
- To compare the uptake and retention characteristics of phenylpiperazines with MIBG in neuroblastoma models.
Main Methods:
- In vitro pharmacological studies using human neuroblastoma cell lines (SK-N-SH and SK-N-BE(2C)).
- Assessment of phenylpiperazine inhibition of MIBG uptake and direct [125I]IPP uptake and retention.
- In vivo biodistribution measurements of [125I]IPP in normal rats.
Main Results:
- Several phenylpiperazines demonstrated significant affinity for neuroblastoma cells, inhibiting MIBG uptake with IC50 values in the low micromolar range.
- [125I]IPP showed time-dependent cellular uptake and retention characteristics similar to MIBG.
- In vivo biodistribution of [125I]IPP in rats mirrored that of MIBG.
Conclusions:
- Radiolabeled phenylpiperazines exhibit significant affinity for neuroblastoma.
- Their uptake and retention properties are comparable to MIBG, indicating potential as diagnostic and therapeutic agents for neural crest tumors.
- Further investigation into phenylpiperazines for neuroblastoma management is warranted.