Radiolabeled (R)‐(–)‐5‐iodo‐3′‐O‐[2‐(ε‐guanidinohexanoyl)‐2‐phenylacetyl]‐2′‐deoxyuridine: A new theranostic for neuroblastoma. (19th March 2020)

• Record Type: Journal Article
• Authors: Kortylewicz, Zbigniew P.; Coulter, Don W.; Han, Guang; Baranowska‐Kortylewicz, Janina
• Is Part Of: Journal of labelled compounds & radiopharmaceuticals. Volume 63:Number 7(2020)
• Page Start: 312
• Page End: 324
• Publication Date: 2020-03-19
• Subjects: Auger electron emitters -- DNA targeted -- MIBG -- neuroblastoma -- norepinephrine transporter -- radioactive guanidines -- theranostics; Tracers (Chemistry) -- Periodicals; Radiopharmaceuticals -- Periodicals; 615.8424
• DOI: 10.1002/jlcr.3836
• Languages: English
• ISSNs: 0362-4803

Abstract

Abstract : Neuroblastoma, the most common extracranial solid tumor in children, accounts for nearly 8% of childhood cancers in the United States. It is a disease with pronounced clinical and biological heterogeneities. The amplification of MYCN, whose key tumorigenic functions include the promotion of proliferation, facilitation of the cell's entry into the S phase, and prevention of cells from leaving the cell cycle, correlates with poor prognosis. Patients with a high proliferation index disease have low survival rates. Neuroblastoma is one of the most radioresponsive of all human tumors. To exploit this radiosensitivity, radioactive guanidine ( R )‐(–)‐5‐[ 125 I]iodo‐3′‐ O ‐[2‐(ε‐guanidinohexanoyl)‐2‐phenylacetyl]‐2′‐deoxyuridine (9, GPAID) was designed. This compound enters neuroblastoma cells much like metaiodobenzylguanidine (MIBG). Additionally, it cotargets DNA of proliferating cells, an attribute especially advantageous in the treatment of MYCN ‐amplified tumors. GPAID was synthesized from the trimethylstannyl precursor with an average yield of >90% at the no‐carrier‐added specific activities. The norepinephrine transporter‐aided delivery of GPAID to neuroblastoma cells was established in the competitive uptake studies with nonradioactive MIBG. The intracellular processing and DNA targeting properties were confirmed in the subcellular distribution experiments. Studies in a mouse model of neuroblastoma demonstrated the therapeutic potential of GPAID. The tin precursor of GPAID can be used to prepare compounds radiolabeled with single‐photon emission computed tomography (SPECT)‐ and positron‐emission tomography (PET)‐compatible radionuclides. Accordingly, these reagents can function as theranostics useful in the individualized and comprehensive treatment strategies comprising treatment planning and the assessment of tumor responses as well as the targeted molecular radiotherapy employing treatment doses derived from the imaging data. Abstract : GPAID was designed to treat high‐risk neuroblastoma, including relapsed or refractory disease. GPAID targets neuroblastoma cells in the same way as MIBG. It also cotargets DNA of proliferating cells, an attribute especially advantageous in the treatment of MYCN ‐amplified tumors.