Radioiodinated PARP1 tracers for glioblastoma imaging

Abstract

BackgroundAlthough the understanding of the genetic and molecular basis of cancer has advanced significantly over the past several decades, imaging and treatment options for glioblastoma patients have been more limited (N Engl J Med 359:492-507, 2008). This is in part due to difficulties in diagnosing this disease early, combined with its diffuse, infiltrative growth. This study was aimed at the development of a novel diagnostic tool for glioblastoma through the synthesis of a small molecule based on radioiodinated poly(ADP-ribose)polymerase 1 (PARP1) targeted tracers. This PARP1 is a biomarker that is overexpressed in glioblastoma tissue, but has only low expression levels in the healthy brain (Neoplasia 16:432-40, 2014).MethodsA library of PARP1 inhibitors (iodo-PARPis) was synthesized. Based on their pharmacokinetic properties and nuclear PARP1 binding, the most successful inhibitor was radiolabeled with 131I and 124I. Biodistribution as well as imaging experiments were performed in orthotopic and subcutaneous mouse models of glioblastoma.ResultsOne member of our iodo-poly(ADP-ribose)polymerase 1 (PARP1) inhibitor library, I2-PARPi, shows promising biophysical properties for in vivo application. All synthesized tracers have IC50 values in the nanomolar range (9 ± 2–107 ± 4 nM) and were able to inhibit the uptake of a fluorescent PARP1 inhibitor analog (PARPi-FL). I2-PARPi was able to reduce the uptake of PARPi-FL by 78 ± 4 % in vivo. In mouse models of glioblastoma, we show that the radioiodinated inhibitor analog has high uptake in tumor tissue (U251 MG xenograft, tumor, 0.43 ± 0.06 %ID/g; brain, 0.01 ± 0.00 %ID/g; muscle, 0.03 ± 0.01 %ID/g; liver, 2.35 ± 0.57 %ID/g; thyroid, 0.24 ± 0.06 %ID/g). PET and SPECT imaging performed in orthotopic glioblastoma models with [124I]- and [131I]-I2-PARPi showed selective accumulation in the tumor tissue. These results were also verified using autoradiography of tumor sections, which displayed focal selective uptake of the tracer in the tumor regions as confirmed by histology. The uptake could be blocked through pre-injection of excess unlabeled PARP1 inhibitor (Olaparib).ConclusionsWe have successfully synthesized and radioiodinated the PARP1 selective tracer I2-PARPi. The novel tracer shows selective binding to tumor tissue, both in vitro and in models of glioblastoma, and has the potential to serve as a selective PET imaging agent for brain tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0123-1) contains supplementary material, which is available to authorized users.

Molecular Imaging of PARP

“…It is chemically identical to 18 F-PARPi except that 131 I (SPECT) or 124 I (PET) takes the place of 18 F in the halogenated benzene ring. Like 18 F-PARPi, 124/131 I-PARPi was first studied in orthotopic U251 tumors (14). Autoradiography showed high tumor-to-brain (16:1) and tumor-to-muscle (6:1) ratios and high specificity (65% blocking).…”

A Radiotracer Strategy to Quantify PARP-1 Expression In Vivo Provides a Biomarker That Can Enable Patient Selection for PARP Inhibitor Therapy

“…Finally, baseline biopsies are generally not repeated during therapy to allow for direct assessment of drug efficacy. Alternative approaches to assessing PARP include noninvasive PET and single-photon emission tomography (16–18). These reports consist of in vitro and in vivo proof-of-concept studies showing the basic capabilities of radiotracers to image PARP.…”

Evaluation of aromatic radiobromination by nucleophilic substitution using diaryliodonium salt precursors

“…We have prepared a radiobromine‐labeled olaparib derivative ( 13 ) (Scheme ) by conjugating the amine precursor ( 12 ) with 4‐[*Br]bromobenzoic acid; this compound is now available for evaluation as a radiotracer for poly ADP ribose polymerase‐1 (PARP‐1), a critical target for cancer therapy . The direct labeling using electrophilic destannylation of a tributyltin precursor may not work, based on reports on the synthesis of the corresponding radioiodine‐labeled olaparib derivative . The method reported here has allowed us to radiosynthesize 13 for a preliminary evaluation simply under the conventional conjugation reaction conditions.…”

“…21,22 The direct labeling using electrophilic destannylation of a tributyltin precursor may not work, based on reports on the synthesis of the corresponding radioiodine-labeled olaparib derivative. 23,24 The method reported here has allowed us to radiosynthesize 13 for a preliminary evaluation simply under the conventional conjugation reaction conditions. The radiosynthesis of compound 13, which still needs optimization, is in Data S1.…”