Dataset Information

Two experts and a newbie: [¹⁸F]PARPi vs [¹⁸F]FTT vs [¹⁸F]FPyPARP-a comparison of PARP imaging agents.

ABSTRACT:

Purpose

Imaging of PARP expression has emerged as valuable strategy for prediction of tumor malignancy. While [¹⁸F]PARPi and [¹⁸F]FTT are already in clinical translation, both suffer from mainly hepatobiliary clearance hampering their use for detection of abdominal lesions, e.g., liver metastases. Our novel radiotracer [¹⁸F]FPyPARP aims to bridge this gap with a higher renal clearance and an easily translatable synthesis route for potential clinical application.

Methods

We developed a less lipophilic variant of [¹⁸F]PARPi by exchange of the fluorobenzoyl residue with a fluoronicotinoyl group and automated the radiosyntheses of the three radiotracers. We then conducted a comparative side-by-side study of [¹⁸F]PARPi, [¹⁸F]FPyPARP, and [¹⁸F]FTT in NOD.CB17-Prkdc^scid/J mice bearing HCC1937 xenografts to assess xenograft uptake and pharmacokinetics focusing on excretion pathways.

Results

Together with decent uptake of all three radiotracers in the xenografts (tumor-to-blood ratios 3.41 ± 0.83, 3.99 ± 0.99, and 2.46 ± 0.35, respectively, for [¹⁸F]PARPi, [¹⁸F]FPyPARP, and [¹⁸F]FTT), a partial shift from hepatobiliary to renal clearance of [¹⁸F]FPyPARP was observed, whereas [¹⁸F]PARPi and [¹⁸F]FTT show almost exclusive hepatobiliary clearance.

Conclusion

These findings imply that [¹⁸F]FPyPARP is an alternative to [¹⁸F]PARPi and [¹⁸F]FTT for PET imaging of PARP enzymes.

SUBMITTER: Stotz S

PROVIDER: S-EPMC8803746 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Two experts and a newbie: [18F]PARPi vs [18F]FTT vs [18F]FPyPARP-a comparison of PARP imaging agents.

Stotz Sophie S Kinzler Johannes J Nies Anne T AT Schwab Matthias M Maurer Andreas A

European journal of nuclear medicine and molecular imaging 20210906 3

<h4>Purpose</h4>Imaging of PARP expression has emerged as valuable strategy for prediction of tumor malignancy. While [18F]PARPi and [18F]FTT are already in clinical translation, both suffer from mainly hepatobiliary clearance hampering their use for detection of abdominal lesions, e.g., liver metastases. Our novel radiotracer [18F]FPyPARP aims to bridge this gap with a higher renal clearance and an easily translatable synthesis route for potential clinical appli ...[more]

PMID: 34486071

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Project description:BackgroundTriple-negative breast cancer (TNBC) lacks biomarkers for targeted therapy. Auger emitters display the best therapeutic effect, if delivered directly into the nucleus proximal to DNA. The nuclear protein Poly (ADP-ribose)-Polymerase 1 (PARP1) is a suitable target against which few inhibitors (PARPi) are clinically approved for treatment of breast cancer with germline BRCA mutation (BRCAmut). In this study, a theranostic approach was investigated in a TNBC xenografted mouse model by radiolabelling a close derivative of a PARPi Olaparib (termed PARPi-01) with the Auger emitters 123/125I.MethodsTNBC cell line MDA-MB-231 was subcutaneously implanted in female NOD/SCID mice. At a tumour size of ~ 500mm3, [123I]PARPi-01 was administered intravenously, and SPECT/CT images were obtained at 4 h or 24 h post injection (p.i). A therapy study was performed with [125I]PARPi-01 in 4 doses (10 MBq/dose, 10 days apart). Tumour growth was monitored by CT scans longitudinally once per week. Upon reaching study endpoint, tissues were harvested and stained with TUNEL assay for detection of apoptosis induction.ResultsSPECT/CT images showed rapid hepatobiliary tracer clearance at 4 h post injection (p.i.). Retention in thyroid at 24 h p.i. suggested tracer deiodination in vivo. The tumour and liver uptake were 0.2%ID/g and 2.5%ID/g, respectively. The tumour: blood ratio was 1.3. Endogenous therapy induced a significant delay in tumour growth (doubling time increased from 8.3 to 14.2 days), but no significant survival advantage. Significantly higher apoptosis ratio was observed in [125I]PARPi-01 treated tumour tissues. No radiotoxicity was detected in the liver and thyroid.ConclusionConsidering the radio-cytotoxic effect in the tumour tissue and a delay on tumour doubling time, [125I]PARPi-01 presents a potential radiotherapeutics for treatment of TNBC. Improvements to overcome the suboptimal pharmacokinetics are necessary for its potential clinical application.