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-Prkdcscid/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.

Fully Automated, High-Dose Radiosynthesis of [18F]PARPi

“…This study proposed a revised radiosynthesis of [ 18 F]PARPi, with many advantages over the previously published methods, including a higher RCY, higher final dose, and high A m [11,12,15].…”

“…In this study, we present the development of a revised protocol of the synthesis of [ 18 F]PARPi reported by Carney and colleagues, leading to a fully automated, highyielding, and high-dose production of this PET tracer. When we started working on this study, Stotz and co-workers published a novel two-step approach (Scheme 1), which was fully automated on GE Healthcare TRACERlab [15]. The required trimethylammonium precursor is commercially available, albeit less affordable than the precursor needed for the protocol reported by Carney and for this work.…”

DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

“…Both clinically translated PET imaging agents, [ 18 F]FTT and [ 18 F]PARPi, are characterized by hepatobiliary clearance, which complicates imaging of abdominal lesions, e.g., liver metastases. To address this limitation, Stotz et al introduced [ 18 F]FPyPARP as a less lipophilic variant by exchanging the fluorobenzoyl residue with a fluoronicotinoyl group [ 50 ]. A side-by-side in vivo comparison of [ 18 F]FPyPARP to [ 18 F]FTT and [ 18 F]PARPi revealed a partial shift to renal clearance, but since tumor-to-liver ratios remained well below “1”, it is likely that further modifications and a stronger shift to renal clearance would be required for PARP1 imaging of abdominal lesions.…”

Poly (ADP-ribose) polymerases as PET imaging targets for central nervous system diseases

“…Despite its high PARP1 binding affinity, [ 18 F]9e, a derivative of AZD2461, was reported to be non-BBB penetrant in nonhuman primates ( 21 ). [ 18 F]FPyPARP was designed and synthesized to improve the renal clearance profile of the PARP PET tracers used in humans, and it provided advantage for imaging abdominal lesions which might facilitate the development of new strategies in personalized cancer therapy ( 22 ). Ex vivo studies of [ 123 I]PARPi, a potential PARP SPECT imaging agent, showed high specificity to PARP1 ( 23 ), while [ 131 I]PARPi showed the potential as a PARP PET imaging agent for brain tumors ( 24 ).…”