An ¹⁸F-Labeled Poly(ADP-ribose) Polymerase Positron Emission Tomography Imaging Agent

Abstract

Poly(ADP-ribose) polymerase (PARP) is involved in repair of DNA breaks and is over-expressed in a wide variety of tumors, making PARP an attractive biomarker for positron emission tomography (PET) and single photon emission computed tomography imaging. Consequently, over the past decade, there has been a drive to develop nuclear imaging agents targeting PARP. Here, we report the discovery of a PET tracer that is based on the potent PARP inhibitor olaparib (1). Our lead PET tracer candidate, [18F]20, was synthesized and evaluated as a potential PARP PET radiotracer in mice bearing subcutaneous glioblastoma xenografts using ex vivo biodistribution and PET–magnetic resonance imaging techniques. Results showed that [18F]20 could be produced in a good radioactivity yield and exhibited specific PARP binding allowing visualization of tumors over-expressing PARP. [18F]20 is therefore a potential candidate radiotracer for in vivo PARP PET imaging.

[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging

“…In our previously reported study, we showed the strong potential of [ 18 F]olaparib, a radio-isotopologue of the AstraZeneca compound olaparib, for PET imaging of PARP in a mouse model of human PDAC [17]. Other studies have demonstrated the ability of a range of radiolabelled PARP compounds to monitor PARP expression in a variety of preclinical cancer models [17][18][19][20]. However, among the 17member PARP family, most studies focus on the implication of PARP1, but other isoforms are generally overlooked.…”

“…Fluorine-18 is the most widely used PET radionuclide due to its appropriate half-life (t 1/2 = 109.8 min), good spatial resolution and-most importantly-due to the stability of the C-F bond [15,16]. A number of groups have demonstrated the potential of 18 F-labelled PARP inhibitors in preclinical studies [17][18][19][20], reviewed in [13] and [14]. [ 18 F]PARPi is a 18 F-labelled PARP structurally related to olaparib [21].…”

Advancements in PARP1 Targeted Nuclear Imaging and Theranostic Probes

“…Most reported radiotracers have shown an increase in lipophilicity and a predominantly hepatobiliary clearance. For example, the radionuclide conjugation of olaparib elevated lipophilicity for olaparib derivatives 18 F-20 and 18 F-PARPi from Log P oct = 1.95 to Log P oct = 2.51 and Log P CHI = 2.15, respectively [15,16]. [19] PET, Optical Preclinical 18 F-PARPi-FL Keliher et al, [20] PET, Optical Preclinical [16] PET, Optical…”

“…Together with this, low dissociation constants (K i = 1.2nM−5nM) prevent passive diffusion of PARPis out of the nucleus, avoiding quick wash-out [32]. Similarly, high %PPB (> 95%) reduces the tissue penetration ability, and thus decreases the drug uptake by organs, and would require a higher dosage application [15]. In the case of brain malignancies like glioblastoma multiforme (GBM), the penetration of the blood-brain barrier (BBB) is essential for imaging and therapy.…”

“…In the case of brain malignancies like glioblastoma multiforme (GBM), the penetration of the blood-brain barrier (BBB) is essential for imaging and therapy. For this, the optimal drug parameters are Log P oct :2-3, MW < 450 Da, and PPB < 95% [15]. PARPis have shown different BBB penetration abilities in preclinical studies.…”