Quinazoline-2,4(1 H,3 H)-dione Scaffold for development of a novel PARP-targeting PET probe for tumor imaging

Overexpression of Poly (ADP-ribose) polymerase (PARP) is associated with many diseases such as oncological diseases. Several PARP-targeting radiotracers have been developed to detect tumor in recent years. Two ¹⁸F labelled probes based on Olaparib and Rucaparib molecular scaffolds have been evaluated in clinical trials, but their slow hepatic clearance hinders their tumor imaging performance. Although a number of positron emission tomography (PET) probes with lower liver uptake have been designed, the tumor to background ratios remains to be low. Therefore, we designed a probe with low lipid-water partition coefficient to solve this problem.

A pyridine-containing quinazoline-2,4(1 H,3 H)-dione PARP-targeting group was rationally designed and used to conjugate with the chelator 2,2’,2’’,2’’’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) to prepare the lead compound named as SMIC-2001 for radiolabeling. In vitro experiments, the lipid-water partition coefficient, stability, binding affinity, and cellular uptake of [⁶⁸Ga]Ga-SMIC-2001 were determined. In vivo experiments, the U87MG xenograft models were used to evaluate its tumor imaging properties.

[⁶⁸Ga]Ga-SMIC-2001 showed a low Log D_7.4 (-3.82 ± 0.06) and high affinity for PARP-1 (48.13 nM). In vivo study revealed that it exhibited a high tumor-to-background contrast in the U87MG xenograft models and mainly renal clearance. And the ratios of tumor to main organs were high except for the kidney (e.g. tumor to liver ratio reached 2.20 ± 0.51) at 60 min p.i.

In summary, pyridine-containing quinazoline-2,4(1 H,3 H)-dione is a novel PARP-targeting molecular scaffold for imaging probe development, and [⁶⁸Ga]Ga-SMIC-2001 is a highly promising PET probe capable of imaging tumors with PARP overexpression.