Synthesis, Radiolabeling, and Preliminary in vivo Evaluation of [⁶⁸Ga] IPCAT-NOTA as an Imaging Agent for Dopamine Transporter

Abstract

Introduction

Novel radiotracer development for imaging dopamine transporters is a subject of interest because although [^99mTc]TRODAT-1, [¹²³I]β-CIT, and [¹²³I]FP-CIT are commercially available; ⁹⁹Mo/^99mTc generator is in short supply and ¹²³I production is highly dependent on compact cyclotron. Therefore, we designed a novel positron emission tomography (PET) tracer based on a tropane derivative through C-2 modification to conjugate NOTA for chelating ⁶⁸Ga, a radioisotope derived from a ⁶⁸Ge/⁶⁸Ga generator.

Methods

IPCAT-NOTA 22 was synthesized and labeled with [⁶⁸Ga]GaCl₄⁻ at room temperature. Biological studies on serum stability, LogP, and in vitro autoradiography (binding assay and competitive assay) were performed. Furthermore, ex vivo autoradiography, biodistribution, and dynamic PET imaging studies were performed in Sprague Dawley rats.

Results

[⁶⁸Ga]IPCAT-NOTA 24 obtained had a radiochemical yield of ≥90% and a specific activity of 4.25 MBq/nmol. [⁶⁸Ga]IPCAT-NOTA 24 of 85% radiochemical purity (RCP%) was stable at 37°C for up to 60 minutes in serum with a lipophilicity of 0.88. The specific binding ratio (SBR%) reached 15.8 ± 6.7 at 60 minutes, and the 85% specific uptake could be blocked through co-injection at 100- and 1000-fold of the cold precursor in in vitro binding studies. Tissue regional distribution studies in rats with [⁶⁸Ga]IPCAT-NOTA 24 showed striatal uptake (0.02% at 5 minutes and 0.007% at 60 minutes) with SBR% of 6%, 25%, and 62% at 5–15, 30–40, and 60–70 minutes, respectively, in NanoPET studies. The RCP% of [⁶⁸Ga]IPCAT-NOTA 24 at 30 minutes in vivo remained 67.65%.

Conclusion

Data described here provide new information on the design of PET probe of conjugate/pendent approach for DAT imaging. Another chelator or another direct method of intracranial injection must be used to prove the relation between [⁶⁸Ga]IPCAT-NOTA 24 uptake and transporter localization.

Keywords:

• Parkinson disease
• dopamine transporter
• Ga-68

Acknowledgments

Authors would like to thank Cheng-Li, Chou Ph.D. for providing the LogP estimation of QSAR computer models by Discovery Studio software and the financial support of MOST (NSC 104-3111-Y-042A-065).

Disclosure

Shiou-Shiow Farn and Kang-Wei Chang are co-first authors. The authors declare that they have no conflicts of interest.