Preclinical Evaluation of [F]FP-CIT, the Radiotracer Targeting Dopamine Transporter for Diagnosing Parkinson's Disease: Pharmacokinetic and Efficacy Analysis

Overview

Journal EJNMMI Res

Date 2024 Jul 3

PMID 38958796

Authors

Jae Hun Ahn

Min Hwan Kim

Kyongkyu Lee

Keumrok Oh

Hyunwoo Lim

Hee Seup Kil

Soon Jeong Kwon

Jae Yong Choi

Dae Yoon Chi

Yong Jin Lee

Affiliations

Soon will be listed here.

Abstract

Background: N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (FP-CIT), the representative cocaine derivative used in dopamine transporter imaging, is a promising biomarker, as it reflects the severity of Parkinson's disease (PD). I- and F-labeled FP-CIT has been used for PD diagnosis. However, preclinical studies evaluating [F]FP-CIT as a potential diagnostic biomarker are scarce. Among translational research advancements from bench to bedside, translating preclinical findings into clinical practice is one-directional. The aim of this study is to employ a circular approach, beginning back from the preclinical stage, progressing to the supplementation of [F]FP-CIT, and subsequently returning to clinical application. We investigated the pharmacokinetic properties of [F]FP-CIT and its efficacy for PD diagnosis using murine models.

Results: Biodistribution, metabolite and excretion analyses were performed in mice and PD models were induced in rats using 6-hydroxydopamine (6-OHDA). The targeting efficiency of [F]FP-CIT for the dopamine receptor was assessed through animal PET/CT imaging. Subsequently, correlation analysis was conducted between animal PET/CT imaging results and immunohistochemistry (IHC) targeting tyrosine hydroxylase. Rapid circulation was confirmed after [F]FP-CIT injection. [F]FP-CIT reached the highest uptake of 23.50 ± 12.46%ID/g in the striatum 1 min after injection, and it was rapidly excreted within 60 min. The major metabolic organs of [F]FP-CIT were confirmed to be the intestines, liver, and kidneys. Its uptake in the intestine was approximately 5% ID/g. The uptake in the liver gradually increased, with excretion beginning after reaching a maximum after 60 min. The kidneys exhibited rapid elimination after 10 min. In the excretion study, rapid elimination was verified, with 21.46 ± 9.53% of the compound excreted within a 6 h period. Additionally, the efficacy of [F]FP-CIT PET was demonstrated in the PD model, with a high correlation with IHC for both the absolute value (R = 0.803, p = 0.0017) and the ratio value (R = 0.973, p = 0.0011).

Conclusions: This study fills the gap regarding insufficient preclinical studies on [F]FP-CIT, including its ADME, metabolites, and efficiency. The pharmacological results, including accurate diagnosis, rapid circulation, and [F]FP-CIT excretion, provide complementary evidence that [F]FP-CIT can be used safely and efficiently to diagnose PD in clinics, although it is already used in clinics.

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