Radiosynthesis and Preclinical Evaluation of [18F]F-DPA, A Novel Pyrazolo[1,5a]pyrimidine Acetamide TSPO Radioligand, in Healthy Sprague Dawley Rats

Abstract

PurposeMany neurological conditions result in the overexpression of the translocator protein 18 kDa (TSPO), today recognized as a biomarker for microglial activation and neuroinflammation imaging. The pyrazolo[1,5-a]pyrimidine acetamides are a particularly attractive class of TSPO-specific ligands, prompting the development of several positron emission tomography (PET) radiotracers. This includes F-DPA, a recently reported fluorinated ligand (K i = 1.7 nM), wherein the fluorine atom is directly linked to the phenyl moiety without the presence of an alkyl or alkoxy spacer chain. Reported here is the preparation of [18F]F-DPA using [18F]Selectfluor bis(triflate) and the preliminary evaluation of [18F]F-DPA in healthy rats. Its metabolic profile and biodistribution in rats are compared with that of [18F]DPA-714, a closely related structure.Procedures[18F]F-DPA was synthesized by electrophilic fluorination using [18F]Selectfluor bis(triflate), [18F]DPA-714 was synthesized by conventional nucleophilic fluorination. The biodistribution of both radiotracers was compared in Sprague Dawley rats. Radiometabolites of both radiotracers in plasma and brain homogenates were analyzed by radioTLC.ResultsThe radiochemical yield of [18F]F-DPA was 15 ± 3 % and the specific activity was 7.8 ± 0.4 GBq/μmol. The radiochemical purity exceeded 99 %. The in vivo time activity curves of [18F]F-DPA demonstrate rapid entry into the brain and a concentration equilibrium at 20–30 min after injection. The metabolic profiles at 90 min after radiotracer injection in the plasma show that unchanged [18F]F-DPA and [18F]DPA-714 account for 28.3 ± 6.4 and 11.1 ± 2.6 % of the remaining radioactivity, respectively. In the brain, unchanged [18F]F-DPA accounts for 93.5 ± 2.8 % of the radioactivity; whereas for [18F]DPA-714, this value is 53.6 ± 1.6 %.Conclusions[18F]Selectfluor bis(triflate) was successfully used to label F-DPA with fluorine-18. The labeling position on the aromatic moiety imparts a higher stability compared to [18F]DPA-714 with regard to in vivo metabolism. [18F]F-DPA is a promising new radiotracer and warrants further investigation in animal models of disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s11307-016-1040-z) contains supplementary material, which is available to authorized users.

A Facile Radiolabeling of [18F]FDPA via Spirocyclic Iodonium Ylides: Preliminary PET Imaging Studies in Preclinical Models of Neuroinflammation

“…22 Electrophilic fluorination starting with carrier-added [ 18 F]F 2 to prepare [ 18 F]Selectfluor as a labeling reagent was recently performed by Solin and co-workers, to prepare [ 18 F]2 , and resulted in 15 ± 3% decay corrected yields with a low specific activity of 7.8 ± 0.5 GBq/μmol (0.21 ± 0.01 Ci/μmol). 23 However, because a low-cold-mass PET ligand injection is critical to detect inflammatory events, 24, 25 there is an unmet and urgent need for [ 18 F]2 with high specific activity to evaluate the potential of this radioligand in PET imaging of neuroinflammation.…”

Pyrazoles as Key Scaffolds for the Development of Fluorine-18-Labeled Radiotracers for Positron Emission Tomography (PET)

“…In 2017, Keller et al compared the activity of 38 with its analogue [ 18 F]F-DPA (39) (Figure 15), which presents the radionuclide directly linked to the phenyl ring. This study showed that compound 39 is metabolically more stable than its analogue 38 in rats' brains, being regarded as a promising TSPO radiotracer, because it shows a higher ratio between specific and nonspecific binding [81]. Later, in 2018, the same author described the potential of [ 18 F]F-DPA 39 to visualize activated microglia at an early stage of AD pathology.…”

A concisely automated synthesis of TSPO radiotracer [18F]FDPA based on spirocyclic iodonium ylide method and validation for human use

“…24 Electrophilic fluorination with [ 18 F]Selectfluor as a labeling reagent was also performed to prepare [ 18 F]FDPA. Although the obtained radioactivity by this method was applied for rodent PET imaging, 22,23 the complicated labeling procedure 27 as well as the low molar specific activities of ca. 7.7 GBq/μmol (0.2 Ci/μmol) 22,23,[25][26][27] would be challenging for further translational research.…”

“…18 19 [ 18 F]FDPA, an analog of [ 18 F]DPA-714, showed excellent binding affinity for TSPO (Ki = 2.0 ± 0.8 nM using the same [ 3 H]PK11195 binding assay and positive controls described in the DPA-714 work), 11 excellent selectivity toward central benzodiazepine receptor (Ki > 1 mM), and reasonable lipophilicity (LogD = 2.34) for crossing blood-brain barrier. 20,21 More importantly, its aryl-18 F bond significantly reduced the potential generation of radiolabeled metabolites in the brain and plasma, 22 which would help PET quantification. Solin 22,23 and our group 21 have conducted PET imaging studies on APP/PS1 transgenic mouse model.…”

“…The initial efforts toward radiosynthesis of [ 18 F]FDPA were reported by Solin, Dollé, and co-workers, 20 and with modified synthesis in recent publications. [22][23][24][25][26][27] However, the challenging radiofluorination process, ie, complex labeling procedures and facilities, low molar activity, long radiolabeling time, even trace, and unrepeatable production, posed limitations for advancing large-scale multicenter trials and widespread application. In our previous work, we reported the manual radiofluorination of [ 18 F] FDPA 21 using adamantyl auxiliary-based spirocyclic iodonium ylide (SCIDY) precursor (Scheme 1).…”