Evaluation of PET Imaging Performance of the TSPO Radioligand [18F]DPA-714 in Mouse and Rat Models of Cancer and Inflammation

Abstract

PurposeMany radioligands have been explored for imaging the 18-kDa translocator protein (TSPO), a diagnostic and therapeutic target for inflammation and cancer. Here, we investigated the TSPO radioligand [18F]DPA-714 for positron emission tomography (PET) imaging of cancer and inflammation.Procedures[18F]DPA-714 PET imaging was performed in 8 mouse and rat models of breast and brain cancer and 4 mouse and rat models of muscular and bowel inflammation.Results[18F]DPA-714 showed different uptake levels in healthy organs and malignant tissues of mice and rats. Although high and displaceable [18F]DPA-714 binding is observed ex vivo, TSPO-positive PET imaging of peripheral lesions of cancer and inflammation in mice did not show significant lesion-to-background signal ratios. Slower [18F]DPA-714 metabolism and muscle clearance in mice compared to rats may explain the elevated background signal in peripheral organs in this species.ConclusionAlthough TSPO is an evolutionary conserved protein, inter- and intra-species differences call for further exploration of the pharmacological parameters of TSPO radioligands.Electronic supplementary materialThe online version of this article (doi:10.1007/s11307-015-0877-x) contains supplementary material, which is available to authorized users.

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

“…This protein has a key role in the regulation of several cellular processes: steroid biosynthesis, cholesterol metabolism, apoptosis and cellular metabolism [64]. TSPO is highly expressed in organs involved in steroid synthesis as adrenal glands, testis, ovaries and pituitary glands [65]. In the central nervous system (CNS) and liver, TSPO expression is modest.…”

“…For these reasons, TSPO is considered a very promising target for the early imaging of neuroinflammation [66] and a possible indirect marker of neuronal loss progression, multiple sclerosis and AD [66][67][68] and has high relevance in neuroscience. The expression of this protein is also elevated in several cancers: colon, breast, glioma, prostate, colorectal, liver and ovary cancer, relating TSPO with disease progression and survival [2,64,65,69]. These evidences increased the interest in TSPO and led to the development of several radiolabeled ligands for the evaluation of the expression of this protein and detection of some of the aforementioned diseases by PET imaging.…”

“…This drug inhibits the activation of microglial cells [75]. Furthermore, the radiotracer 38 was used on studies of rodent models of excitotoxicity, herpes encephalitis [76], astrocytic activation, excitotoxically lesioned nonhuman primate brains, abdominal aortic aneurysm [77], rheumatoid arthritis [78,79] and neuroinflammatory changes in the brain after morphine exposure [65,67]. It demonstrated a good uptake in the primate brain and an eight-fold higher uptake in the lesioned striatum of a quinolinic acid-lesioned rat model of activated microglia.…”

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

“…As a result, next‐generation TSPO radiotracers have been developed recently to overcome the limitations of [ 11 C]PK11195. Among these, [ 18 F]DPA‐714 ( K i = 7.0 ± 0.4 nM) showed excellent PET imaging profile due to the lower nonspecific binding and higher signal‐to‐noise ratio as compared with [ 11 C]PK11195, and has been translated to clinical studies for evaluation of AD and amyotrophic lateral sclerosis . However, the fluoro‐ethoxyl functionality resulted in the formation of [ 18 F]‐labeled small metabolites such as [ 18 F]deethyl, [ 18 F]hydroxyl, and [ 18 F]carboxylic acid derivatives, which would compromise the imaging performance and further quantification …”

“…8 As a result, nextgeneration TSPO radiotracers 9 have been developed recently to overcome the limitations of [ 11 C]PK11195. Among these, [ 18 F]DPA-714 [10][11][12][13][14][15][16] (K i = 7.0 ± 0.4 nM) showed excellent PET imaging profile due to the lower nonspecific binding and higher signal-to-noise ratio as compared with [ 11 C]PK11195, 17 and has been translated to clinical studies for evaluation of AD 15 and amyotrophic lateral sclerosis. 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.…”