Preclinical Evaluation of ⁶⁸Ga-DOTA-NT-20.3: A Promising PET Imaging Probe To Discriminate Human Pancreatic Ductal Adenocarcinoma from Pancreatitis

Abstract

Neurotensin receptor 1 (NTSR1) is overexpressed in human pancreatic ductal adenocarcinoma (PDAC). Specific noninvasive positron-emission tomography (PET) imaging probes may improve the diagnostic accuracy and the monitoring of therapy for patients with PDAC. Here, we report the use of the 68 Ga-labeled neurotensin (NTS) analogue DOTA-NT-20.3 to image human PDAC in animal models and to discriminate tumors from pancreatitis. In addition to the preclinical study, two tissue microarray slides, constructed by small core biopsies (2−5) from standard paraffin-embedded tumor tissues, were used to confirm the high (78%) positivity rate of NTSR1 expression in human PDAC. PET imaging, biodistribution, blocking, and histology studies were performed in subcutaneous AsPC-1 pancreatic tumor-bearing mice. 68 Ga-DOTA-NT-20.3 PET images showed rapid tumor uptake and high contrast between the tumor and background with a fast blood clearance and a moderate accumulation in the kidneys. Ex vivo biodistribution showed low uptake in normal pancreas (0.22% IA/g) and in the remaining organs at 1 h postinjection, kidney retention (5.38 ± 0.54% IA/g), and fast clearance from blood and confirmed high uptake in tumors (5.28 ± 0.93% IA/g), leading to a tumor-to-blood ratio value of 6 at 1 h postinjection. The significant decrease of tumor uptake in a blocking study demonstrated the specificity of 68 Ga-DOTA-N-T20.3 to target NTSR1 in vivo. PET imaging was also conducted in an orthotopic xenograft model that allows tumors to grow in their native microenvironment and in an experimental pancreatitis model generated by caerulein injections. As opposed to 2-[ 18 F]fluoro-deoxyglucose, 68 Ga-DOTA-NT-20.3 distinguishes PDAC from pancreatitis. Thus, 68 Ga-DOTA-NT-20.3 is a promising PET imaging probe for imaging PDAC in humans.

Optimizing the Profile of [99mTc]Tc–NT(7–13) Tracers in Pancreatic Cancer Models by Means of Protease Inhibitors

“…To our knowledge, these are the highest uptake values reported for AsPC-1 xenografts in mice for radiolabeled NT-radiotracers. For example, [ 68 Ga]Ga-DOTA-NT-20.3 (Ac-Lys(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-Pro-Me-Arg-Arg-Pro-Tyr-Tle-Leu-OH) reached 5.28% ± 0.93% IA/g uptake at 1 h pi, with about the same values found in the kidneys [52].…”

<p>Differentiation of chronic mass-forming pancreatitis from pancreatic ductal adenocarcinoma using contrast-enhanced computed tomography</p>

“…As both PDAC and CMFP may present as a pancreatic mass, the overlap in their clinical and imaging findings makes their early preoperative and differential diagnosis difficult 6–9,11–13. Misdiagnosis of CMFP as PDAC may put extra burdens on patients and result in unnecessary intervention procedures, and misdiagnosis of PDAC as CMFP may result in delayed surgical treatment 20.…”

“…Given the small amount of material aspirated in these biopsies, obtaining an accurate representation of heterogeneous and large neoplasms can be challenging 5. Therefore, noninvasive imaging modalities including computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography, and 18F-FDG positron emission tomography (PET)/CT play crucial roles in accurate differential diagnosis, personalized treatment, and evaluation of therapeutic effects in both entities 4,6–11…”

A comparative study of peptide-based imaging agents [68Ga]Ga-PSMA-11, [68Ga]Ga-AMBA, [68Ga]Ga-NODAGA-RGD and [68Ga]Ga-DOTA-NT-20.3 in preclinical prostate tumour models

“…The eluate from the 68 Ge/ 68 Ga generator (1.5 mL, 150-300 MBq) was adjusted to pH=3-3.5 with sodium acetate (0.8 mol/L). The 68 Ga-labellings of DOTA-NT-20.3 (15 nmol), DOTA-AMBA (8 nmol) and NODAGA-RGD (7.8 nmol) peptides were performed using a R&D Synchrom module (Raytest, Germany) at LIMP laboratory as previously described [17][18][19].…”