PT  - JOURNAL ARTICLE
AU  - Boyle, Amanda
AU  - Tong, Junchao
AU  - Zoghbi, Sami
AU  - Pike, Victor
AU  - Innis, Robert
AU  - Vasdev, Neil
TI  - Repurposing [<sup>11</sup>C]MC1 for imaging COX-2 in colorectal cancer xenograft mouse models
DP  - 2021 May 01
TA  - Journal of Nuclear Medicine
PG  - 1466--1466
VI  - 62
IP  - supplement 1
4099  - http://jnm.snmjournals.org/content/62/supplement_1/1466.short
4100  - http://jnm.snmjournals.org/content/62/supplement_1/1466.full
SO  - J Nucl Med2021 May 01; 62
AB  - 1466Objectives: Cyclooxygenase-2 (COX-2) is a putative biomarker for neuroinflammation as well as cancer progression and prognosis. The radiopharmaceutical [11C]MC1 has recently been translated for human brain-PET studies (ClinicalTrials.gov identifier: NCT04582916, NCT04396873) to explore the role of COX-2 in major depressive disorder and dementia. Our laboratories have recently repurposed a COX-1 neuro-PET radiopharmaceutical for oncology [1]. The aim of the current study is to evaluate [11C]MC1 for the detection of COX-2 in human colorectal cancer xenograft mouse models. Methods: Radiosynthesis of [11C]MC1 was performed as previously described [2]. Human colorectal cancer xenograft mouse models were prepared by injecting 5 X 106 HT-29 (COX-2 positive) or HCT-116 (COX-2 negative) cells subcutaneously (s.c.) on the right flank of ICRscid mice. Dynamic PET/MRI imaging of [11C]MC1 was performed, including blocking with MC1 and celecoxib, ex vivo biodistribution, and radiometabolite analysis of plasma and tumor homogenates, in addition to cellular uptake and immunohistochemistry studies. Results: Cell uptake was significantly higher in HT-29 cells compared to HCT-116 cells, plateauing from 20-60 min at 2.5 ± 0.15 % radioactivity / 105 cells vs 1.7 ± 0.05 % radioactivity / 105 cells (p=0.0009). Immunohistochemical staining for COX-2 was consistent with overexpression in HT-29 xenografts and low expression in HCT-116 xenografts. HT-29 xenografts were well visualized with [11C]MC1 (0-60 min average image). Time-activity curves show tumor radioactivity accumulation that quickly reached a plateau at 10-60 min with an average uptake of 3.07 ± 0.65 %ID/g (40-60 min, n=6). The signal in the tumor was significantly higher than muscle tissue, 0.78 ± 0.25 %ID/g (p=0.0002) and was significantly reduced in groups of mice (n=2-3) pre-treated with 33 mg/kg non-radiolabeled MC1 to 1.62 ± 0.29 %ID/g (p=0.045), or 67 mg/kg celecoxib to 1.18 %ID/g (p=0.0052). COX-2 negative HCT-116 xenografts had tumor radioactivity accumulation and was similar to that of muscle tissue with 0.71 ± 0.27 %ID/g. In vivo PET imaging analyses were validated by biodistribution studies. In radiometabolite analyses (n=3) the parent compound, [11C]MC1, accounted for 91.2 ± 1.0 % of radioactivity in HT-29 tumor homogenates, versus 8.8 ± 5.8 % in cardiac blood plasma, at 40 min post-injection of the radiotracer (n=3). Conclusions: Our preclinical studies indicate that [11C]MC1 has favorable in vitro and in vivo radiobiological profiles for studying the role of peripheral COX-2. Repurposing of this radiopharmaceutical would allow rapid translation of the first COX-2-targeted imaging agent to benefit patients suffering from colorectal cancer. References: [1] Boyle AJ, et al. Repurposing [11C]PS13 for PET imaging of cyclooxygenase-1 (COX-1) in ovarian cancer xenograft mouse models. J Nucl Med, 2020;in press. DOI: 10.2967/jnumed.120.249367. [2] Pike, VW & Innis, RB, et al. Evaluation of two potent and selective PET radioligands to image COX-1 and COX-2 in rhesus monkeys. J Nucl Med. 2018;59:1907-12.