[64Cu]XYIMSR-06: A dual-motif CAIX ligand for PET imaging of clear cell renal cell carcinoma

Abstract

Carbonic anhydrase IX (CAIX) is a cell surface enzyme that is over-expressed in approximately 95% of cases of clear cell renal cell carcinoma (ccRCC), the most common renal cancer. We synthesized and performed in vitro and in vivo evaluation of a dual-motif ligand, [64Cu]XYIMSR-06, for imaging CAIX expression on ccRCC tumors using positron emission tomography (PET). [64Cu]XYIMSR-06 was generated in yields of 51.0 ± 4.5% (n=5) and specific activities of 4.1 – 8.9 GBq/μmol (110-240 Ci/mmol). Tumor was visualized on PET images by 1 h post-injection with high tumor-to-background levels (>100 tumor-to-blood and -muscle) achieved within 24 h. Biodistribution studies demonstrated a maximum tumor uptake of 19.3% injected dose per gram of radioactivity at 4 h. Tumor-to-blood, -muscle and -kidney ratios were 129.6 ± 18.8, 84.3 ± 21.0 and 2.1 ± 0.3, respectively, at 8 h post-injection. At 24 h a tumor-to-kidney ratio of 7.1 ± 2.5 was achieved. These results indicate pharmacokinetics superior to those of previously reported imaging agents binding to CAIX. [64Cu]XYIMSR-06 is a new low-molecular-weight PET ligand targeting CAIX, which can image localized and metastatic ccRCC.

Design, synthesis and evaluation of18F-labeled cationic carbonic anhydrase IX inhibitors for PET imaging

“…Most recently, Pomper's group radiolabeled a dual motif CA-IX inhibitor consisting of a 4,4-bis(4-hydroxyphenyl)valeric acid and a succinyl acetazolamide group with 111 In (via DOTA chelator) and 64 Cu (via NOTA chelator) and acheived tumor uptakes values of 14.5-26.0%ID/g at 1 h p.i. 29,30 . Krall et al 31 reported the synthesis and evaluation of a 99m Tc-labeled acetazolamide derivative with excellent tumor targeting (22%ID/g at 3 h p.i.)…”

“…CA-IX inhibitors have also been used as delivery vectors of cytotoxic payloads to target tumor cells within hypoxic niches [16][17][18] . Complementing these therapeutic efforts has been the development of CA-IX radiotracers derived from inhibitors for positron emission tomography (PET) and single photon emission computed tomography (SPECT) applications [19][20][21][22][23][24][25][26][27][28][29][30][31] . PET and SPECT can generate images of high resolution and sensitivity, while providing quantitative information on drug target expression.…”

Carbonic Anhydrase IX in Renal Cell Carcinoma, Implications for Disease Management

“…Minn et al [ 45 ] developed a novel dual motif ligand for PET/CT detection of localized and metastatic ccRCC. 64 Cu-XYIMSR-06 is a small size synthesized molecule added with radioactive copper, presenting high affinity for CAIX.…”

Multiplexed imaging for diagnosis and therapy

“…Recent findings of deficient 13 C-lactate production in isocitrate dehydrogenase 1 mutant brain tumours, compared to glioblastomas, for example, provide also opportunities for tumour typing with hyperPET. Besides direct clinical application, the multiplexing of MR using hyperpolarized bicarbonate (H 13 CO3 -) with other techniques evaluating tissue acidity 183 and carbonic anhydrase-IX (CAIX) expression [184][185][186] could improve the understanding of the relationship between pH of tumour tissue and its microenvironment, and could potentially lead to the clinical translation of these agents.…”