Assessment of cellular proliferation in tumors by PET using 18F-ISO-1

Abstract

This first study in humans was designed to evaluate the safety and dosimetry of a cellular proliferative marker, N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-(18)F-fluoroethoxy)-5-methylbenzamide ((18)F-ISO-1), and evaluate the feasibility of imaging tumor proliferation by PET in patients with newly diagnosed malignant neoplasms.

Methods: Patients with biopsy-proven lymphoma, breast cancer, or head and neck cancer underwent (18)F-ISO-1 PET. Tumor (18)F-ISO-1 uptake was assessed semiquantitatively by maximum standardized uptake value, ratios of tumor to normal tissue and tumor to muscle, and relative distribution volume ratio. The PET results were correlated with tumor Ki-67 and mitotic index, from in vitro assays of the tumor tissue. The biodistribution of (18)F-ISO-1 and human dosimetry were evaluated.

Results: Thirty patients with primary breast cancer (n = 13), head and neck cancer (n = 10), and lymphoma (n = 7) were evaluated. In the entire group, tumor maximum standardized uptake value and tumor-to-muscle ratio correlated significantly with Ki-67 (τ = 0.27, P = 0.04, and τ = 0.38, P = 0.003, respectively), but no significant correlation was observed between Ki-67 and tumor-to-normal-tissue ratio (τ = 0.07, P = 0.56) or distribution volume ratio (τ = 0.26, P = 0.14). On the basis of whole-body PET data, the gallbladder is the dose-limiting organ, with an average radiation dose of 0.091 mGy/MBq. The whole-body and effective doses were 0.012 mGy/MBq and 0.016 mSv/MBq, respectively. No adverse effects of (18)F-ISO-1 were encountered.

Conclusion: The presence of a significant correlation between (18)F-ISO-1 and Ki-67 makes this agent promising for evaluation of the proliferative status of solid tumors. The relatively small absorbed doses to normal organs allow for the safe administration of up to 550 MBq, which is sufficient for PET imaging in clinical trials.

FIGURE 1

Transaxial ¹⁸F-ISO PET and PET/CT image of patient with breast cancer (left), head and neck cancer (middle), and lymphoma (right) showing different degrees of uptake in their tumors (arrows).

FIGURE 2

Correlation of ¹⁸F-ISO-1, as expressed by T/M, with low (<35%) and high (>35%) expression of Ki-67 (top), and correlation of Ki-67 with ¹⁸F-ISO-1 expressed by T/M (bottom)

FIGURE 3

Time–activity curve of ¹⁸F-ISO-1 activity, as expressed by Bq/mL in blood (taken from left ventricle), breast tumor, and contralateral normal breast tissue. Inset shows constant ratios of activities reached 20 min after injection.

FIGURE 4

Representative coronal image of normal biodistribution of ¹⁸F-ISO-1 in dosimetry patient 5 at 30 and 150 min after injection. Infiltration of dose at site of injection in patient's left arm is seen. GB = gallbladder; GI = gastrointestinal.