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


CONCLUSIONS
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.
Division of Nuclear Medicine and Radiological Sciences, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri 63110, USA. dehdashtif@mir.wustl.edu
Farrokh
F
Dehdashti
Richard
R
Laforest
Feng
F
Gao
Kooresh I
KI
Shoghi
Rebecca L
RL
Aft
Brian
B
Nussenbaum
Friederike H
FH
Kreisel
Nancy L
NL
Bartlett
Amanda
A
Cashen
Nina
N
Wagner-Johnston
Nina
N
Wagner-Johnson
Robert H
RH
Mach
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D005462:Fluorine Radioisotopes; D006258:Head and Neck Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology*; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008223:Lymphoma / Q000000981:diagnostic imaging* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index; D049268:Positron-Emission Tomography; D011829:Radiation Dosage; D019275:Radiopharmaceuticals
D001549:Benzamides; D005462:Fluorine Radioisotopes; D019394:Ki-67 Antigen; D019275:Radiopharmaceuticals