Shorouk Dannoon

Radiation dose estimation using preclinical imaging with 124I-metaiodobenzylguanidine (MIBG) PET.

PURPOSE A pretherapyI124-metaiodobenzylguanidine (MIBG) positron emission tomography (PET)/computed tomography (CT) provides a potential method to estimate radiation dose to normal organs, as well as tumors prior to I131-MIBG treatment of neuroblastoma or pheochromocytoma. The aim of this work was to estimate human-equivalent internal radiation dose of I124-MIBG using PET/CT data in a murine xenograft model. METHODS Athymic mice subcutaneously implanted with NB1691 cells that express high levels of human norepinephrine transporter(n=4) were imaged using small animal microPET/CT over 96 h (approximate imaging time points: 0.5, 2, 24, 52, and 96 h) after intravenous administration of 3.07-4.84 MBq of I124-MIBG via tail vein. The tumors did not accumulate I124-MIBG to a detectable level. All four animals were considered as control and organ radiation dosimetry was performed. Volumes of interest were drawn on the coregistered CT images for thyroid, heart, lung, liver, kidney, and bladder, and transferred to PET images to obtain pharmacokinetic data. Based on tabulated organ mass distributions for both mice and adult male human, preclinical pharmacokinetic data were extrapolated to their human-equivalent values. Radiation dose estimations for different age groups were performed using the OLINDA|EXM software with modified tissue weighting factors in the recent International Commission on Radiological Protection (ICRP) Publication 103. RESULTS The mean effective dose fromI124-MIBG using weighting factors from ICRP 103 to the adult male was estimated at 0.25 mSv/MBq. In different age groups, effective doses using values from ICRP 103 were estimated as follows: Adult female: 0.34, 15-yr-old: 0.39 mSv/MBq, 10-yr-old: 0.58 mSv/MBq, 5-yr-old: 1.03 mSv/MBq, 1-yr-old: 1.92 mSv/MBq, and newborn: 3.75 mSv/MBq. For comparison, the reported effective dose equivalent of I124-NaI for adult male (25% thyroid uptake, MIRD Dose Estimate Report No. 5) was 6.5 mSv/MBq. CONCLUSIONS The authors estimated human-equivalent internal radiation dose ofI124-MIBG using preclinical imaging data. As a reference, the effective dose estimation showed that I124-MIBG would deliver less radiation dose than I124-NaI, a radiotracer already being used in patients with thyroid cancer.

A high-affinity [(18)F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer.

INTRODUCTION In this study, a structurally modified phosphoramidate scaffold, with improved prostate-specific membrane antigen (PSMA) avidity, stability and in vivo characteristics, as a PET imaging agent for prostate cancer (PCa), was prepared and evaluated. METHODS p-Fluorobenzoyl-aminohexanoate and 2-(3-hydroxypropyl)glycine were introduced into the PSMA-targeting scaffold yielding phosphoramidate 5. X-ray crystallography was performed on the PSMA/5 complex. [(18)F]5 was synthesized, and cell uptake and internalization studies were conducted in PSMA(+) LNCaP and CWR22Rv1 cells and PSMA(-) PC-3 cells. In vivo PET imaging and biodistribution studies were performed at 1 and 4 h post injection in mice bearing CWR22Rv1 tumor, with or without blocking agent. RESULTS The crystallographic data showed interaction of the p-fluorobenzoyl group with an arene-binding cleft on the PSMA surface. In vitro studies revealed elevated uptake of [(18)F]5 in PSMA(+) cells (2.2% in CWR22Rv1 and 12.1% in LNCaP) compared to PSMA(-) cells (0.08%) at 4 h. In vivo tumor uptake of 2.33% ID/g and tumor-to-blood ratio of 265:1 was observed at 4 h. CONCLUSIONS We have successfully synthesized, radiolabeled and evaluated a new PSMA-targeted PET agent. The crystal structure of the PSMA/5 complex highlighted the interactions within the arene-binding cleft contributing to the overall complex stability. The high target uptake and rapid non-target clearance exhibited by [(18)F]5 in PSMA(+) xenografts substantiates its potential use for PET imaging of PCa. ADVANCES IN KNOWLEDGE The only FDA-approved imaging agent for PCa, Prostascint®, targets PSMA but suffers from inherent shortcomings. The data acquired in this manuscript confirmed that our new generation of [(18)F]-labeled PSMA inhibitor exhibited promising in vivo performance as a PET imaging agent for PCa and is well-positioned for subsequent clinical trials. Implications for Patient Care Our preliminary data demonstrate that this tracer possesses the required imaging characteristics to be sensitive and specific for PCa imaging in patients at all stages of the disease.

Synthesis and evaluation of constrained phosphoramidate inhibitors of prostate-specific membrane antigen

Prostate-specific membrane antigen (PSMA) is a cell-surface enzyme-biomarker that is actively pursued for targeted delivery of imaging and therapeutic agents for prostate cancer. Our lab has developed PSMA inhibitors based on a phosphoramidate scaffold, which has shown both high selectivity for PSMA-positive tumors and rapid clearance in vivo when radiolabeled with (18)F. However, this scaffold exhibits hydrolytic instability under low pH and high temperature conditions, barring the use of other imaging or therapeutic radionuclides such as (68)Ga or (177)Lu. Previous studies in our lab have shown a trend in increasing acid stability as the distance between the phosphoramidate core and the α-carboxylate of the P1 residue is increased. Therefore, a new generation of phosphoramidate inhibitors was developed based on trans-4-hydroxyproline as the P1 residue to restrict the interaction of the α-carboxylate to the phosphoramidate core. These hydroxyproline inhibitors demonstrated comparable IC50 values to earlier generations as well as enhanced thermal and acid stability.

Structure–Activity Relationship of 18F-Labeled Phosphoramidate Peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-Targeted Inhibitor Analogues for PET Imaging of Prostate Cancer

A series of phosphoramidate-based prostate specific membrane antigen (PSMA) inhibitors of increasing lipophilicity were synthesized (4, 5, and 6), and their fluorine-18 analogs were evaluated for use as positron emission tomography (PET) imaging agents for prostate cancer. To gain insight into their modes of binding, they were also cocrystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50 values ranging from 0.4 to 1.3 nM. In vitro assays showed binding and rapid internalization (80-95%, 2 h) of the radiolabeled ligands in PSMA(+) cells. In vivo distribution demonstrated significant uptake in CWR22Rv1 (PSMA(+)) tumor, with tumor to blood ratios of 25.6:1, 63.6:1, and 69.6:1 for [(18)F]4, [(18)F]5, and [(18)F]6, respectively, at 2 h postinjection. Installation of aminohexanoic acid (AH) linkers in the phosphoramidate scaffold improved their PSMA binding and inhibition and was critical for achieving suitable in vivo imaging properties, positioning [(18)F]5 and [(18)F]6 as favorable candidates for future prostate cancer imaging clinical trials.

Quantification of Changes in Skeletal Muscle Amino Acid Kinetics in Adult Humans in Response to Exercise via Positron-emission Tomography with L-[methyl-11C] methionine

Dynamic positron emission tomography (PET) imaging of with L-[methyl- 11 C]methionine (11C-MET) was developed in the late 1990’s to non-invasively estimate skeletal muscle protein synthesis, but no studies have shown that the measurements respond to resistance exercise, which stimulates protein synthesis in humans. Ten healthy women aged 25-75 years underwent a 14-hour fast, followed by unilateral knee extension and flexion exercise and consumption of an 8-ounce serving of fruit juice. Five subjects underwent dynamic 11C-MET PET imaging of the mid-thigh 2-3 hours after exercise and five were imaged 1 hour after exercise. Images were processed to obtain the Patlak slope K i , which describes the fractional extraction rate of 11C-MET into skeletal muscle protein. Additionally, the images were processed with a three-compartment kinetic model to determine rate constants for 11C-MET transport between muscle tissue, protein and plasma. All subjects showed excellent mid-thigh uptake of 11C-MET. Subjects imaged 2-3 hours after exercise showed no unilateral enhancement. However, subjects imaged one hour post-exercise showed an enhancement of 11C-MET uptake in the exercised leg compared to the control leg, corresponding to K i elevations between 3.8% - 31.1%. From the three-compartment analysis, the increased uptake corresponded primarily to an increased rate constant for extraction of 11C-MET from plasma to skeletal muscle tissue. Finally, older subjects tended to have smaller values of K i than the younger subjects. In summary, 11C-MET kinetics is responsive to a unilateral exercise stimulus, and this technique may prove useful to study skeletal muscle amino acid kinetics in response to exercise, aging and other conditions