PET radiopharmaceuticals beyond FDG, Why they are important?

How they are prepared?

By: Mehdi Akhlaghi

Organic & Radio chemist, PhD

Tehran University of Medical Sciences

November 12-14, 2014

At present, more than 95% of PET studies worldwide are performed in

oncologic patients, using F-18 Fluorodeoxyglucose (FDG). But, despite its

high diagnostic accuracy in determining the pivotal role in the restaging

(and staging), FDG is handicapped by false negative and positive results,

creating limitations in the differential diagnosis of cancer.

Moreover, PET- FDG shares finding with all the other diagnostic techniques

(CT, MRI) to answer all the questions of the oncologist, the surgeon, and the

radiotherapist. It cannot function alone, either in the diagnostic field, or in

giving all the information connected with prognosis and pursue a “tailored

strategy” for each patient. Therefore, despite its primary role, there is a

wide range of indications in oncologic patients that other radiotracers may

be useful, and in this lecture we shall try to understand them.

In oncology, the results concerning neoplastic lesions not detected by the

procedure are called false negative results of FDG. Conversely, false

positive results are those connected with benign lesions, showing FDG

uptake.

Introduction

A hybrid PET-CT scanner permits higher accuracy with respectto PET alone, because of the added morphostructuralinformation and the anatomical location of the FDG activityallowed by CT.

Despite using PET-CT, false negative and false positive resultsare, however, present. An improvement in sensitivity andspecificity with the use of PET radiotracers other than FDG, cantherefore significantly increase overall diagnostic accuracy.

Introduction

IntroductionWith respect to methodology, many causes can affect glucose kinetics, creating difficulties in FDG utilization.The major problem is; high glucose serum levels, asobserved, in particular, in diabetes.other conditions can determine an unfavorabledistribution of FDG. For example a nonspecific FDGuptake requires correct timing for a reliable evaluationof patients who have undergone surgery, adiotherapy,or chemotherapy or have inflammation.

Therefore, the availability of radiotracers not affectedby conditions such as high glucose levels,inflammation, altered permeability or vascularity, canhelp in finding a rationale to choose an alternative toFDG. Thus, a more effective clinical value can bereached, for example, in diabetic patients, or when theclinical history of the patient suggests that the analysisobtained by using FDG is not reliable.

False negative results of PET-FDG are mainly due to lesions that are toosmall to be PET’s spatial resolution, which is usually above 5 mm. It hasto be pointed out that the positive indicators as FDG, i.e., radiotracerswith a higher uptake in lesions than in the surrounding normal tissue,can also occasionally detect lesions that are less than the spatialresolution value.

the detectability of the lesion depends mainly on theLesion/background (L/B) ratio. It depends more on the uptakemechanism of the radiotracer than on the PET scanner. With respect toFDG, a higher L/B can be achieved by different radiotracers allowing ahigher tumor uptake and/or a lower background activity.

Radiotracers Allowing a Higher Tumors Uptake Radiotracers Allowing a Lower Background Radiotracers Allowing a Increased Specificity Radiotracers Allowing an Improved Diagnostic Accuracy

The choice of an alternative radiotracer should be based on a deep and strong knowledge of the pathophysiological premises of their uptake mechanism.

Introduction

Examples

Examples

Examples

Strategy

Gaseous Target

Gaseous !! or Liquid Target

Radiotracers Allowing a Increased Specificity

PET Radiotracers

Small moleculesPeptide and steroidal molecules

molecules for Hypoxia

New routes for radiolabeling

New routes for F-18 radiolabeling

18F-Labeling Using Click Cycloadditions

Eckert & Ziegler11C Modular-Lab Chemistry Solution

Ga-68-labeling of peptides• Y-90-labeling of peptides• Lu-177- labeling of peptides• Cu-64-radionuclide purification• Cu-64-radiolabeling• C-11-methylation• C-11-methyliodide production• F-18-labeling• I-123/124/131-labeling• automated generator elutions

Production of any 11C tracer, e.g. [11C]Methionine, [11C]Choline, [11C]DASP or [11C]Raclopride and any 18F tracer by nucleophilic or electrophilic substitution, e.g. [18F]Dopa, [18F]FDG, [18F]FLT, [18F]Miso, et

18F 68Ga 11C 177Lu 64Cu 99mTc •18F-FDG (dual run)≥ 70%•Nucleo 18F-DOPA ≥ 35%•18F-Choline ≥ 25%•18F-MPPF ≥ 30%•18F-Meta-Tyr. ≥ 25%•68Ga-DOTA 55 / 65%•11C-Methionine ≥ 22%•18F-MISO,18F-FLT, 18F-Tyrosine, 18F-NaF, 18F-Estradiol, 18F-Ethyl-Tyrosine, …

FASTlab FDG Cassette: phosphate buffer formulationFASTlab FDG Cassette: citrate buffer formulationFASTlab NaF CassetteFASTlab FMISO CassetteFASTlab FLT Cassette

•[18F]NaF

•[18F]FLT

•[18F]FMiso

•[18F]FCholine

•[18F]FA(FAcetate)

•[18F]FET

•[18F]FES

•[18F]SFB

•[18F]MPPF (HPLC)

•[18F]Fallypride (HPLC)

•[18F]FHBG

•[18F]-L-DOPA

The Synthera employs a single use disposable system, the IFP™ (integrated fluidic processor) and a set of commercially available reagents for the synthesis of a wide variety of compounds: FDG, NaF, FLT, FCH, FDOPA, FMISO and others

[18F]FDG 2–[18F]fluorodeoxyglucose Use: Measure of glycolysis Yield*: n=6 RCY=61.0% +/– 12.9%

[18F]FAC 2–deoxy–2–[18F]fluoro–β–D–arabinofuranosyl Use: Assay for deoxycytidine kinase Yield*: n=5 RCY=31.3% +/– 6.0%

[18F]FMAU 2–deoxy–2–[18F]flouro–5–methyl–1–β–L arabinofuranosyl uracil Use: Monitor cellular proliferation; PET reporter probe for reporter gene imaging Yield*: n=3 RCY=45.2% +/– 1.5%

[18F]FEAU [18F]SFB

N–succinimidyl–4–[18F]fluorobenzoate Use: Most actively used prosthetic group for protein/peptide/antibody labeling Yield*: n=5 RCY=69.5% +/– 9.1%

[18F]FLT [18F]fluorothymidine Use: Monitor cellular proliferation Yield*: n=5 RCY=11.9% +/– 1.6%

[18F]FHBG [18F]Fallypride *All data reported is un-optimized. Radiochemical yield (RCY) is decay corrected.

100% starting activity defined by [18F]fluoride released into reactor vial 1, after[18F]fluoride trap and release.

SOFIE–optimized protocols are available with every ELIXYS purchase.Check back for a list of reagent kits coming soon!

But the latest revolution

Thanks for your attention

Hope to be useful