Novel Tracer Applications

Electronic cigarette (EC) use has increased dramatically, particularly among adolescents and young adults, and, like cigarette use, can cause pulmonary inflammation and increase the risk of lung disease. Methods: This preliminary study used PET with ¹⁸F-6-(1/2)(2-fluoro-propyl)-4-methylpyridin-2-amine (¹⁸F-NOS) to quantify inducible nitric oxide synthase expression to characterize oxidative stress and inflammation in the lungs in vivo in 3 age- and sex-matched groups: 5 EC users, 5 cigarette smokers, and 5 controls who had never smoked or vaped. Results: EC users showed greater ¹⁸F-NOS nondisplaceable binding potential (BP_ND) than cigarette smokers (P = 0.03) and controls (P = 0.01), whereas BP_ND in cigarette smokers did not differ from that in controls (P > 0.1). ¹⁸F-NOS lung tissue delivery and inducible nitric oxide synthase distribution volume did not significantly differ among groups. Although there were no group differences in peripheral inflammatory biomarker concentrations, ¹⁸F-NOS BP_ND correlated with the proinflammatory cytokine tumor necrosis factor-α concentrations (r_s = 0.87, P = 0.05) in EC users. Additionally, when EC users and cigarette smokers were pooled together, number of vaping episodes or cigarettes per day correlated with interleukin-6 levels (r_s = 0.86, P = 0.006). Conclusion: This is the first PET imaging study to compare lung inflammation between EC and cigarette users in vivo. We found preliminary evidence that EC users have greater pulmonary inflammation than cigarette smokers and controls, with a positive association between pulmonary and peripheral measures of inflammation.

Purpose

Prostate-specific membrane antigen (PSMA) is a promising molecular target for imaging of prostate adenocarcinoma. ⁶⁸Ga-P16-093, a small molecule PSMA ligand, previously showed equivalent diagnostic performance compared to ⁶⁸Ga-PSMA-11 PET/CT in a pilot study of prostate cancer patients with biochemical recurrence (BCR). We performed a pilot study for further characterization of ⁶⁸Ga-P16-093 including comparison to conventional imaging.

Procedures

Patients were enrolled into two cohorts. The biodistribution cohort included 8 treated prostate cancer patients without recurrence, who underwent 6 whole body PET/CT scans with urine sampling for dosimetry using OLINDA/EXM. The dynamic cohort included 15 patients with BCR and 2 patients with primary prostate cancer. Two patients with renal cell carcinoma were also enrolled for exploratory use. A dynamic PET/CT was followed by 2 whole body scans for imaging protocol optimization based on bootstrapped replicates. ⁶⁸Ga-P16-093 PET/CT was compared for diagnostic performance against available ¹⁸F-fluciclovine PET/CT, ^99mTc-MDP scintigraphy, diagnostic CT, and MRI.

Results

⁶⁸Ga-P16-093 deposited similar effective dose (0.024 mSv/MBq) and lower urinary bladder dose (0.064 mSv/MBq) compared to ⁶⁸Ga-PSMA-11. The kidneys were the critical organ (0.290 mSv/MBq). While higher injected activities were preferable, lower injected activities at 74–111 MBq (2–3 mCi) yielded 80% retention in signal-to-noise ratio. The optimal injection-to-scan interval was 60 min, with acceptable delay up to 90 min. ⁶⁸Ga-P16-093 PET/CT showed superior diagnostic performance over conventional imaging with overall patient-level lesion detection rate of 71%, leading to a change in management in 42% of the patients.

Conclusions

Based on its favorable imaging characteristics and diagnostic performance in prostate cancer, ⁶⁸Ga-P16-093 PET/CT merits further investigation in larger clinical studies.

The poly-(adenosine diphosphate-ribose) polymerase (PARP) family of proteins participates in numerous functions, most notably the DNA damage response. Cancer vulnerability to DNA damage has led to development of several PARP inhibitors (PARPi). This class of drugs has demonstrated therapeutic efficacy in ovarian, breast, and prostate cancers, but with variable response. Consequently, clinics need to select patients likely to benefit from these targeted therapies. In vivo imaging of ¹⁸F-fluorthanatrace uptake has been shown to correspond to PARP-1 expression in tissue. This study characterized the pharmacokinetics of ¹⁸F-fluorthanatrace and tested kinetic and static models to guide metric selection in future studies assessing ¹⁸F-fluorthanatrace as a biomarker of response to PARPi therapy. Methods: Fourteen prospectively enrolled ovarian cancer patients were injected with ¹⁸F-fluorthanatrace and imaged dynamically for 60 min after injection followed by up to 2 whole-body scans, with venous blood activity and metabolite measurements. SUV_max and SUV_peak were extracted from dynamic images and whole-body scans. Kinetic parameter estimates and SUVs were assessed for correlations with tissue PARP-1 immunofluorescence (n = 7). Simulations of population kinetic parameters enabled estimation of measurement bias and precision in parameter estimates. Results:¹⁸F-fluorthanatrace blood clearance was variable, but labeled metabolite profiles were similar across patients, supporting use of a population parent fraction curve. The total distribution volume from a reversible 2-tissue-compartment model and Logan reference tissue distribution volume ratio (DVR) from the first hour of PET acquisition correlated with tumor PARP-1 expression by immunofluorescence (r = 0.76 and 0.83, respectively; P < 0.05). DVR bias and precision estimates were 6.4% and 29.1%, respectively. SUV_max and SUV_peak acquired from images with midpoints of 57.5, 110 ± 3, and 199 ± 4 min highly correlated with PARP-1 expression (mean ± SD, r ≥ 0.79; P < 0.05). Conclusion: Tumor SUV_max and SUV_peak at 55-60 min after injection and later and DVR from at least 60 min appear to be robust noninvasive measures of PARP-1 binding. ¹⁸F-fluorthanatrace uptake in ovarian cancer was best described by models of reversible binding. However, pharmacokinetic patterns of tracer uptake were somewhat variable, especially at later time points.

Dopamine D3 receptors have key roles in behavioral reward, addiction, Parkinson’s disease, and schizophrenia, and there is interest in studying their role in these disorders using PET. However, current PET radiotracers for studying D3 receptors in humans all bind to both D2 and D3 due to similarities between the two receptors. Selective D2 and D3 radioligands would aid investigation of the differences between D2 and D3 circuitry in the central nervous system. While there are currently in vitromeasures of ligand D3/D2 selectivity, there is a need for an in vivo PET measure of D3/D2 selectivity. This review discusses current PET imaging of dopamine D2/D3 receptors and proposes methodology for quantitating in vivo selectivity of probes for PET imaging of dopamine D3 receptors

Background: [18F]Fluortriopride (FTP) was developed as a dopamine D3-selective radiotracer, thought to be important to neurobiological reward pathways and implicated in drug addiction, Parkinson’s disease, and schizophrenia. Preclinical radiation dosimetry studies found the gallbladder wall received the highest dose. A gallbladder dose reduction intervention was simulated using a novel reduction model for healthy adults following fatty-meal consumption. The goals of this study were to assess whole body FTP human dosimetry and determine the feasibility of reducing absorbed dose to the gallbladder wall.

Results: Effective dose without a fatty meal was 0.022 ± 0.002 mSv/MBq (± standard deviation) with highest organ dose of 0.436 ± 0.178 mSv/MBq to the gallbladder wall (n = 10). Predicted gallbladder dose reduction with fatty meal consumed was 67.4% (n = 10). Meal consumption by four repeat volunteers decreased average gallbladder dose by 71.3% (n = 4) compared to the original ten volunteers.

Conclusions: Observed effective doses were adequately low to continue studying FTP uptake in humans. Validated dosimetry simulations indicate up to a 71% reduction in gallbladder dose can be achieved by employing intrinsic physiology to contract the gallbladder via fatty meal ingestion. This methodology for predicting gallbladder absorbed dose reduction from fatty meal consumption can be applied to other radiopharmaceuticals and radiotherapies.

We report the design, testing, and in vivo application of pH-sensitive contrast agents designed specifically for Cerenkov imaging. Radioisotopes used for PET emit photons via Cerenkov radiation. The multispectral emission of Cerenkov radiation allows for selective bandwidth quenching, in which a band of photons is quenched by absorption by a functional dye. Under acidic conditions, ¹⁸F-labeled derivatives emit the full spectrum of Cerenkov light. Under basic conditions, the dyes change color and a wavelength-dependent quenching of Cerenkov emission is observed. 

Methods: Mono- and di-¹⁸F-labeled derivatives of phenolsulfonphthalein (phenol red) and meta-cresolsulfonphthalein (cresol purple) were synthesized by electrophilic fluorination. Cerenkov emission was measured at different wavelengths as a function of pH in vitro. Intramolecular response was measured in fluorinated probes and intermolecular quenching by mixing phenolphthalein with ¹⁸F-FDG. Monofluorocresol purple (MFCP) was tested in mice treated with acetazolamide to cause urinary alkalinization, and Cerenkov images were compared with PET images. 

Results: Fluorinated pH indicators were produced with radiochemical yields of 4%–11% at greater than 90% purity. Selective Cerenkov quenching was observed intramolecularly with difluorophenol red or monofluorocresol purple and intermolecularly in phenolphthalein ¹⁸F-FDG mixtures. The probes were selectively quenched in the bandwidth closest to the indicator’s absorption maximum (λ_max) at pHs above the indicator pK_a (the negative logarithm of the acid dissociation constant). Addition of acid or base to the probes resulted in reversible switching from unquenched to quenched emission. In vivo, the bladders of acetazolamide-treated mice exhibited a wavelength-dependent quenching in Cerenkov emission, with the greatest reduction occurring near the λ_max. Ratiometric imaging at 2 wavelengths showed significant decreases in Cerenkov emission at basic pH and allowed the estimation of absolute pH in vivo. 

Conclusion: We have created contrast agents that selectively quench photons emitted during Cerenkov radiation within a given bandwidth. In the presence of a functional dye, such as a pH indicator, this selective quenching allows for a functional determination of pH in vitro and in vivo. This method can be used to obtain functional information from radiolabeled probes using multimodal imaging. This approach allows for the imaging of nonfluorescent chromophores and is generalizable to any functional dye that absorbs at suitable wavelengths.

The nicotine metabolite ratio (NMR), a stable measure of hepatic nicotine metabolism via the CYP2A6 pathway and total nicotine clearance, is a predictive biomarker of response to nicotine replacement therapy, with increased quit rates in slower metabolizers. Nicotine binds directly to nicotinic acetylcholine receptors (nAChRs) to exert its psychoactive effects. This study examined the relationship between NMR and nAChR (α4β2* subtype) availability using PET imaging of the radiotracer 2-¹⁸F-fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-¹⁸F-FA-85380, or 2-¹⁸F-FA). 

Methods: Twenty-four smokers—12 slow metabolizers (NMR < 0.26) and 12 normal metabolizers (NMR ≥ 0.26)—underwent 2-¹⁸F-FA-PET brain imaging after overnight nicotine abstinence (18 h before scanning), using a validated bolus-plus-infusion protocol. Availability of nAChRs was compared between NMR groups in a priori volumes of interest, with total distribution volume (V_T/f_P) being the measure of nAChR availability. Cravings to smoke were assessed before and after the scans. 

Results: Thalamic nAChR α4β2* availability was significantly reduced in slow nicotine metabolizers (P = 0.04). Slow metabolizers exhibited greater reductions in cravings after scanning than normal metabolizers; however, craving was unrelated to nAChR availability. 

Conclusion: The rate of nicotine metabolism is associated with thalamic nAChR availability. Additional studies could examine whether altered nAChR availability underlies the differences in treatment response between slow and normal metabolizers of nicotine.